<clinical_study>
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  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02263508</url>
  </required_header>
  <id_info>
    <org_study_id>20110265</org_study_id>
    <secondary_id>2014-000185-22</secondary_id>
    <secondary_id>KEYNOTE-034</secondary_id>
    <nct_id>NCT02263508</nct_id>
  </id_info>
  <brief_title>Pembrolizumab With Talimogene Laherparepvec or Placebo in Unresected Melanoma</brief_title>
  <acronym>MASTERKEY-265</acronym>
  <official_title>A Phase 1b/3, Multicenter, Trial of Talimogene Laherparepvec in Combination With Pembrolizumab (MK-3475) for Treatment of Unresectable Stage IIIB to IVM1c Melanoma (MASTERKEY-265)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Amgen</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Merck Sharp &amp; Dohme LLC</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Amgen</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The primary objectives of the Phase 1b part of the study are to evaluate the safety, as&#xD;
      assessed by incidence of dose limiting toxicity (DLT), of talimogene laherparepvec in&#xD;
      combination with pembrolizumab in adults with previously untreated, unresectable, stage IIIB&#xD;
      to IVM1c melanoma.&#xD;
&#xD;
      The primary objective of Phase 3 are to evaluate the efficacy of talimogene laherparepvec&#xD;
      with pembrolizumab versus placebo with pembrolizumab, as assessed by progression-free&#xD;
      survival (PFS) (response evaluation by blinded independent central review using modified&#xD;
      Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) and overall survival (OS).&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Terminated</overall_status>
  <start_date type="Actual">December 8, 2014</start_date>
  <completion_date type="Actual">March 11, 2021</completion_date>
  <primary_completion_date type="Actual">March 11, 2021</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Phase 1b was an open-label, single-arm study. Phase 3 was a randomized, double-blind, placebo-controlled study design.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Phase 1b: Number of Participants With Dose-limiting Toxicities (DLTs)</measure>
    <time_frame>The DLT evaluation period was 6 weeks from the initial administration of pembrolizumab (week 6 to 12).</time_frame>
    <description>A DLT was defined as any toxicity related to study drug which met any of the following criteria based on Common Terminology Criteria for Adverse Events (CTCAE) version 4.0:&#xD;
Grade 4 non-hematologic toxicity.&#xD;
Grade 3 or higher pneumonitis.&#xD;
Grade 3 non-hematologic toxicity lasting &gt; 3 days despite optimal supportive care, excluding grade 3 fatigue.&#xD;
Any grade 3 or higher non-hematologic laboratory value if medical intervention was required, or the abnormality lead to hospitalization, or the abnormality persisted for &gt; 1 week.&#xD;
Febrile neutropenia grade 3 or grade 4.&#xD;
Thrombocytopenia &lt; 25 x 10^9/L if associated with a bleeding event which does not result in hemodynamic instability but required an elective platelet infusion, or a life-threatening bleeding event which resulted in urgent intervention and admission to intensive care unit.&#xD;
Grade 5 toxicity (ie, death).&#xD;
Any other intolerable toxicity leading to permanent discontinuation of talimogene laherparepvec or pembrolizumab.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Phase 3: Progression Free Survival (PFS) by Blinded Independent Central Review (BICR) Assessed Using Modified RECIST 1.1</measure>
    <time_frame>From randomization until the data-cut-off date of 02 March 2020; median (range) time on follow-up was 25.5 (0.6, 44.7) months in the Placebo + Pembrolizumab arm and 25.6 (0.3, 45.8) months in the Talimogene Laherparepvec + Pembrolizumab arm.</time_frame>
    <description>PFS per modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 is defined as the interval from randomization to the earlier event of progressive disease (PD) per modified RECIST 1.1 or death from any cause.&#xD;
PD: Increase in size of target lesions from nadir by ≥ 20% and ≥ 5 mm absolute increase above nadir, or the appearance of a new lesion.&#xD;
Median PFS was calculated using the Kaplan-Meier method. Participants without an event were censored at their last evaluable tumor assessment if available; otherwise on their randomization date.&#xD;
The primary analysis of PFS was specified to be conducted when 407 PFS events had occurred (data cut-off date 02 March 2020).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Phase 3: Overall Survival</measure>
    <time_frame>From randomization until the end of study; median (range) time on follow-up was 34.8 (0.6, 58.3) months in the Placebo + Pembrolizumab arm and 36.8 (0.3, 58.4) months in the Talimogene Laherparepvec + Pembrolizumab arm.</time_frame>
    <description>Overall survival (OS) is defined as the interval from randomization to death from any cause.&#xD;
Median overall survival was calculated using the Kaplan-Meier method. Participants without an event were censored at their last known alive date.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Phase 1b: Objective Response Rate (ORR)</measure>
    <time_frame>Tumor assessments were performed at week 6 (prior to initiation of pembrolizumab), week 18, and every 12 weeks thereafter until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 58.6 (1.4, 61.6) months.</time_frame>
    <description>ORR is defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) using the modified Immune-related Response Criteria (irRC), by Investigator assessment.&#xD;
CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline, response must have been confirmed by a second, consecutive assessment at least 4 weeks apart.&#xD;
Radiographic imaging for assessment of lesions was performed using computed tomography (CT), positron emission tomography (PET), magnetic resonance imaging (MRI), or ultrasound. Clinical measurement of cutaneous, subcutaneous, and palpable nodal tumor lesions was conducted with calipers.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phase 1b: Best Overall Response (BOR)</measure>
    <time_frame>Tumor assessments were performed at week 6 (prior to initiation of pembrolizumab), week 18, and every 12 weeks thereafter until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 58.6 (1.4, 61.6) months.</time_frame>
    <description>Best overall response is defined as the best overall visit response in the following order: CR, PR, stable disease (SD), progressive disease (PD), or unevaluable (UE), based on investigator assessment using the modified irRC up to the start of any subsequent anti-cancer therapy.&#xD;
CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline; PD was defined as an increase in tumor area ≥ 25% relative to nadir; and SD was defined as any outcome not meeting the criteria for response or PD with ≥ 77 days elapsed after enrollment. Responses and PD must have been confirmed by a second, consecutive assessment at least 4 weeks apart.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phase 1b: Durable Response Rate (DRR)</measure>
    <time_frame>Tumor assessments were performed at week 6 (prior to initiation of pembrolizumab), week 18, and every 12 weeks thereafter until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 58.6 (1.4, 61.6) months.</time_frame>
    <description>DRR is defined as the percentage of participants with a best overall response of CR or PR using the modified irRC per Investigator assessment with a duration of response of at least 6 months.&#xD;
CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline, response must have been confirmed by a second, consecutive assessment at least 4 weeks apart.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phase 1b: Duration of Response (DOR)</measure>
    <time_frame>Tumor assessments were performed at week 6 (prior to initiation of pembrolizumab), week 18, and every 12 weeks thereafter until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 58.6 (1.4, 61.6) months.</time_frame>
    <description>Duration of response (DOR) is defined as the time from the date of an initial response (CR or PR) that is subsequently confirmed to the earlier of confirmed PD or death. Participants who had not ended their response at the time of analysis were censored at their last evaluable tumor assessment before start of the first subsequent anticancer therapy.&#xD;
CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline; PD was defined as an increase in tumor area ≥ 25% relative to nadir. Response and PD must have been confirmed by a second, consecutive assessment at least 4 weeks apart.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phase 1b: Disease Control Rate (DCR)</measure>
    <time_frame>Tumor assessments were performed at week 6 (prior to initiation of pembrolizumab), week 18, and every 12 weeks thereafter until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 58.6 (1.4, 61.6) months.</time_frame>
    <description>DCR is defined as the percentage of participants with a best overall response of CR, PR, or SD using the modified irRC per Investigator assessment.&#xD;
CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline, response must have been confirmed by a second, consecutive assessment at least 4 weeks apart; and SD was defined as any outcome not meeting the criteria for response or PD with ≥ 84 days elapsed after enrollment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phase 1b: Progression-free Survival (PFS)</measure>
    <time_frame>From first dose until the end of study; median (range) time on follow-up was 70.6 (1.4, 74.5) months.</time_frame>
    <description>Progression-free survival is defined as the time from first dose to the earlier event of confirmed PD per modified irRC or death from any cause. PFS was estimated using the Kaplan-Meier method. Participants without an event were censored at their last evaluable tumor assessment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phase 1b: Overall Survival (OS)</measure>
    <time_frame>From first dose until the end of study; median (range) time on follow-up was 70.6 (1.4, 74.5) months.</time_frame>
    <description>Overall survival is defined as the interval from first dose to death from any cause.&#xD;
OS was estimated using the Kaplan-Meier method. Participants without an event were censored at their last known alive date.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phase 3: Complete Response Rate Assessed Using Modified irRC-RECIST (iCRR)</measure>
    <time_frame>Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.</time_frame>
    <description>Complete response rate per modified Immune-related Response Criteria (irRC) simulating RECIST 1.1 (irRC-RECIST) is defined as the percentage of participants with a best overall response of complete response assessed using the modified irRC-RECIST (iCR) evaluated by blinded independent central review.&#xD;
iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks after the criteria were first met. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm.&#xD;
Modifications to the irRC-RECIST 1.1 included an increase in the total number of target lesions and new measurable lesions to 10 with a maximum of 5 target lesions per organ, and target lesions must have been measurable by CT or MRI only.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phase 3: Progression Free Survival Assessed Using Modified irRC-RECIST (iPFS)</measure>
    <time_frame>From randomization until the data cut-off date of 29 September 2020; median time on follow-up was 30.6 (0.6, 53.0) months in the Placebo + Pembrolizumab arm and 31.4 (0.3, 52.5) months in the Talimogene Laherparepvec + Pembrolizumab arm.</time_frame>
    <description>PFS per modified irRC-RECIST is defined as the interval from randomization to the earlier event of progressive disease assessed by modified irRC-RECIST (iPD) evaluated by blinded independent central review, or death from any cause.&#xD;
iPD: Increase in tumor burden ≥ 20% and at least 5 mm absolute increase relative to nadir (minimum recorded tumor burden) confirmed by a repeat, consecutive assessment at least 4 weeks after the initial detection.&#xD;
Median iPFS was calculated using the Kaplan-Meier method. Participants without an event were censored at their last evaluable tumor assessment if available; otherwise on their randomization date.&#xD;
The primary analysis of iPFS was specified to be conducted when 256 iPFS events had occurred (data cut-off date 29 September 2020).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phase 3: Overall Survival Excluding Stage IVM1c Participants</measure>
    <time_frame>From randomization until the end of study; median (range) time on follow-up was 34.8 (0.6, 58.3) months in the Placebo + Pembrolizumab arm and 36.8 (0.3, 58.4) months in the Talimogene Laherparepvec + Pembrolizumab arm.</time_frame>
    <description>Overall survival is defined as the interval from randomization to death from any cause.&#xD;
Median OS was calculated using the Kaplan-Meier method. Participants without an event were censored at the last known alive date.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phase 3: Objective Response Rate Assessed Using Modified RECIST 1.1</measure>
    <time_frame>Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.</time_frame>
    <description>ORR is defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) assessed using modified RECIST version 1.1, evaluated by blinded independent central review.&#xD;
CR was defined as the disappearance of all lesions except lymph node short axis &lt; 10 mm; PR was defined as a ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required.&#xD;
Modifications to conventional RECIST 1.1 included the following: target lesions were measurable on CT or MRI; otherwise, they were considered as nontarget lesions. A maximum of 10 target lesions was allowed with up to 5 per organ.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phase 3: Best Overall Response Assessed Using Modified RECIST 1.1</measure>
    <time_frame>Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.</time_frame>
    <description>BOR is defined as the best overall visit response up to and including the first overall visit response of PD in the following order: CR, PR, SD, non-CR/Non-PD (NN), PD or UE per modified RECIST 1.1, evaluated by BICR.&#xD;
CR: Disappearance of all lesions except lymph node short axis &lt; 10 mm; PR: ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required; NN: Persistence of ≥ 1 non-target lesions and/or maintenance of tumor marker level above normal limits; SD: Neither sufficient shrinkage of target lesions to qualify for CR or PR nor sufficient increase to qualify for PD and ≥ 84 days from randomization; PD: Increase from nadir by ≥ 20% or ≥ 5 mm of target lesions or any new lesion; Missing: No postbaseline assessment, or assessments on or after the start of first subsequent anticancer therapy, including complete or partial removal/reduction of any target lesion which contained melanoma on pathology evaluation or pathology results were unknown.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phase 3: Durable Response Rate (DRR) Assessed Using Modified RECIST 1.1</measure>
    <time_frame>Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.</time_frame>
    <description>DRR is defined as the percentage of participants with a CR or PR per modified RECIST 1.1 evaluated by blinded independent central review, with a duration of response of ≥ 6 months.&#xD;
CR was defined as the disappearance of all lesions except lymph node short axis &lt; 10 mm; PR was defined as a ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phase 3: Duration of Response (DOR) Assessed Using Modified RECIST 1.1</measure>
    <time_frame>From randomization until the data cut-off date of 29 September 2020; median time on follow-up was 30.6 (0.6, 53.0) months in the Placebo + Pembrolizumab arm and 31.4 (0.3, 52.5) months in the Talimogene Laherparepvec + Pembrolizumab arm.</time_frame>
    <description>Duration of response (DOR) is defined as the time from the date of an initial response of CR or PR to the earlier of PD per modified RECIST 1.1, or death. Participants who had not ended their response at the time of analysis were censored at their last evaluable tumor assessment date before start of the first subsequent anticancer therapy.&#xD;
CR was defined as the disappearance of all lesions except lymph node short axis &lt; 10 mm; PR was defined as a ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required. PD was defined as an increase from nadir by ≥ 20% or ≥ 5 mm absolute increase above nadir of target lesions or appearance of any new lesion.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phase 3: Disease Control Rate (DCR) Assessed Using RECIST 1.1</measure>
    <time_frame>Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.</time_frame>
    <description>Disease control rate (DCR) per modified RECIST 1.1 is defined as the percentage of participants with a best overall response of CR, PR or SD evaluated by blinded independent central review.&#xD;
CR was defined as the disappearance of all lesions except lymph node short axis &lt; 10 mm; PR was defined as a ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required. SD was defined as neither sufficient shrinkage of target lesions to qualify for CR or PR nor sufficient increase to qualify for PD with ≥ 84 days elapsed after randomization.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phase 3: Objective Response Rate Assessed Using Modified irRC-RECIST (iORR)</measure>
    <time_frame>Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.</time_frame>
    <description>Objective response rate per modified irRC-RECIST is defined as the percentage of participants with a best overall response of iCR or partial response assessed using modified irRC-RECIST (iPR) evaluated by blinded independent central review.&#xD;
iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm.&#xD;
iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation.&#xD;
Modifications to the irRC-RECIST 1.1 included an increase in the total number of target lesions and new measurable lesions to 10 with a maximum of 5 target lesions per organ, and target lesions must be measurable by CT or MRI only.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phase 3: Best Overall Response Assessed Using Modified irRC-RECIST</measure>
    <time_frame>Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.</time_frame>
    <description>BOR is defined as the best overall visit response in the following order: iCR, iPR, stable disease per modified irRC-RECIST (iSD), iPD, or UE per modified irRC-RECIST (iUE), evaluated by BICR.&#xD;
iCR: Disappearance of all lesions confirmed by consecutive assessment ≥ 4 weeks from the date first documented. Reduction of any pathological lymph node to &lt;10 mm.&#xD;
iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed ≥ 4 weeks after first documentation.&#xD;
iPD: Increase in tumor burden ≥ 20 % and at least 5 mm absolute increase relative to nadir confirmed ≥ 4 weeks from initial detection.&#xD;
iSD: Neither sufficient shrinkage to qualify for iCR or iPR nor sufficient increase to qualify for iPD and ≥ 84 days from randomization.&#xD;
Missing: No postbaseline assessment, or assessments after start of first subsequent anticancer therapy, including complete or partial removal/reduction of any target lesion which contained melanoma on pathology evaluation or pathology results were unknown.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phase 3: Durable Response Rate Assessed Using Modified irRC-RECIST (iDRR)</measure>
    <time_frame>Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.</time_frame>
    <description>Durable response rate per modified irRC-RECIST is defined as the percentage of participants with a best overall response of iCR or iPR per modified irRC-RECIST evaluated by blinded independent central review with a duration of response ≥ 6 months.&#xD;
iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm.&#xD;
iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phase 3: Duration of Response Assessed Using Modified irRC-RECIST (iDOR)</measure>
    <time_frame>From randomization until the data cut-off date of 29 September 2020; median time on follow-up was 30.6 (0.6, 53.0) months in the Placebo + Pembrolizumab arm and 31.4 (0.3, 52.5) months in the Talimogene Laherparepvec + Pembrolizumab arm.</time_frame>
    <description>Duration of response per modified irRC-RECIST is defined as the time from the date of an initial response of iCR or iPR that was subsequently confirmed to the earlier of iPD per modified irRC-RECIST evaluated by blinded independent central review, or death. Participants who had not ended their response at the time of analysis were censored at their last evaluable tumor assessment date before the start of the first subsequent anticancer therapy.&#xD;
iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm.&#xD;
iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phase 3: Disease Control Rate Assessed Using Modified irRC-RECIST (iDCR)</measure>
    <time_frame>Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.</time_frame>
    <description>Disease control rate per modified irRC-RECIST is defined as the percentage of participants with a best overall response of iCR, iCR, or iSD assessed using modified irRC-RECIST evaluated by blinded independent central review.&#xD;
iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm.&#xD;
iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation.&#xD;
iSD: Neither sufficient shrinkage to qualify for iCR or iPR nor sufficient increase to qualify for iPD with ≥ 84 days elapsed after randomization.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phase 3: Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Core Module (EORTC QLQ-C30) Global Health Status (GHS)/Quality of Life (QOL) Score</measure>
    <time_frame>Baseline and day 1 of weeks 3, 6, 9, 12, then every 6 weeks until end of study treatment; median (range) duration of treatment was 39.0 (0.1, 107.3) weeks in Placebo + Pembrolizumab and 54.1 (0.1, 109.6) weeks in Talimogene Laherparepvec + Pembrolizumab.</time_frame>
    <description>The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status/quality of life scale, 5 functional scales, and 9 symptom scales/items.&#xD;
The global health/QoL scale consists of 2 questions that ask participants to rate their overall health and overall quality of life during the past week on a scale from 1 (very poor) to 7 (excellent). The GHS/QoL subscale score was derived as the mean of each score then transformed to a scale from 0 to 100 where higher scores represent a better health status and a positive change from baseline indicates improvement.&#xD;
The overall change from baseline (calculated from all on-treatment visits) was calculated using a restricted maximum likelihood-based mixed model for repeated measures (MMRM) (see model details in statistical analysis section).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Treatment-emergent Adverse Events (TEAEs)</measure>
    <time_frame>From first dose to 30 days after last dose (90 days for SAEs); median (range) duration was 48 (5.1, 110.1) weeks in Phase 1b, 39 (0.1, 107.3) weeks in Placebo + Pembrolizumab and 56 (0.1, 109.6) weeks in Phase 3 Talimogene Laherparepvec + Pembrolizumab.</time_frame>
    <description>An adverse event (AE) is any untoward medical occurrence in a clinical trial subject, including worsening of a pre-existing medical condition. The event does not necessarily have a causal relationship with study treatment. TEAEs include AEs from the first dose of study drug to 30 days after the last dose.&#xD;
A serious adverse event (SAE) is an AE that met at least 1 of the following criteria:&#xD;
fatal&#xD;
life threatening&#xD;
required in-patient hospitalization or prolongation of existing hospitalization&#xD;
resulted in persistent or significant disability/incapacity&#xD;
congenital anomaly/birth defect&#xD;
other medically important serious event. Treatment-emergent SAEs are any SAE occurring from first dose of study drug through 90 days after the last dose or 30 days after the last dose if new anticancer therapy was started, whichever was earlier.&#xD;
AEs were graded for severity using CTCAE version 4.0, where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Life-threatening; Grade 5 = Fatal.</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">713</enrollment>
  <condition>Melanoma</condition>
  <arm_group>
    <arm_group_label>Phase 1b: Talimogene Laherparepvec + Pembrolizumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ plaque-forming units (PFU)/mL by intralesional injection. Subsequent doses of talimogene laherparepvec at up to 4 mL of 10⁸ PFU/mL began 3 weeks after the first dose and were administered every 2 weeks until disappearance of injectable lesions, complete response (CR), confirmed disease progression (PD) per modified Immune-related Response Criteria (irRC), intolerance of study treatment, 24 months from the date of the first dose of pembrolizumab, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 2 weeks starting at the time of the third dose of talimogene laherparepvec (week 6) until confirmed PD per modified irRC, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Phase 3 : Placebo + Pembrolizumab</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Phase 3: Talimogene Laherparepvec + Pembrolizumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Talimogene Laherparepvec</intervention_name>
    <description>Talimogene laherparepvec administered by intratumoral injection</description>
    <arm_group_label>Phase 1b: Talimogene Laherparepvec + Pembrolizumab</arm_group_label>
    <arm_group_label>Phase 3: Talimogene Laherparepvec + Pembrolizumab</arm_group_label>
    <other_name>IMLYGIC®</other_name>
    <other_name>OncoVEX^GM-CSF</other_name>
    <other_name>T-VEC</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pembrolizumab</intervention_name>
    <description>Administered at a dose of 200 mg as an intravenous infusion over approximately 30 minutes.</description>
    <arm_group_label>Phase 1b: Talimogene Laherparepvec + Pembrolizumab</arm_group_label>
    <arm_group_label>Phase 3 : Placebo + Pembrolizumab</arm_group_label>
    <arm_group_label>Phase 3: Talimogene Laherparepvec + Pembrolizumab</arm_group_label>
    <other_name>MK-3475</other_name>
    <other_name>Keytruda®</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Administered by intratumoral injection</description>
    <arm_group_label>Phase 3 : Placebo + Pembrolizumab</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Key Inclusion Criteria:&#xD;
&#xD;
          -  Age ≥ 18 years with histologically confirmed diagnosis of melanoma and stage IIIB to&#xD;
             IVM1c for whom surgery is not recommended.&#xD;
&#xD;
          -  Subjects must have measurable disease and be a candidate for intralesional therapy&#xD;
             administration into cutaneous, subcutaneous, or nodal lesions.&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.&#xD;
&#xD;
          -  Adequate hematologic, hepatic, renal, and coagulation function.&#xD;
&#xD;
          -  Subjects with serine/threonine protein kinase B-Raf V600 (BRAFV600) wild-type tumors&#xD;
             must not have received any prior systemic anticancer treatment consisting of&#xD;
             chemotherapy, immunotherapy, or targeted therapy given in a non-adjuvant setting for&#xD;
             unresectable stage IIIB to IVM1c melanoma.&#xD;
&#xD;
          -  Subjects with B-Raf V600 (BRAFV600) mutated tumors who have received prior BRAF&#xD;
             inhibitor therapy either alone or in combination with mitogen-activated protein kinase&#xD;
             kinase (MEK) inhibitor as their only prior systemic therapy are eligible.&#xD;
&#xD;
          -  Subjects who received prior adjuvant therapy for melanoma will not be excluded&#xD;
             (including, but not limited to, interferon, ipilimumab, limb infusion/perfusion, or&#xD;
             use of investigational agents in the adjuvant setting) with the exception that prior&#xD;
             adjuvant therapy with inhibitors of programmed cell death-1 (PD-1) or programmed cell&#xD;
             death ligand 1 (PD-L1) is not allowed. However, if the subject received adjuvant&#xD;
             therapy, the subject must have completed therapy at least 28 days prior to enrollment.&#xD;
&#xD;
          -  Subjects must have a tumor sample that is adequate for PD-L1 assessment prior to&#xD;
             randomization.&#xD;
&#xD;
        Key Exclusion Criteria:&#xD;
&#xD;
          -  Subjects must not have clinically active cerebral metastases.&#xD;
&#xD;
          -  Subjects must not have primary uveal or mucosal melanoma, history or evidence of&#xD;
             melanoma associated with immunodeficiency states or history of other malignancy within&#xD;
             the past 3 years.&#xD;
&#xD;
          -  Subjects may not have been previously treated with talimogene laherparepvec, any other&#xD;
             oncolytic virus, pembrolizumab, or any other inhibitor of PD-1, PD-L1, or PD-L2.&#xD;
&#xD;
          -  Subjects must not have history or evidence of symptomatic autoimmune pneumonitis,&#xD;
             glomerulonephritis, vasculitis, other symptomatic autoimmune disease, documented&#xD;
             history of autoimmune disease or syndrome requiring systemic treatment in the past 2&#xD;
             years (ie, with use of disease modifying agents, steroids or immunosuppressive agents)&#xD;
             except vitiligo or resolved childhood asthma/atopy, or evidence of clinically&#xD;
             significant immunosuppression.&#xD;
&#xD;
          -  Subjects must not have active herpetic skin lesions or prior complications of herpetic&#xD;
             infection and must not require intermittent or chronic treatment with an antiherpetic&#xD;
             drug (eg, acyclovir), other than intermittent topical use.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>95 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>MD</last_name>
    <role>Study Director</role>
    <affiliation>Amgen</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Birmingham</city>
        <state>Alabama</state>
        <zip>35243</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Mobile</city>
        <state>Alabama</state>
        <zip>36608</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Beverly Hills</city>
        <state>California</state>
        <zip>90211</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Duarte</city>
        <state>California</state>
        <zip>91010</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Encinitas</city>
        <state>California</state>
        <zip>92024</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>La Jolla</city>
        <state>California</state>
        <zip>92037</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90024</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90025</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Riverside</city>
        <state>California</state>
        <zip>92505</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94115</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94117</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Santa Monica</city>
        <state>California</state>
        <zip>90404</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Miami Beach</city>
        <state>Florida</state>
        <zip>33140</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <zip>33136</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Orlando</city>
        <state>Florida</state>
        <zip>32806</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Atlanta</city>
        <state>Georgia</state>
        <zip>30322</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60611</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60637</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Louisville</city>
        <state>Kentucky</state>
        <zip>40202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21237</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02215</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Detroit</city>
        <state>Michigan</state>
        <zip>48201</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Fridley</city>
        <state>Minnesota</state>
        <zip>55432</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110-1093</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Hackensack</city>
        <state>New Jersey</state>
        <zip>07601</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Buffalo</city>
        <state>New York</state>
        <zip>14263</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10016</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10032</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10065</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Cincinnati</city>
        <state>Ohio</state>
        <zip>45209</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Cleveland</city>
        <state>Ohio</state>
        <zip>44195</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19107</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19111</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15232</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Germantown</city>
        <state>Tennessee</state>
        <zip>38138</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Knoxville</city>
        <state>Tennessee</state>
        <zip>37920</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37232</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75246</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Murray</city>
        <state>Utah</state>
        <zip>84107</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Salt Lake City</city>
        <state>Utah</state>
        <zip>84112</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Seattle</city>
        <state>Washington</state>
        <zip>98109-1023</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>North Sydney</city>
        <state>New South Wales</state>
        <zip>2060</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Waratah</city>
        <state>New South Wales</state>
        <zip>2298</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Wollongong</city>
        <state>New South Wales</state>
        <zip>2500</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Southport</city>
        <state>Queensland</state>
        <zip>4215</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Woolloongabba</city>
        <state>Queensland</state>
        <zip>4102</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Woodville South</city>
        <state>South Australia</state>
        <zip>5011</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Geelong</city>
        <state>Victoria</state>
        <zip>3220</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Heidelberg</city>
        <state>Victoria</state>
        <zip>3084</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Melbourne</city>
        <state>Victoria</state>
        <zip>3000</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Prahran</city>
        <state>Victoria</state>
        <zip>3181</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Murdoch</city>
        <state>Western Australia</state>
        <zip>6150</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Graz</city>
        <zip>8036</zip>
        <country>Austria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Innsbruck</city>
        <zip>6020</zip>
        <country>Austria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Salzburg</city>
        <zip>5020</zip>
        <country>Austria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Wien</city>
        <zip>1090</zip>
        <country>Austria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Bruxelles</city>
        <zip>1200</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Liege</city>
        <zip>4000</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Edmonton</city>
        <state>Alberta</state>
        <zip>T6G 1Z2</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Kingston</city>
        <state>Ontario</state>
        <zip>K7L 2V7</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>London</city>
        <state>Ontario</state>
        <zip>N6A 4L6</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Ottawa</city>
        <state>Ontario</state>
        <zip>K1H 8L6</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5G 2M9</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
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      <address>
        <city>Preston</city>
        <zip>PR2 9HT</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Southampton</city>
        <zip>SO16 6YD</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Australia</country>
    <country>Austria</country>
    <country>Belgium</country>
    <country>Canada</country>
    <country>Czechia</country>
    <country>Finland</country>
    <country>France</country>
    <country>Germany</country>
    <country>Greece</country>
    <country>Hungary</country>
    <country>Italy</country>
    <country>Korea, Republic of</country>
    <country>Netherlands</country>
    <country>Poland</country>
    <country>Portugal</country>
    <country>Russian Federation</country>
    <country>South Africa</country>
    <country>Spain</country>
    <country>Switzerland</country>
    <country>United Kingdom</country>
    <country>United States</country>
  </location_countries>
  <removed_countries>
    <country>Czech Republic</country>
  </removed_countries>
  <link>
    <url>http://www.amgentrials.com</url>
    <description>AmgenTrials clinical trials website</description>
  </link>
  <reference>
    <citation>Ribas A, Dummer R, Puzanov I, VanderWalde A, Andtbacka RHI, Michielin O, Olszanski AJ, Malvehy J, Cebon J, Fernandez E, Kirkwood JM, Gajewski TF, Chen L, Gorski KS, Anderson AA, Diede SJ, Lassman ME, Gansert J, Hodi FS, Long GV. Oncolytic Virotherapy Promotes Intratumoral T Cell Infiltration and Improves Anti-PD-1 Immunotherapy. Cell. 2017 Sep 7;170(6):1109-1119.e10. doi: 10.1016/j.cell.2017.08.027. Erratum In: Cell. 2018 Aug 9;174(4):1031-1032.</citation>
    <PMID>28886381</PMID>
  </reference>
  <reference>
    <citation>Dummer R, Hoeller C, Gruter IP, Michielin O. Combining talimogene laherparepvec with immunotherapies in melanoma and other solid tumors. Cancer Immunol Immunother. 2017 Jun;66(6):683-695. doi: 10.1007/s00262-017-1967-1. Epub 2017 Feb 25.</citation>
    <PMID>28238174</PMID>
  </reference>
  <reference>
    <citation>Chesney JA, Ribas A, Long GV, Kirkwood JM, Dummer R, Puzanov I, Hoeller C, Gajewski TF, Gutzmer R, Rutkowski P, Demidov L, Arenberger P, Shin SJ, Ferrucci PF, Haydon A, Hyngstrom J, van Thienen JV, Haferkamp S, Guilera JM, Rapoport BL, VanderWalde A, Diede SJ, Anderson JR, Treichel S, Chan EL, Bhatta S, Gansert J, Hodi FS, Gogas H. Randomized, Double-Blind, Placebo-Controlled, Global Phase III Trial of Talimogene Laherparepvec Combined With Pembrolizumab for Advanced Melanoma. J Clin Oncol. 2023 Jan 20;41(3):528-540. doi: 10.1200/JCO.22.00343. Epub 2022 Aug 23.</citation>
    <PMID>35998300</PMID>
  </reference>
  <verification_date>November 2022</verification_date>
  <study_first_submitted>September 26, 2014</study_first_submitted>
  <study_first_submitted_qc>October 9, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 13, 2014</study_first_posted>
  <results_first_submitted>March 8, 2022</results_first_submitted>
  <results_first_submitted_qc>April 22, 2022</results_first_submitted_qc>
  <results_first_posted type="Actual">May 16, 2022</results_first_posted>
  <last_update_submitted>November 10, 2022</last_update_submitted>
  <last_update_submitted_qc>November 10, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">November 14, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Talimogene Laherparepvec</keyword>
  <keyword>pembrolizumab</keyword>
  <keyword>KEYNOTE-034</keyword>
  <keyword>MASTERKEY-265</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Melanoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pembrolizumab</mesh_term>
    <mesh_term>Talimogene laherparepvec</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
    <ipd_time_frame>Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication (or other new use) have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.</ipd_time_frame>
    <ipd_access_criteria>Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors, and if not approved, may be further arbitrated by a Data Sharing Independent Review Panel. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the link below.</ipd_access_criteria>
    <ipd_url>https://www.amgen.com/datasharing</ipd_url>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>January 15, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/08/NCT02263508/Prot_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>January 16, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/08/NCT02263508/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>This study was conducted at 134 centers in Australia, Canada, Europe, South Africa, South Korea, and the United States.&#xD;
Phase 1b was an open-label, single-arm study and Phase 3 was a randomized, double-blind, placebo-controlled study.</recruitment_details>
      <pre_assignment_details>In Phase 3 participants were randomized equally to 1 of 2 arms. Randomization was stratified by stage of disease: less advanced stages (IIIB, IIIC, and IVM1a) versus more advanced stages (IVM1b and IVM1c) and by prior serine/threonine protein kinase B-Raf (BRAF) inhibitor therapy (no prior BRAF inhibitor versus BRAF inhibitor with or without mitogen-activated extracellular signal-regulated kinase [MEK] inhibitor).</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Phase 1b: Talimogene Laherparepvec + Pembrolizumab</title>
          <description>Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ plaque-forming units (PFU)/mL by intralesional injection on day 1 of week 1. Subsequent doses of talimogene laherparepvec at up to 4 mL of 10⁸ PFU/mL began 3 weeks after the first dose and were administered every 2 weeks until disappearance of injectable lesions, complete response (CR), confirmed disease progression (PD) per modified Immune-related Response Criteria (irRC), intolerance of study treatment, 24 months from the date of the first dose of pembrolizumab, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 2 weeks starting at the time of the third dose of talimogene laherparepvec (week 6) until confirmed PD per modified irRC, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
        </group>
        <group group_id="P2">
          <title>Phase 3: Placebo + Pembrolizumab</title>
          <description>Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
        </group>
        <group group_id="P3">
          <title>Phase 3: Talimogene Laherparepvec + Pembrolizumab</title>
          <description>Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="21"/>
                <participants group_id="P2" count="346"/>
                <participants group_id="P3" count="346"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Received Talimogene Laherparepvec/Placebo</title>
              <participants_list>
                <participants group_id="P1" count="21"/>
                <participants group_id="P2" count="345"/>
                <participants group_id="P3" count="343"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Received Pembrolizumab</title>
              <participants_list>
                <participants group_id="P1" count="21"/>
                <participants group_id="P2" count="345"/>
                <participants group_id="P3" count="343"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="21"/>
                <participants group_id="P2" count="346"/>
                <participants group_id="P3" count="346"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="23"/>
                <participants group_id="P3" count="17"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Sponsor Decision</title>
              <participants_list>
                <participants group_id="P1" count="12"/>
                <participants group_id="P2" count="165"/>
                <participants group_id="P3" count="182"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="7"/>
                <participants group_id="P3" count="7"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Death</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
                <participants group_id="P2" count="151"/>
                <participants group_id="P3" count="140"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>All enrolled participants</population>
      <group_list>
        <group group_id="B1">
          <title>Phase 1b: Talimogene Laherparepvec + Pembrolizumab</title>
          <description>Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ plaque-forming units (PFU)/mL by intralesional injection on day 1 of week 1. Subsequent doses of talimogene laherparepvec at up to 4 mL of 10⁸ PFU/mL began 3 weeks after the first dose and were administered every 2 weeks until disappearance of injectable lesions, complete response (CR), confirmed disease progression (PD) per modified Immune-related Response Criteria (irRC), intolerance of study treatment, 24 months from the date of the first dose of pembrolizumab, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 2 weeks starting at the time of the third dose of talimogene laherparepvec (week 6) until confirmed PD per modified irRC, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
        </group>
        <group group_id="B2">
          <title>Phase 3: Placebo + Pembrolizumab</title>
          <description>Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
        </group>
        <group group_id="B3">
          <title>Phase 3: Talimogene Laherparepvec + Pembrolizumab</title>
          <description>Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
        </group>
        <group group_id="B4">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="21"/>
            <count group_id="B2" value="346"/>
            <count group_id="B3" value="346"/>
            <count group_id="B4" value="713"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="21"/>
                    <count group_id="B2" value="346"/>
                    <count group_id="B3" value="346"/>
                    <count group_id="B4" value="713"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="60.2" spread="13.4"/>
                    <measurement group_id="B2" value="62.3" spread="14.5"/>
                    <measurement group_id="B3" value="63.1" spread="13.7"/>
                    <measurement group_id="B4" value="62.6" spread="14.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="21"/>
                    <count group_id="B2" value="346"/>
                    <count group_id="B3" value="346"/>
                    <count group_id="B4" value="713"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                    <measurement group_id="B2" value="127"/>
                    <measurement group_id="B3" value="147"/>
                    <measurement group_id="B4" value="287"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="219"/>
                    <measurement group_id="B3" value="199"/>
                    <measurement group_id="B4" value="426"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="21"/>
                    <count group_id="B2" value="346"/>
                    <count group_id="B3" value="346"/>
                    <count group_id="B4" value="713"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="13"/>
                    <measurement group_id="B4" value="22"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="21"/>
                    <measurement group_id="B2" value="337"/>
                    <measurement group_id="B3" value="331"/>
                    <measurement group_id="B4" value="689"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="21"/>
                    <count group_id="B2" value="346"/>
                    <count group_id="B3" value="346"/>
                    <count group_id="B4" value="713"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="7"/>
                    <measurement group_id="B4" value="11"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black (or African American)</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="21"/>
                    <measurement group_id="B2" value="335"/>
                    <measurement group_id="B3" value="327"/>
                    <measurement group_id="B4" value="683"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Other</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="10"/>
                    <measurement group_id="B4" value="16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Disease Stage per the American Joint Committee on Cancer (AJCC) 7th Edition</title>
          <description>Stage IIIB: Ulcerated lesion and 1 lymph node or 2-3 nodes with micrometastasis, or any-depth lesion with no ulceration, and 1 lymph node or 2-3 nodes with macrometastasis; Stage IIIC: Ulcerated lesion and 1 lymph node with macrometastasis; 2-3 nodes with macrometastasis or ≥4 metastatic lymph nodes, matted lymph nodes, or in-transit met(s)/satellite(s); Stage IV: M1a: Spread to skin, subcutaneous tissue, or lymph nodes; normal lactate dehydrogenase (LDH) level; M1b: Spread to lungs, normal LDH; M1c: Spread to all other visceral organs, normal LDH or any distant disease with elevated LDH.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="21"/>
                    <count group_id="B2" value="346"/>
                    <count group_id="B3" value="346"/>
                    <count group_id="B4" value="713"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Stage IIIB - IVM1a</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="169"/>
                    <measurement group_id="B3" value="169"/>
                    <measurement group_id="B4" value="347"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Stage IVM1b/c</title>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                    <measurement group_id="B2" value="177"/>
                    <measurement group_id="B3" value="177"/>
                    <measurement group_id="B4" value="366"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Prior Serine/Threonine Protein Kinase B-Raf (BRAF) Inhibitor Therapy</title>
          <population>Prior BRAF inhibitor therapy was not collected in Phase 1b</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="0"/>
                    <count group_id="B2" value="346"/>
                    <count group_id="B3" value="346"/>
                    <count group_id="B4" value="692"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Yes</title>
                  <measurement_list>
                    <measurement group_id="B2" value="29"/>
                    <measurement group_id="B3" value="29"/>
                    <measurement group_id="B4" value="58"/>
                  </measurement_list>
                </category>
                <category>
                  <title>No</title>
                  <measurement_list>
                    <measurement group_id="B2" value="317"/>
                    <measurement group_id="B3" value="317"/>
                    <measurement group_id="B4" value="634"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Programmed Cell Death-1 Ligand 1 (PD-L1) Status</title>
          <description>PD-L1 expression in tumor cells was assessed at a central laboratory using a clinical trial immunohistochemistry assay (22C3 antibody) and scored on a unique melanoma (MEL) scale of 0 to 5; a score ≥ 2 (membranous staining in ≥ 1% of cells within tumor nests, including neoplastic cells and intercalated and contiguous immune cells) was considered positive.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="21"/>
                    <count group_id="B2" value="346"/>
                    <count group_id="B3" value="346"/>
                    <count group_id="B4" value="713"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Positive</title>
                  <measurement_list>
                    <measurement group_id="B1" value="17"/>
                    <measurement group_id="B2" value="218"/>
                    <measurement group_id="B3" value="231"/>
                    <measurement group_id="B4" value="466"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Positive</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="128"/>
                    <measurement group_id="B3" value="115"/>
                    <measurement group_id="B4" value="247"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>BRAF V600 Mutation Status</title>
          <description>Mutation status of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) gene was based on a gene mutation that results in an amino acid substitution from valine (V) to glutamic acid (E) at codon 600 (V600E) and/or a substitution from valine to lysine (K) (V600K).</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="21"/>
                    <count group_id="B2" value="346"/>
                    <count group_id="B3" value="346"/>
                    <count group_id="B4" value="713"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Mutation</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="116"/>
                    <measurement group_id="B3" value="124"/>
                    <measurement group_id="B4" value="244"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Mutation not present</title>
                  <measurement_list>
                    <measurement group_id="B1" value="17"/>
                    <measurement group_id="B2" value="215"/>
                    <measurement group_id="B3" value="211"/>
                    <measurement group_id="B4" value="443"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Missing/unknown</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="15"/>
                    <measurement group_id="B3" value="11"/>
                    <measurement group_id="B4" value="26"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Phase 1b: Number of Participants With Dose-limiting Toxicities (DLTs)</title>
        <description>A DLT was defined as any toxicity related to study drug which met any of the following criteria based on Common Terminology Criteria for Adverse Events (CTCAE) version 4.0:&#xD;
Grade 4 non-hematologic toxicity.&#xD;
Grade 3 or higher pneumonitis.&#xD;
Grade 3 non-hematologic toxicity lasting &gt; 3 days despite optimal supportive care, excluding grade 3 fatigue.&#xD;
Any grade 3 or higher non-hematologic laboratory value if medical intervention was required, or the abnormality lead to hospitalization, or the abnormality persisted for &gt; 1 week.&#xD;
Febrile neutropenia grade 3 or grade 4.&#xD;
Thrombocytopenia &lt; 25 x 10^9/L if associated with a bleeding event which does not result in hemodynamic instability but required an elective platelet infusion, or a life-threatening bleeding event which resulted in urgent intervention and admission to intensive care unit.&#xD;
Grade 5 toxicity (ie, death).&#xD;
Any other intolerable toxicity leading to permanent discontinuation of talimogene laherparepvec or pembrolizumab.</description>
        <time_frame>The DLT evaluation period was 6 weeks from the initial administration of pembrolizumab (week 6 to 12).</time_frame>
        <population>The DLT analysis set included DLT-evaluable participants enrolled in Phase 1b who had the opportunity to be on treatment for at least 6 weeks from the initial dose of pembrolizumab and received at least 2 doses of talimogene laherparepvec and 2 doses of pembrolizumab in combination (ie, on the same day), or those who otherwise experienced a DLT within 6 weeks after starting the combination therapy.</population>
        <group_list>
          <group group_id="O1">
            <title>Phase 1b: Talimogene Laherparepvec + Pembrolizumab</title>
            <description>Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ plaque-forming units (PFU)/mL by intralesional injection on day 1 of week 1. Subsequent doses of talimogene laherparepvec at up to 4 mL of 10⁸ PFU/mL began 3 weeks after the first dose and were administered every 2 weeks until disappearance of injectable lesions, complete response (CR), confirmed disease progression (PD) per modified Immune-related Response Criteria (irRC), intolerance of study treatment, 24 months from the date of the first dose of pembrolizumab, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 2 weeks starting at the time of the third dose of talimogene laherparepvec (week 6) until confirmed PD per modified irRC, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
          </group>
        </group_list>
        <measure>
          <title>Phase 1b: Number of Participants With Dose-limiting Toxicities (DLTs)</title>
          <description>A DLT was defined as any toxicity related to study drug which met any of the following criteria based on Common Terminology Criteria for Adverse Events (CTCAE) version 4.0:&#xD;
Grade 4 non-hematologic toxicity.&#xD;
Grade 3 or higher pneumonitis.&#xD;
Grade 3 non-hematologic toxicity lasting &gt; 3 days despite optimal supportive care, excluding grade 3 fatigue.&#xD;
Any grade 3 or higher non-hematologic laboratory value if medical intervention was required, or the abnormality lead to hospitalization, or the abnormality persisted for &gt; 1 week.&#xD;
Febrile neutropenia grade 3 or grade 4.&#xD;
Thrombocytopenia &lt; 25 x 10^9/L if associated with a bleeding event which does not result in hemodynamic instability but required an elective platelet infusion, or a life-threatening bleeding event which resulted in urgent intervention and admission to intensive care unit.&#xD;
Grade 5 toxicity (ie, death).&#xD;
Any other intolerable toxicity leading to permanent discontinuation of talimogene laherparepvec or pembrolizumab.</description>
          <population>The DLT analysis set included DLT-evaluable participants enrolled in Phase 1b who had the opportunity to be on treatment for at least 6 weeks from the initial dose of pembrolizumab and received at least 2 doses of talimogene laherparepvec and 2 doses of pembrolizumab in combination (ie, on the same day), or those who otherwise experienced a DLT within 6 weeks after starting the combination therapy.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="21"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Phase 3: Progression Free Survival (PFS) by Blinded Independent Central Review (BICR) Assessed Using Modified RECIST 1.1</title>
        <description>PFS per modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 is defined as the interval from randomization to the earlier event of progressive disease (PD) per modified RECIST 1.1 or death from any cause.&#xD;
PD: Increase in size of target lesions from nadir by ≥ 20% and ≥ 5 mm absolute increase above nadir, or the appearance of a new lesion.&#xD;
Median PFS was calculated using the Kaplan-Meier method. Participants without an event were censored at their last evaluable tumor assessment if available; otherwise on their randomization date.&#xD;
The primary analysis of PFS was specified to be conducted when 407 PFS events had occurred (data cut-off date 02 March 2020).</description>
        <time_frame>From randomization until the data-cut-off date of 02 March 2020; median (range) time on follow-up was 25.5 (0.6, 44.7) months in the Placebo + Pembrolizumab arm and 25.6 (0.3, 45.8) months in the Talimogene Laherparepvec + Pembrolizumab arm.</time_frame>
        <population>All participants randomized in Phase 3.</population>
        <group_list>
          <group group_id="O1">
            <title>Phase 3: Placebo + Pembrolizumab</title>
            <description>Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
          </group>
          <group group_id="O2">
            <title>Phase 3: Talimogene Laherparepvec + Pembrolizumab</title>
            <description>Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
          </group>
        </group_list>
        <measure>
          <title>Phase 3: Progression Free Survival (PFS) by Blinded Independent Central Review (BICR) Assessed Using Modified RECIST 1.1</title>
          <description>PFS per modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 is defined as the interval from randomization to the earlier event of progressive disease (PD) per modified RECIST 1.1 or death from any cause.&#xD;
PD: Increase in size of target lesions from nadir by ≥ 20% and ≥ 5 mm absolute increase above nadir, or the appearance of a new lesion.&#xD;
Median PFS was calculated using the Kaplan-Meier method. Participants without an event were censored at their last evaluable tumor assessment if available; otherwise on their randomization date.&#xD;
The primary analysis of PFS was specified to be conducted when 407 PFS events had occurred (data cut-off date 02 March 2020).</description>
          <population>All participants randomized in Phase 3.</population>
          <units>months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="346"/>
                <count group_id="O2" value="346"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8.5" lower_limit="5.72" upper_limit="13.54"/>
                    <measurement group_id="O2" value="14.3" lower_limit="10.25" upper_limit="22.11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.13</p_value>
            <method>Stratified log-rank test</method>
            <method_desc>Stratified by randomization factors (disease stage, prior BRAF inhibitor therapy) and baseline PD-L1 status.</method_desc>
            <param_type>Hazard Ratio (HR)</param_type>
            <param_value>0.86</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.71</ci_lower_limit>
            <ci_upper_limit>1.04</ci_upper_limit>
            <estimate_desc>Cox proportional hazards model stratified by randomization factors (disease stage, prior BRAF inhibitor therapy) and baseline PD-L1 status.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Phase 3: Overall Survival</title>
        <description>Overall survival (OS) is defined as the interval from randomization to death from any cause.&#xD;
Median overall survival was calculated using the Kaplan-Meier method. Participants without an event were censored at their last known alive date.</description>
        <time_frame>From randomization until the end of study; median (range) time on follow-up was 34.8 (0.6, 58.3) months in the Placebo + Pembrolizumab arm and 36.8 (0.3, 58.4) months in the Talimogene Laherparepvec + Pembrolizumab arm.</time_frame>
        <population>All participants randomized in Phase 3</population>
        <group_list>
          <group group_id="O1">
            <title>Phase 3: Placebo + Pembrolizumab</title>
            <description>Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
          </group>
          <group group_id="O2">
            <title>Phase 3: Talimogene Laherparepvec + Pembrolizumab</title>
            <description>Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
          </group>
        </group_list>
        <measure>
          <title>Phase 3: Overall Survival</title>
          <description>Overall survival (OS) is defined as the interval from randomization to death from any cause.&#xD;
Median overall survival was calculated using the Kaplan-Meier method. Participants without an event were censored at their last known alive date.</description>
          <population>All participants randomized in Phase 3</population>
          <units>months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="346"/>
                <count group_id="O2" value="346"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" lower_limit="NA" upper_limit="NA">Could not be estimated due to the low number of events</measurement>
                    <measurement group_id="O2" value="NA" lower_limit="NA" upper_limit="NA">Could not be estimated due to the low number of events</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.77</p_value>
            <method>Stratified log-rank test</method>
            <method_desc>Stratified by randomization factors (disease stage, prior BRAF inhibitor therapy) and baseline PD-L1 status.</method_desc>
            <param_type>Hazard Ratio (HR)</param_type>
            <param_value>0.97</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.77</ci_lower_limit>
            <ci_upper_limit>1.21</ci_upper_limit>
            <estimate_desc>Cox proportional hazards model stratified by randomization factors (disease stage, prior BRAF inhibitor therapy) and baseline PD-L1 status.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Phase 1b: Objective Response Rate (ORR)</title>
        <description>ORR is defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) using the modified Immune-related Response Criteria (irRC), by Investigator assessment.&#xD;
CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline, response must have been confirmed by a second, consecutive assessment at least 4 weeks apart.&#xD;
Radiographic imaging for assessment of lesions was performed using computed tomography (CT), positron emission tomography (PET), magnetic resonance imaging (MRI), or ultrasound. Clinical measurement of cutaneous, subcutaneous, and palpable nodal tumor lesions was conducted with calipers.</description>
        <time_frame>Tumor assessments were performed at week 6 (prior to initiation of pembrolizumab), week 18, and every 12 weeks thereafter until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 58.6 (1.4, 61.6) months.</time_frame>
        <population>All participants enrolled in Phase 1b who received ≥ 1 dose of talimogene laherparepvec or pembrolizumab.&#xD;
Participants with no post-baseline tumor assessments were counted as non-responders.</population>
        <group_list>
          <group group_id="O1">
            <title>Phase 1b: Talimogene Laherparepvec + Pembrolizumab</title>
            <description>Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ plaque-forming units (PFU)/mL by intralesional injection on day 1 of week 1. Subsequent doses of talimogene laherparepvec at up to 4 mL of 10⁸ PFU/mL began 3 weeks after the first dose and were administered every 2 weeks until disappearance of injectable lesions, complete response (CR), confirmed disease progression (PD) per modified Immune-related Response Criteria (irRC), intolerance of study treatment, 24 months from the date of the first dose of pembrolizumab, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 2 weeks starting at the time of the third dose of talimogene laherparepvec (week 6) until confirmed PD per modified irRC, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
          </group>
        </group_list>
        <measure>
          <title>Phase 1b: Objective Response Rate (ORR)</title>
          <description>ORR is defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) using the modified Immune-related Response Criteria (irRC), by Investigator assessment.&#xD;
CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline, response must have been confirmed by a second, consecutive assessment at least 4 weeks apart.&#xD;
Radiographic imaging for assessment of lesions was performed using computed tomography (CT), positron emission tomography (PET), magnetic resonance imaging (MRI), or ultrasound. Clinical measurement of cutaneous, subcutaneous, and palpable nodal tumor lesions was conducted with calipers.</description>
          <population>All participants enrolled in Phase 1b who received ≥ 1 dose of talimogene laherparepvec or pembrolizumab.&#xD;
Participants with no post-baseline tumor assessments were counted as non-responders.</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="21"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="61.9" lower_limit="38.4" upper_limit="81.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Phase 1b: Best Overall Response (BOR)</title>
        <description>Best overall response is defined as the best overall visit response in the following order: CR, PR, stable disease (SD), progressive disease (PD), or unevaluable (UE), based on investigator assessment using the modified irRC up to the start of any subsequent anti-cancer therapy.&#xD;
CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline; PD was defined as an increase in tumor area ≥ 25% relative to nadir; and SD was defined as any outcome not meeting the criteria for response or PD with ≥ 77 days elapsed after enrollment. Responses and PD must have been confirmed by a second, consecutive assessment at least 4 weeks apart.</description>
        <time_frame>Tumor assessments were performed at week 6 (prior to initiation of pembrolizumab), week 18, and every 12 weeks thereafter until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 58.6 (1.4, 61.6) months.</time_frame>
        <population>All participants enrolled in Phase 1b who received ≥ 1 dose of talimogene laherparepvec or pembrolizumab.</population>
        <group_list>
          <group group_id="O1">
            <title>Phase 1b: Talimogene Laherparepvec + Pembrolizumab</title>
            <description>Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ plaque-forming units (PFU)/mL by intralesional injection on day 1 of week 1. Subsequent doses of talimogene laherparepvec at up to 4 mL of 10⁸ PFU/mL began 3 weeks after the first dose and were administered every 2 weeks until disappearance of injectable lesions, complete response (CR), confirmed disease progression (PD) per modified Immune-related Response Criteria (irRC), intolerance of study treatment, 24 months from the date of the first dose of pembrolizumab, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 2 weeks starting at the time of the third dose of talimogene laherparepvec (week 6) until confirmed PD per modified irRC, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
          </group>
        </group_list>
        <measure>
          <title>Phase 1b: Best Overall Response (BOR)</title>
          <description>Best overall response is defined as the best overall visit response in the following order: CR, PR, stable disease (SD), progressive disease (PD), or unevaluable (UE), based on investigator assessment using the modified irRC up to the start of any subsequent anti-cancer therapy.&#xD;
CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline; PD was defined as an increase in tumor area ≥ 25% relative to nadir; and SD was defined as any outcome not meeting the criteria for response or PD with ≥ 77 days elapsed after enrollment. Responses and PD must have been confirmed by a second, consecutive assessment at least 4 weeks apart.</description>
          <population>All participants enrolled in Phase 1b who received ≥ 1 dose of talimogene laherparepvec or pembrolizumab.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="21"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Complete Response (CR)</title>
                  <measurement_list>
                    <measurement group_id="O1" value="9"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Partial Response (PR)</title>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Stable Disease (SD)</title>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Progressive Disease (PD)</title>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unable to Evaluate (UE)</title>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Phase 1b: Durable Response Rate (DRR)</title>
        <description>DRR is defined as the percentage of participants with a best overall response of CR or PR using the modified irRC per Investigator assessment with a duration of response of at least 6 months.&#xD;
CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline, response must have been confirmed by a second, consecutive assessment at least 4 weeks apart.</description>
        <time_frame>Tumor assessments were performed at week 6 (prior to initiation of pembrolizumab), week 18, and every 12 weeks thereafter until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 58.6 (1.4, 61.6) months.</time_frame>
        <population>All participants enrolled in Phase 1b who received ≥ 1 dose of talimogene laherparepvec or pembrolizumab.</population>
        <group_list>
          <group group_id="O1">
            <title>Phase 1b: Talimogene Laherparepvec + Pembrolizumab</title>
            <description>Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ plaque-forming units (PFU)/mL by intralesional injection on day 1 of week 1. Subsequent doses of talimogene laherparepvec at up to 4 mL of 10⁸ PFU/mL began 3 weeks after the first dose and were administered every 2 weeks until disappearance of injectable lesions, complete response (CR), confirmed disease progression (PD) per modified Immune-related Response Criteria (irRC), intolerance of study treatment, 24 months from the date of the first dose of pembrolizumab, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 2 weeks starting at the time of the third dose of talimogene laherparepvec (week 6) until confirmed PD per modified irRC, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
          </group>
        </group_list>
        <measure>
          <title>Phase 1b: Durable Response Rate (DRR)</title>
          <description>DRR is defined as the percentage of participants with a best overall response of CR or PR using the modified irRC per Investigator assessment with a duration of response of at least 6 months.&#xD;
CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline, response must have been confirmed by a second, consecutive assessment at least 4 weeks apart.</description>
          <population>All participants enrolled in Phase 1b who received ≥ 1 dose of talimogene laherparepvec or pembrolizumab.</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="21"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="57.1" lower_limit="34.0" upper_limit="78.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Phase 1b: Duration of Response (DOR)</title>
        <description>Duration of response (DOR) is defined as the time from the date of an initial response (CR or PR) that is subsequently confirmed to the earlier of confirmed PD or death. Participants who had not ended their response at the time of analysis were censored at their last evaluable tumor assessment before start of the first subsequent anticancer therapy.&#xD;
CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline; PD was defined as an increase in tumor area ≥ 25% relative to nadir. Response and PD must have been confirmed by a second, consecutive assessment at least 4 weeks apart.</description>
        <time_frame>Tumor assessments were performed at week 6 (prior to initiation of pembrolizumab), week 18, and every 12 weeks thereafter until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 58.6 (1.4, 61.6) months.</time_frame>
        <population>All participants enrolled in Phase 1b who received ≥ 1 dose of talimogene laherparepvec or pembrolizumab with a CR or PR.</population>
        <group_list>
          <group group_id="O1">
            <title>Phase 1b: Talimogene Laherparepvec + Pembrolizumab</title>
            <description>Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ plaque-forming units (PFU)/mL by intralesional injection on day 1 of week 1. Subsequent doses of talimogene laherparepvec at up to 4 mL of 10⁸ PFU/mL began 3 weeks after the first dose and were administered every 2 weeks until disappearance of injectable lesions, complete response (CR), confirmed disease progression (PD) per modified Immune-related Response Criteria (irRC), intolerance of study treatment, 24 months from the date of the first dose of pembrolizumab, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 2 weeks starting at the time of the third dose of talimogene laherparepvec (week 6) until confirmed PD per modified irRC, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
          </group>
        </group_list>
        <measure>
          <title>Phase 1b: Duration of Response (DOR)</title>
          <description>Duration of response (DOR) is defined as the time from the date of an initial response (CR or PR) that is subsequently confirmed to the earlier of confirmed PD or death. Participants who had not ended their response at the time of analysis were censored at their last evaluable tumor assessment before start of the first subsequent anticancer therapy.&#xD;
CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline; PD was defined as an increase in tumor area ≥ 25% relative to nadir. Response and PD must have been confirmed by a second, consecutive assessment at least 4 weeks apart.</description>
          <population>All participants enrolled in Phase 1b who received ≥ 1 dose of talimogene laherparepvec or pembrolizumab with a CR or PR.</population>
          <units>months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="13"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" lower_limit="NA" upper_limit="NA">Could not be estimated due to the low number of events</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Phase 1b: Disease Control Rate (DCR)</title>
        <description>DCR is defined as the percentage of participants with a best overall response of CR, PR, or SD using the modified irRC per Investigator assessment.&#xD;
CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline, response must have been confirmed by a second, consecutive assessment at least 4 weeks apart; and SD was defined as any outcome not meeting the criteria for response or PD with ≥ 84 days elapsed after enrollment.</description>
        <time_frame>Tumor assessments were performed at week 6 (prior to initiation of pembrolizumab), week 18, and every 12 weeks thereafter until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 58.6 (1.4, 61.6) months.</time_frame>
        <population>All participants enrolled in Phase 1b who received ≥ 1 dose of talimogene laherparepvec or pembrolizumab.</population>
        <group_list>
          <group group_id="O1">
            <title>Phase 1b: Talimogene Laherparepvec + Pembrolizumab</title>
            <description>Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ plaque-forming units (PFU)/mL by intralesional injection on day 1 of week 1. Subsequent doses of talimogene laherparepvec at up to 4 mL of 10⁸ PFU/mL began 3 weeks after the first dose and were administered every 2 weeks until disappearance of injectable lesions, complete response (CR), confirmed disease progression (PD) per modified Immune-related Response Criteria (irRC), intolerance of study treatment, 24 months from the date of the first dose of pembrolizumab, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 2 weeks starting at the time of the third dose of talimogene laherparepvec (week 6) until confirmed PD per modified irRC, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
          </group>
        </group_list>
        <measure>
          <title>Phase 1b: Disease Control Rate (DCR)</title>
          <description>DCR is defined as the percentage of participants with a best overall response of CR, PR, or SD using the modified irRC per Investigator assessment.&#xD;
CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline, response must have been confirmed by a second, consecutive assessment at least 4 weeks apart; and SD was defined as any outcome not meeting the criteria for response or PD with ≥ 84 days elapsed after enrollment.</description>
          <population>All participants enrolled in Phase 1b who received ≥ 1 dose of talimogene laherparepvec or pembrolizumab.</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="21"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="66.7" lower_limit="43.0" upper_limit="85.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Phase 1b: Progression-free Survival (PFS)</title>
        <description>Progression-free survival is defined as the time from first dose to the earlier event of confirmed PD per modified irRC or death from any cause. PFS was estimated using the Kaplan-Meier method. Participants without an event were censored at their last evaluable tumor assessment.</description>
        <time_frame>From first dose until the end of study; median (range) time on follow-up was 70.6 (1.4, 74.5) months.</time_frame>
        <population>All participants enrolled in Phase 1b who received ≥ 1 dose of talimogene laherparepvec or pembrolizumab.</population>
        <group_list>
          <group group_id="O1">
            <title>Phase 1b: Talimogene Laherparepvec + Pembrolizumab</title>
            <description>Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ plaque-forming units (PFU)/mL by intralesional injection on day 1 of week 1. Subsequent doses of talimogene laherparepvec at up to 4 mL of 10⁸ PFU/mL began 3 weeks after the first dose and were administered every 2 weeks until disappearance of injectable lesions, complete response (CR), confirmed disease progression (PD) per modified Immune-related Response Criteria (irRC), intolerance of study treatment, 24 months from the date of the first dose of pembrolizumab, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 2 weeks starting at the time of the third dose of talimogene laherparepvec (week 6) until confirmed PD per modified irRC, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
          </group>
        </group_list>
        <measure>
          <title>Phase 1b: Progression-free Survival (PFS)</title>
          <description>Progression-free survival is defined as the time from first dose to the earlier event of confirmed PD per modified irRC or death from any cause. PFS was estimated using the Kaplan-Meier method. Participants without an event were censored at their last evaluable tumor assessment.</description>
          <population>All participants enrolled in Phase 1b who received ≥ 1 dose of talimogene laherparepvec or pembrolizumab.</population>
          <units>months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="21"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" lower_limit="NA" upper_limit="NA">Could not be estimated due to the low number of events</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Phase 1b: Overall Survival (OS)</title>
        <description>Overall survival is defined as the interval from first dose to death from any cause.&#xD;
OS was estimated using the Kaplan-Meier method. Participants without an event were censored at their last known alive date.</description>
        <time_frame>From first dose until the end of study; median (range) time on follow-up was 70.6 (1.4, 74.5) months.</time_frame>
        <population>All participants enrolled in Phase 1b who received ≥ 1 dose of talimogene laherparepvec or pembrolizumab</population>
        <group_list>
          <group group_id="O1">
            <title>Phase 1b: Talimogene Laherparepvec + Pembrolizumab</title>
            <description>Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ plaque-forming units (PFU)/mL by intralesional injection on day 1 of week 1. Subsequent doses of talimogene laherparepvec at up to 4 mL of 10⁸ PFU/mL began 3 weeks after the first dose and were administered every 2 weeks until disappearance of injectable lesions, complete response (CR), confirmed disease progression (PD) per modified Immune-related Response Criteria (irRC), intolerance of study treatment, 24 months from the date of the first dose of pembrolizumab, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 2 weeks starting at the time of the third dose of talimogene laherparepvec (week 6) until confirmed PD per modified irRC, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
          </group>
        </group_list>
        <measure>
          <title>Phase 1b: Overall Survival (OS)</title>
          <description>Overall survival is defined as the interval from first dose to death from any cause.&#xD;
OS was estimated using the Kaplan-Meier method. Participants without an event were censored at their last known alive date.</description>
          <population>All participants enrolled in Phase 1b who received ≥ 1 dose of talimogene laherparepvec or pembrolizumab</population>
          <units>months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="21"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" lower_limit="NA" upper_limit="NA">Could not be estimated due to the low number of events</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Phase 3: Complete Response Rate Assessed Using Modified irRC-RECIST (iCRR)</title>
        <description>Complete response rate per modified Immune-related Response Criteria (irRC) simulating RECIST 1.1 (irRC-RECIST) is defined as the percentage of participants with a best overall response of complete response assessed using the modified irRC-RECIST (iCR) evaluated by blinded independent central review.&#xD;
iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks after the criteria were first met. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm.&#xD;
Modifications to the irRC-RECIST 1.1 included an increase in the total number of target lesions and new measurable lesions to 10 with a maximum of 5 target lesions per organ, and target lesions must have been measurable by CT or MRI only.</description>
        <time_frame>Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.</time_frame>
        <population>All participants randomized in Phase 3</population>
        <group_list>
          <group group_id="O1">
            <title>Phase 3: Placebo + Pembrolizumab</title>
            <description>Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
          </group>
          <group group_id="O2">
            <title>Phase 3: Talimogene Laherparepvec + Pembrolizumab</title>
            <description>Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
          </group>
        </group_list>
        <measure>
          <title>Phase 3: Complete Response Rate Assessed Using Modified irRC-RECIST (iCRR)</title>
          <description>Complete response rate per modified Immune-related Response Criteria (irRC) simulating RECIST 1.1 (irRC-RECIST) is defined as the percentage of participants with a best overall response of complete response assessed using the modified irRC-RECIST (iCR) evaluated by blinded independent central review.&#xD;
iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks after the criteria were first met. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm.&#xD;
Modifications to the irRC-RECIST 1.1 included an increase in the total number of target lesions and new measurable lesions to 10 with a maximum of 5 target lesions per organ, and target lesions must have been measurable by CT or MRI only.</description>
          <population>All participants randomized in Phase 3</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="346"/>
                <count group_id="O2" value="346"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8.1" lower_limit="5.22" upper_limit="10.97"/>
                    <measurement group_id="O2" value="14.5" lower_limit="10.75" upper_limit="18.16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.012</p_value>
            <method>Regression, Logistic</method>
            <method_desc>Logistic regression stratified by randomization stratification factors (disease stage and prior BRAF inhibitor therapy) and the baseline PD-L1 status.</method_desc>
            <param_type>Odds Ratio (OR)</param_type>
            <param_value>1.88</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>1.15</ci_lower_limit>
            <ci_upper_limit>3.07</ci_upper_limit>
            <estimate_desc>Adjusted odds ratio estimated using logistic regression with randomization stratification factors and baseline PD-L1 status.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Phase 3: Progression Free Survival Assessed Using Modified irRC-RECIST (iPFS)</title>
        <description>PFS per modified irRC-RECIST is defined as the interval from randomization to the earlier event of progressive disease assessed by modified irRC-RECIST (iPD) evaluated by blinded independent central review, or death from any cause.&#xD;
iPD: Increase in tumor burden ≥ 20% and at least 5 mm absolute increase relative to nadir (minimum recorded tumor burden) confirmed by a repeat, consecutive assessment at least 4 weeks after the initial detection.&#xD;
Median iPFS was calculated using the Kaplan-Meier method. Participants without an event were censored at their last evaluable tumor assessment if available; otherwise on their randomization date.&#xD;
The primary analysis of iPFS was specified to be conducted when 256 iPFS events had occurred (data cut-off date 29 September 2020).</description>
        <time_frame>From randomization until the data cut-off date of 29 September 2020; median time on follow-up was 30.6 (0.6, 53.0) months in the Placebo + Pembrolizumab arm and 31.4 (0.3, 52.5) months in the Talimogene Laherparepvec + Pembrolizumab arm.</time_frame>
        <population>All participants randomized in Phase 3</population>
        <group_list>
          <group group_id="O1">
            <title>Phase 3 : Placebo + Pembrolizumab</title>
            <description>Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
          </group>
          <group group_id="O2">
            <title>Phase 3: Talimogene Laherparepvec + Pembrolizumab</title>
            <description>Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
          </group>
        </group_list>
        <measure>
          <title>Phase 3: Progression Free Survival Assessed Using Modified irRC-RECIST (iPFS)</title>
          <description>PFS per modified irRC-RECIST is defined as the interval from randomization to the earlier event of progressive disease assessed by modified irRC-RECIST (iPD) evaluated by blinded independent central review, or death from any cause.&#xD;
iPD: Increase in tumor burden ≥ 20% and at least 5 mm absolute increase relative to nadir (minimum recorded tumor burden) confirmed by a repeat, consecutive assessment at least 4 weeks after the initial detection.&#xD;
Median iPFS was calculated using the Kaplan-Meier method. Participants without an event were censored at their last evaluable tumor assessment if available; otherwise on their randomization date.&#xD;
The primary analysis of iPFS was specified to be conducted when 256 iPFS events had occurred (data cut-off date 29 September 2020).</description>
          <population>All participants randomized in Phase 3</population>
          <units>months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="346"/>
                <count group_id="O2" value="346"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="25.3" lower_limit="17.68" upper_limit="NA">Could not be estimated due to the low number of events</measurement>
                    <measurement group_id="O2" value="NA" lower_limit="NA" upper_limit="NA">Could not be estimated due to the low number of events</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.14</p_value>
            <method>Stratified log-rank test</method>
            <method_desc>Stratified by randomization factors (disease stage, prior BRAF inhibitor therapy) and baseline PD-L1 status.</method_desc>
            <param_type>Hazard Ratio (HR)</param_type>
            <param_value>1.05</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.82</ci_lower_limit>
            <ci_upper_limit>1.34</ci_upper_limit>
            <estimate_desc>Cox proportional hazards model stratified by randomization factors (disease stage, prior BRAF inhibitor therapy) and baseline PD-L1 status.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Phase 3: Overall Survival Excluding Stage IVM1c Participants</title>
        <description>Overall survival is defined as the interval from randomization to death from any cause.&#xD;
Median OS was calculated using the Kaplan-Meier method. Participants without an event were censored at the last known alive date.</description>
        <time_frame>From randomization until the end of study; median (range) time on follow-up was 34.8 (0.6, 58.3) months in the Placebo + Pembrolizumab arm and 36.8 (0.3, 58.4) months in the Talimogene Laherparepvec + Pembrolizumab arm.</time_frame>
        <population>Participants randomized in Phase 3 with stage IIIB to IVM1a/b.</population>
        <group_list>
          <group group_id="O1">
            <title>Phase 3: Placebo + Pembrolizumab</title>
            <description>Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
          </group>
          <group group_id="O2">
            <title>Phase 3: Talimogene Laherparepvec + Pembrolizumab</title>
            <description>Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
          </group>
        </group_list>
        <measure>
          <title>Phase 3: Overall Survival Excluding Stage IVM1c Participants</title>
          <description>Overall survival is defined as the interval from randomization to death from any cause.&#xD;
Median OS was calculated using the Kaplan-Meier method. Participants without an event were censored at the last known alive date.</description>
          <population>Participants randomized in Phase 3 with stage IIIB to IVM1a/b.</population>
          <units>months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="203"/>
                <count group_id="O2" value="201"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" lower_limit="NA" upper_limit="NA">Could not be estimated due to the low number of events</measurement>
                    <measurement group_id="O2" value="NA" lower_limit="NA" upper_limit="NA">Could not be estimated due to the low number of events</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.47</p_value>
            <method>Stratified log-rank test</method>
            <method_desc>Stratified by randomization factors (disease stage, prior BRAF inhibitor therapy) and baseline PD-L1 status.</method_desc>
            <param_type>Hazard Ratio (HR)</param_type>
            <param_value>0.88</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.63</ci_lower_limit>
            <ci_upper_limit>1.24</ci_upper_limit>
            <estimate_desc>Cox proportional hazards model stratified by randomization factors (disease stage, prior BRAF inhibitor therapy) and baseline PD-L1 status.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Phase 3: Objective Response Rate Assessed Using Modified RECIST 1.1</title>
        <description>ORR is defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) assessed using modified RECIST version 1.1, evaluated by blinded independent central review.&#xD;
CR was defined as the disappearance of all lesions except lymph node short axis &lt; 10 mm; PR was defined as a ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required.&#xD;
Modifications to conventional RECIST 1.1 included the following: target lesions were measurable on CT or MRI; otherwise, they were considered as nontarget lesions. A maximum of 10 target lesions was allowed with up to 5 per organ.</description>
        <time_frame>Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.</time_frame>
        <population>All participants randomized in Phase 3; Participants with no post-baseline tumor assessments were counted as non-responders.</population>
        <group_list>
          <group group_id="O1">
            <title>Phase 3: Placebo + Pembrolizumab</title>
            <description>Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
          </group>
          <group group_id="O2">
            <title>Phase 3: Talimogene Laherparepvec + Pembrolizumab</title>
            <description>Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
          </group>
        </group_list>
        <measure>
          <title>Phase 3: Objective Response Rate Assessed Using Modified RECIST 1.1</title>
          <description>ORR is defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) assessed using modified RECIST version 1.1, evaluated by blinded independent central review.&#xD;
CR was defined as the disappearance of all lesions except lymph node short axis &lt; 10 mm; PR was defined as a ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required.&#xD;
Modifications to conventional RECIST 1.1 included the following: target lesions were measurable on CT or MRI; otherwise, they were considered as nontarget lesions. A maximum of 10 target lesions was allowed with up to 5 per organ.</description>
          <population>All participants randomized in Phase 3; Participants with no post-baseline tumor assessments were counted as non-responders.</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="346"/>
                <count group_id="O2" value="346"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="41.3" lower_limit="36.14" upper_limit="46.52"/>
                    <measurement group_id="O2" value="48.6" lower_limit="43.29" upper_limit="53.82"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.081</p_value>
            <method>Regression, Logistic</method>
            <method_desc>Logistic regression stratified by randomization stratification factors (disease stage and prior BRAF inhibitor therapy) and the baseline PD-L1 status.</method_desc>
            <param_type>Odds Ratio (OR)</param_type>
            <param_value>1.32</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.97</ci_lower_limit>
            <ci_upper_limit>1.79</ci_upper_limit>
            <estimate_desc>Adjusted odds ratio estimated using logistic regression with randomization stratification factors and baseline PD-L1 status.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Phase 3: Best Overall Response Assessed Using Modified RECIST 1.1</title>
        <description>BOR is defined as the best overall visit response up to and including the first overall visit response of PD in the following order: CR, PR, SD, non-CR/Non-PD (NN), PD or UE per modified RECIST 1.1, evaluated by BICR.&#xD;
CR: Disappearance of all lesions except lymph node short axis &lt; 10 mm; PR: ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required; NN: Persistence of ≥ 1 non-target lesions and/or maintenance of tumor marker level above normal limits; SD: Neither sufficient shrinkage of target lesions to qualify for CR or PR nor sufficient increase to qualify for PD and ≥ 84 days from randomization; PD: Increase from nadir by ≥ 20% or ≥ 5 mm of target lesions or any new lesion; Missing: No postbaseline assessment, or assessments on or after the start of first subsequent anticancer therapy, including complete or partial removal/reduction of any target lesion which contained melanoma on pathology evaluation or pathology results were unknown.</description>
        <time_frame>Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.</time_frame>
        <population>All participants randomized in Phase 3</population>
        <group_list>
          <group group_id="O1">
            <title>Phase 3: Placebo + Pembrolizumab</title>
            <description>Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
          </group>
          <group group_id="O2">
            <title>Phase 3: Talimogene Laherparepvec + Pembrolizumab</title>
            <description>Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
          </group>
        </group_list>
        <measure>
          <title>Phase 3: Best Overall Response Assessed Using Modified RECIST 1.1</title>
          <description>BOR is defined as the best overall visit response up to and including the first overall visit response of PD in the following order: CR, PR, SD, non-CR/Non-PD (NN), PD or UE per modified RECIST 1.1, evaluated by BICR.&#xD;
CR: Disappearance of all lesions except lymph node short axis &lt; 10 mm; PR: ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required; NN: Persistence of ≥ 1 non-target lesions and/or maintenance of tumor marker level above normal limits; SD: Neither sufficient shrinkage of target lesions to qualify for CR or PR nor sufficient increase to qualify for PD and ≥ 84 days from randomization; PD: Increase from nadir by ≥ 20% or ≥ 5 mm of target lesions or any new lesion; Missing: No postbaseline assessment, or assessments on or after the start of first subsequent anticancer therapy, including complete or partial removal/reduction of any target lesion which contained melanoma on pathology evaluation or pathology results were unknown.</description>
          <population>All participants randomized in Phase 3</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="346"/>
                <count group_id="O2" value="346"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Complete response (CR)</title>
                  <measurement_list>
                    <measurement group_id="O1" value="40"/>
                    <measurement group_id="O2" value="62"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Partial response (PR)</title>
                  <measurement_list>
                    <measurement group_id="O1" value="103"/>
                    <measurement group_id="O2" value="106"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Stable disease (SD)</title>
                  <measurement_list>
                    <measurement group_id="O1" value="30"/>
                    <measurement group_id="O2" value="28"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Non-CR/Non-PD (NN)</title>
                  <measurement_list>
                    <measurement group_id="O1" value="16"/>
                    <measurement group_id="O2" value="11"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Progressive disease (PD)</title>
                  <measurement_list>
                    <measurement group_id="O1" value="120"/>
                    <measurement group_id="O2" value="106"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unevaluable (UE)</title>
                  <measurement_list>
                    <measurement group_id="O1" value="11"/>
                    <measurement group_id="O2" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Missing</title>
                  <measurement_list>
                    <measurement group_id="O1" value="26"/>
                    <measurement group_id="O2" value="30"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Phase 3: Durable Response Rate (DRR) Assessed Using Modified RECIST 1.1</title>
        <description>DRR is defined as the percentage of participants with a CR or PR per modified RECIST 1.1 evaluated by blinded independent central review, with a duration of response of ≥ 6 months.&#xD;
CR was defined as the disappearance of all lesions except lymph node short axis &lt; 10 mm; PR was defined as a ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required.</description>
        <time_frame>Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.</time_frame>
        <population>All participants randomized in Phase 3</population>
        <group_list>
          <group group_id="O1">
            <title>Phase 3: Placebo + Pembrolizumab</title>
            <description>Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
          </group>
          <group group_id="O2">
            <title>Phase 3: Talimogene Laherparepvec + Pembrolizumab</title>
            <description>Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
          </group>
        </group_list>
        <measure>
          <title>Phase 3: Durable Response Rate (DRR) Assessed Using Modified RECIST 1.1</title>
          <description>DRR is defined as the percentage of participants with a CR or PR per modified RECIST 1.1 evaluated by blinded independent central review, with a duration of response of ≥ 6 months.&#xD;
CR was defined as the disappearance of all lesions except lymph node short axis &lt; 10 mm; PR was defined as a ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required.</description>
          <population>All participants randomized in Phase 3</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="346"/>
                <count group_id="O2" value="346"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="34.1" lower_limit="29.11" upper_limit="39.10"/>
                    <measurement group_id="O2" value="42.2" lower_limit="36.99" upper_limit="47.40"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.039</p_value>
            <method>Regression, Logistic</method>
            <method_desc>Logistic regression stratified by randomization stratification factors (disease stage and prior BRAF inhibitor therapy) and the baseline PD-L1 status.</method_desc>
            <param_type>Odds Ratio (OR)</param_type>
            <param_value>1.39</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>1.02</ci_lower_limit>
            <ci_upper_limit>1.90</ci_upper_limit>
            <estimate_desc>Adjusted odds ratio estimated using logistic regression with randomization stratification factors and baseline PD-L1 status.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Phase 3: Duration of Response (DOR) Assessed Using Modified RECIST 1.1</title>
        <description>Duration of response (DOR) is defined as the time from the date of an initial response of CR or PR to the earlier of PD per modified RECIST 1.1, or death. Participants who had not ended their response at the time of analysis were censored at their last evaluable tumor assessment date before start of the first subsequent anticancer therapy.&#xD;
CR was defined as the disappearance of all lesions except lymph node short axis &lt; 10 mm; PR was defined as a ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required. PD was defined as an increase from nadir by ≥ 20% or ≥ 5 mm absolute increase above nadir of target lesions or appearance of any new lesion.</description>
        <time_frame>From randomization until the data cut-off date of 29 September 2020; median time on follow-up was 30.6 (0.6, 53.0) months in the Placebo + Pembrolizumab arm and 31.4 (0.3, 52.5) months in the Talimogene Laherparepvec + Pembrolizumab arm.</time_frame>
        <population>Participants randomized in Phase 3 with a CR or PR per modified RECIST.</population>
        <group_list>
          <group group_id="O1">
            <title>Phase 3: Placebo + Pembrolizumab</title>
            <description>Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
          </group>
          <group group_id="O2">
            <title>Phase 3: Talimogene Laherparepvec + Pembrolizumab</title>
            <description>Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
          </group>
        </group_list>
        <measure>
          <title>Phase 3: Duration of Response (DOR) Assessed Using Modified RECIST 1.1</title>
          <description>Duration of response (DOR) is defined as the time from the date of an initial response of CR or PR to the earlier of PD per modified RECIST 1.1, or death. Participants who had not ended their response at the time of analysis were censored at their last evaluable tumor assessment date before start of the first subsequent anticancer therapy.&#xD;
CR was defined as the disappearance of all lesions except lymph node short axis &lt; 10 mm; PR was defined as a ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required. PD was defined as an increase from nadir by ≥ 20% or ≥ 5 mm absolute increase above nadir of target lesions or appearance of any new lesion.</description>
          <population>Participants randomized in Phase 3 with a CR or PR per modified RECIST.</population>
          <units>months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="143"/>
                <count group_id="O2" value="168"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" lower_limit="NA" upper_limit="NA">Could not be estimated due to the low number of events</measurement>
                    <measurement group_id="O2" value="43.7" lower_limit="NA" upper_limit="NA">Could not be estimated due to the low number of events</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Phase 3: Disease Control Rate (DCR) Assessed Using RECIST 1.1</title>
        <description>Disease control rate (DCR) per modified RECIST 1.1 is defined as the percentage of participants with a best overall response of CR, PR or SD evaluated by blinded independent central review.&#xD;
CR was defined as the disappearance of all lesions except lymph node short axis &lt; 10 mm; PR was defined as a ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required. SD was defined as neither sufficient shrinkage of target lesions to qualify for CR or PR nor sufficient increase to qualify for PD with ≥ 84 days elapsed after randomization.</description>
        <time_frame>Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.</time_frame>
        <population>All participants randomized in Phase 3</population>
        <group_list>
          <group group_id="O1">
            <title>Phase 3: Placebo + Pembrolizumab</title>
            <description>Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
          </group>
          <group group_id="O2">
            <title>Phase 3: Talimogene Laherparepvec + Pembrolizumab</title>
            <description>Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
          </group>
        </group_list>
        <measure>
          <title>Phase 3: Disease Control Rate (DCR) Assessed Using RECIST 1.1</title>
          <description>Disease control rate (DCR) per modified RECIST 1.1 is defined as the percentage of participants with a best overall response of CR, PR or SD evaluated by blinded independent central review.&#xD;
CR was defined as the disappearance of all lesions except lymph node short axis &lt; 10 mm; PR was defined as a ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required. SD was defined as neither sufficient shrinkage of target lesions to qualify for CR or PR nor sufficient increase to qualify for PD with ≥ 84 days elapsed after randomization.</description>
          <population>All participants randomized in Phase 3</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="346"/>
                <count group_id="O2" value="346"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="50.0" lower_limit="44.73" upper_limit="55.27"/>
                    <measurement group_id="O2" value="56.6" lower_limit="51.43" upper_limit="61.87"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.11</p_value>
            <method>Regression, Logistic</method>
            <method_desc>Logistic regression stratified by randomization stratification factors (disease stage and prior BRAF inhibitor therapy) and the baseline PD-L1 status.</method_desc>
            <param_type>Odds Ratio (OR)</param_type>
            <param_value>1.28</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.94</ci_lower_limit>
            <ci_upper_limit>1.75</ci_upper_limit>
            <estimate_desc>Adjusted odds ratio estimated using logistic regression with randomization stratification factors and baseline PD-L1 status.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Phase 3: Objective Response Rate Assessed Using Modified irRC-RECIST (iORR)</title>
        <description>Objective response rate per modified irRC-RECIST is defined as the percentage of participants with a best overall response of iCR or partial response assessed using modified irRC-RECIST (iPR) evaluated by blinded independent central review.&#xD;
iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm.&#xD;
iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation.&#xD;
Modifications to the irRC-RECIST 1.1 included an increase in the total number of target lesions and new measurable lesions to 10 with a maximum of 5 target lesions per organ, and target lesions must be measurable by CT or MRI only.</description>
        <time_frame>Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.</time_frame>
        <population>All participants randomized in Phase 3</population>
        <group_list>
          <group group_id="O1">
            <title>Phase 3: Placebo + Pembrolizumab</title>
            <description>Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
          </group>
          <group group_id="O2">
            <title>Phase 3: Talimogene Laherparepvec + Pembrolizumab</title>
            <description>Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
          </group>
        </group_list>
        <measure>
          <title>Phase 3: Objective Response Rate Assessed Using Modified irRC-RECIST (iORR)</title>
          <description>Objective response rate per modified irRC-RECIST is defined as the percentage of participants with a best overall response of iCR or partial response assessed using modified irRC-RECIST (iPR) evaluated by blinded independent central review.&#xD;
iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm.&#xD;
iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation.&#xD;
Modifications to the irRC-RECIST 1.1 included an increase in the total number of target lesions and new measurable lesions to 10 with a maximum of 5 target lesions per organ, and target lesions must be measurable by CT or MRI only.</description>
          <population>All participants randomized in Phase 3</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="346"/>
                <count group_id="O2" value="346"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="39.9" lower_limit="34.72" upper_limit="45.04"/>
                    <measurement group_id="O2" value="49.1" lower_limit="43.87" upper_limit="54.40"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.020</p_value>
            <method>Regression, Logistic</method>
            <method_desc>Logistic regression stratified by randomization stratification factors (disease stage and prior BRAF inhibitor therapy) and the baseline PD-L1 status.</method_desc>
            <param_type>Odds Ratio (OR)</param_type>
            <param_value>1.44</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>1.06</ci_lower_limit>
            <ci_upper_limit>1.96</ci_upper_limit>
            <estimate_desc>Adjusted odds ratio estimated using logistic regression with randomization stratification factors and baseline PD-L1 status.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Phase 3: Best Overall Response Assessed Using Modified irRC-RECIST</title>
        <description>BOR is defined as the best overall visit response in the following order: iCR, iPR, stable disease per modified irRC-RECIST (iSD), iPD, or UE per modified irRC-RECIST (iUE), evaluated by BICR.&#xD;
iCR: Disappearance of all lesions confirmed by consecutive assessment ≥ 4 weeks from the date first documented. Reduction of any pathological lymph node to &lt;10 mm.&#xD;
iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed ≥ 4 weeks after first documentation.&#xD;
iPD: Increase in tumor burden ≥ 20 % and at least 5 mm absolute increase relative to nadir confirmed ≥ 4 weeks from initial detection.&#xD;
iSD: Neither sufficient shrinkage to qualify for iCR or iPR nor sufficient increase to qualify for iPD and ≥ 84 days from randomization.&#xD;
Missing: No postbaseline assessment, or assessments after start of first subsequent anticancer therapy, including complete or partial removal/reduction of any target lesion which contained melanoma on pathology evaluation or pathology results were unknown.</description>
        <time_frame>Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.</time_frame>
        <population>All participants randomized in Phase 3</population>
        <group_list>
          <group group_id="O1">
            <title>Phase 3: Placebo + Pembrolizumab</title>
            <description>Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
          </group>
          <group group_id="O2">
            <title>Phase 3: Talimogene Laherparepvec + Pembrolizumab</title>
            <description>Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
          </group>
        </group_list>
        <measure>
          <title>Phase 3: Best Overall Response Assessed Using Modified irRC-RECIST</title>
          <description>BOR is defined as the best overall visit response in the following order: iCR, iPR, stable disease per modified irRC-RECIST (iSD), iPD, or UE per modified irRC-RECIST (iUE), evaluated by BICR.&#xD;
iCR: Disappearance of all lesions confirmed by consecutive assessment ≥ 4 weeks from the date first documented. Reduction of any pathological lymph node to &lt;10 mm.&#xD;
iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed ≥ 4 weeks after first documentation.&#xD;
iPD: Increase in tumor burden ≥ 20 % and at least 5 mm absolute increase relative to nadir confirmed ≥ 4 weeks from initial detection.&#xD;
iSD: Neither sufficient shrinkage to qualify for iCR or iPR nor sufficient increase to qualify for iPD and ≥ 84 days from randomization.&#xD;
Missing: No postbaseline assessment, or assessments after start of first subsequent anticancer therapy, including complete or partial removal/reduction of any target lesion which contained melanoma on pathology evaluation or pathology results were unknown.</description>
          <population>All participants randomized in Phase 3</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="346"/>
                <count group_id="O2" value="346"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Complete response (iCR)</title>
                  <measurement_list>
                    <measurement group_id="O1" value="28"/>
                    <measurement group_id="O2" value="50"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Partial response (iPR)</title>
                  <measurement_list>
                    <measurement group_id="O1" value="110"/>
                    <measurement group_id="O2" value="120"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Stable disease (iSD)</title>
                  <measurement_list>
                    <measurement group_id="O1" value="57"/>
                    <measurement group_id="O2" value="51"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Progressive disease (iPD)</title>
                  <measurement_list>
                    <measurement group_id="O1" value="56"/>
                    <measurement group_id="O2" value="65"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unevaluable (iUE)</title>
                  <measurement_list>
                    <measurement group_id="O1" value="69"/>
                    <measurement group_id="O2" value="30"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Missing</title>
                  <measurement_list>
                    <measurement group_id="O1" value="26"/>
                    <measurement group_id="O2" value="30"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Phase 3: Durable Response Rate Assessed Using Modified irRC-RECIST (iDRR)</title>
        <description>Durable response rate per modified irRC-RECIST is defined as the percentage of participants with a best overall response of iCR or iPR per modified irRC-RECIST evaluated by blinded independent central review with a duration of response ≥ 6 months.&#xD;
iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm.&#xD;
iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation.</description>
        <time_frame>Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.</time_frame>
        <population>All participants randomized in Phase 3</population>
        <group_list>
          <group group_id="O1">
            <title>Phase 3: Placebo + Pembrolizumab</title>
            <description>Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
          </group>
          <group group_id="O2">
            <title>Phase 3: Talimogene Laherparepvec + Pembrolizumab</title>
            <description>Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
          </group>
        </group_list>
        <measure>
          <title>Phase 3: Durable Response Rate Assessed Using Modified irRC-RECIST (iDRR)</title>
          <description>Durable response rate per modified irRC-RECIST is defined as the percentage of participants with a best overall response of iCR or iPR per modified irRC-RECIST evaluated by blinded independent central review with a duration of response ≥ 6 months.&#xD;
iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm.&#xD;
iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation.</description>
          <population>All participants randomized in Phase 3</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="346"/>
                <count group_id="O2" value="346"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="34.4" lower_limit="29.39" upper_limit="39.40"/>
                    <measurement group_id="O2" value="45.7" lower_limit="40.42" upper_limit="50.91"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.004</p_value>
            <method>Regression, Logistic</method>
            <method_desc>Logistic regression stratified by randomization stratification factors (disease stage and prior BRAF inhibitor therapy) and the baseline PD-L1 status.</method_desc>
            <param_type>Odds Ratio (OR)</param_type>
            <param_value>1.59</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>1.16</ci_lower_limit>
            <ci_upper_limit>2.17</ci_upper_limit>
            <estimate_desc>Adjusted odds ratio estimated using logistic regression with randomization stratification factors and baseline PD-L1 status.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Phase 3: Duration of Response Assessed Using Modified irRC-RECIST (iDOR)</title>
        <description>Duration of response per modified irRC-RECIST is defined as the time from the date of an initial response of iCR or iPR that was subsequently confirmed to the earlier of iPD per modified irRC-RECIST evaluated by blinded independent central review, or death. Participants who had not ended their response at the time of analysis were censored at their last evaluable tumor assessment date before the start of the first subsequent anticancer therapy.&#xD;
iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm.&#xD;
iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation.</description>
        <time_frame>From randomization until the data cut-off date of 29 September 2020; median time on follow-up was 30.6 (0.6, 53.0) months in the Placebo + Pembrolizumab arm and 31.4 (0.3, 52.5) months in the Talimogene Laherparepvec + Pembrolizumab arm.</time_frame>
        <population>Participants randomized in Phase 3 with a iCR or iPR per modified irRC-RECIST.</population>
        <group_list>
          <group group_id="O1">
            <title>Phase 3: Placebo + Pembrolizumab</title>
            <description>Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
          </group>
          <group group_id="O2">
            <title>Phase 3: Talimogene Laherparepvec + Pembrolizumab</title>
            <description>Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
          </group>
        </group_list>
        <measure>
          <title>Phase 3: Duration of Response Assessed Using Modified irRC-RECIST (iDOR)</title>
          <description>Duration of response per modified irRC-RECIST is defined as the time from the date of an initial response of iCR or iPR that was subsequently confirmed to the earlier of iPD per modified irRC-RECIST evaluated by blinded independent central review, or death. Participants who had not ended their response at the time of analysis were censored at their last evaluable tumor assessment date before the start of the first subsequent anticancer therapy.&#xD;
iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm.&#xD;
iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation.</description>
          <population>Participants randomized in Phase 3 with a iCR or iPR per modified irRC-RECIST.</population>
          <units>months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="138"/>
                <count group_id="O2" value="170"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" lower_limit="NA" upper_limit="NA">Could not be estimated due to the low number of events</measurement>
                    <measurement group_id="O2" value="43.7" lower_limit="34.53" upper_limit="43.73"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Phase 3: Disease Control Rate Assessed Using Modified irRC-RECIST (iDCR)</title>
        <description>Disease control rate per modified irRC-RECIST is defined as the percentage of participants with a best overall response of iCR, iCR, or iSD assessed using modified irRC-RECIST evaluated by blinded independent central review.&#xD;
iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm.&#xD;
iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation.&#xD;
iSD: Neither sufficient shrinkage to qualify for iCR or iPR nor sufficient increase to qualify for iPD with ≥ 84 days elapsed after randomization.</description>
        <time_frame>Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.</time_frame>
        <population>All participants randomized in Phase 3</population>
        <group_list>
          <group group_id="O1">
            <title>Phase 3: Placebo + Pembrolizumab</title>
            <description>Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
          </group>
          <group group_id="O2">
            <title>Phase 3: Talimogene Laherparepvec + Pembrolizumab</title>
            <description>Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
          </group>
        </group_list>
        <measure>
          <title>Phase 3: Disease Control Rate Assessed Using Modified irRC-RECIST (iDCR)</title>
          <description>Disease control rate per modified irRC-RECIST is defined as the percentage of participants with a best overall response of iCR, iCR, or iSD assessed using modified irRC-RECIST evaluated by blinded independent central review.&#xD;
iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm.&#xD;
iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation.&#xD;
iSD: Neither sufficient shrinkage to qualify for iCR or iPR nor sufficient increase to qualify for iPD with ≥ 84 days elapsed after randomization.</description>
          <population>All participants randomized in Phase 3</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="346"/>
                <count group_id="O2" value="346"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="56.4" lower_limit="51.13" upper_limit="61.58"/>
                    <measurement group_id="O2" value="63.9" lower_limit="58.81" upper_limit="68.93"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.058</p_value>
            <method>Regression, Logistic</method>
            <method_desc>Logistic regression stratified by randomization stratification factors (disease stage and prior BRAF inhibitor therapy) and the baseline PD-L1 status.</method_desc>
            <param_type>Odds Ratio (OR)</param_type>
            <param_value>1.35</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.99</ci_lower_limit>
            <ci_upper_limit>1.85</ci_upper_limit>
            <estimate_desc>Adjusted odds ratio estimated using logistic regression with randomization stratification factors and baseline PD-L1 status.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Phase 3: Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Core Module (EORTC QLQ-C30) Global Health Status (GHS)/Quality of Life (QOL) Score</title>
        <description>The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status/quality of life scale, 5 functional scales, and 9 symptom scales/items.&#xD;
The global health/QoL scale consists of 2 questions that ask participants to rate their overall health and overall quality of life during the past week on a scale from 1 (very poor) to 7 (excellent). The GHS/QoL subscale score was derived as the mean of each score then transformed to a scale from 0 to 100 where higher scores represent a better health status and a positive change from baseline indicates improvement.&#xD;
The overall change from baseline (calculated from all on-treatment visits) was calculated using a restricted maximum likelihood-based mixed model for repeated measures (MMRM) (see model details in statistical analysis section).</description>
        <time_frame>Baseline and day 1 of weeks 3, 6, 9, 12, then every 6 weeks until end of study treatment; median (range) duration of treatment was 39.0 (0.1, 107.3) weeks in Placebo + Pembrolizumab and 54.1 (0.1, 109.6) weeks in Talimogene Laherparepvec + Pembrolizumab.</time_frame>
        <population>Participants randomized in Phase 3 who received at least one dose of study therapy and had both a baseline and at least one on-treatment assessment.</population>
        <group_list>
          <group group_id="O1">
            <title>Phase 3: Placebo + Pembrolizumab</title>
            <description>Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
          </group>
          <group group_id="O2">
            <title>Phase 3: Talimogene Laherparepvec + Pembrolizumab</title>
            <description>Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
          </group>
        </group_list>
        <measure>
          <title>Phase 3: Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Core Module (EORTC QLQ-C30) Global Health Status (GHS)/Quality of Life (QOL) Score</title>
          <description>The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status/quality of life scale, 5 functional scales, and 9 symptom scales/items.&#xD;
The global health/QoL scale consists of 2 questions that ask participants to rate their overall health and overall quality of life during the past week on a scale from 1 (very poor) to 7 (excellent). The GHS/QoL subscale score was derived as the mean of each score then transformed to a scale from 0 to 100 where higher scores represent a better health status and a positive change from baseline indicates improvement.&#xD;
The overall change from baseline (calculated from all on-treatment visits) was calculated using a restricted maximum likelihood-based mixed model for repeated measures (MMRM) (see model details in statistical analysis section).</description>
          <population>Participants randomized in Phase 3 who received at least one dose of study therapy and had both a baseline and at least one on-treatment assessment.</population>
          <units>score on a scale</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="329"/>
                <count group_id="O2" value="328"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.20" spread="1.02"/>
                    <measurement group_id="O2" value="-0.02" spread="1.02"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Mixed Model for Repeated Measures include the fixed and categorical effects of treatment, visit and treatment-by-visit interaction, the fixed and continuous covariates of baseline HRQL score, randomization stratification factors (stage of disease and prior BRAF inhibitor therapy per IVRS) and baseline PD-L1 status (positive and not positive). Random subject effect was modeled using within subject-error correlation structure.</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.84</p_value>
            <method>Mixed Model for Repeated Measures</method>
            <param_type>Difference</param_type>
            <param_value>0.19</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.95</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-1.67</ci_lower_limit>
            <ci_upper_limit>2.05</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Treatment-emergent Adverse Events (TEAEs)</title>
        <description>An adverse event (AE) is any untoward medical occurrence in a clinical trial subject, including worsening of a pre-existing medical condition. The event does not necessarily have a causal relationship with study treatment. TEAEs include AEs from the first dose of study drug to 30 days after the last dose.&#xD;
A serious adverse event (SAE) is an AE that met at least 1 of the following criteria:&#xD;
fatal&#xD;
life threatening&#xD;
required in-patient hospitalization or prolongation of existing hospitalization&#xD;
resulted in persistent or significant disability/incapacity&#xD;
congenital anomaly/birth defect&#xD;
other medically important serious event. Treatment-emergent SAEs are any SAE occurring from first dose of study drug through 90 days after the last dose or 30 days after the last dose if new anticancer therapy was started, whichever was earlier.&#xD;
AEs were graded for severity using CTCAE version 4.0, where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Life-threatening; Grade 5 = Fatal.</description>
        <time_frame>From first dose to 30 days after last dose (90 days for SAEs); median (range) duration was 48 (5.1, 110.1) weeks in Phase 1b, 39 (0.1, 107.3) weeks in Placebo + Pembrolizumab and 56 (0.1, 109.6) weeks in Phase 3 Talimogene Laherparepvec + Pembrolizumab.</time_frame>
        <population>All participants who received at least 1 dose of talimogene laherparepvec or pembrolizumab. One participant who was randomized in Phase 3 to receive placebo received talimogene laherparepvec; thus, the Safety Analysis Set consisted of 344 participants in the Talimogene Laherparepvec + Pembrolizumab group and 344 participants in the Placebo + Pembrolizumab group.</population>
        <group_list>
          <group group_id="O1">
            <title>Phase 1b: Talimogene Laherparepvec + Pembrolizumab</title>
            <description>Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ plaque-forming units (PFU)/mL by intralesional injection on day 1 of week 1. Subsequent doses of talimogene laherparepvec at up to 4 mL of 10⁸ PFU/mL began 3 weeks after the first dose and were administered every 2 weeks until disappearance of injectable lesions, complete response (CR), confirmed disease progression (PD) per modified Immune-related Response Criteria (irRC), intolerance of study treatment, 24 months from the date of the first dose of pembrolizumab, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 2 weeks starting at the time of the third dose of talimogene laherparepvec (week 6) until confirmed PD per modified irRC, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
          </group>
          <group group_id="O2">
            <title>Phase 3: Placebo + Pembrolizumab</title>
            <description>Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
          </group>
          <group group_id="O3">
            <title>Phase 3: Talimogene Laherparepvec + Pembrolizumab</title>
            <description>Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Treatment-emergent Adverse Events (TEAEs)</title>
          <description>An adverse event (AE) is any untoward medical occurrence in a clinical trial subject, including worsening of a pre-existing medical condition. The event does not necessarily have a causal relationship with study treatment. TEAEs include AEs from the first dose of study drug to 30 days after the last dose.&#xD;
A serious adverse event (SAE) is an AE that met at least 1 of the following criteria:&#xD;
fatal&#xD;
life threatening&#xD;
required in-patient hospitalization or prolongation of existing hospitalization&#xD;
resulted in persistent or significant disability/incapacity&#xD;
congenital anomaly/birth defect&#xD;
other medically important serious event. Treatment-emergent SAEs are any SAE occurring from first dose of study drug through 90 days after the last dose or 30 days after the last dose if new anticancer therapy was started, whichever was earlier.&#xD;
AEs were graded for severity using CTCAE version 4.0, where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Life-threatening; Grade 5 = Fatal.</description>
          <population>All participants who received at least 1 dose of talimogene laherparepvec or pembrolizumab. One participant who was randomized in Phase 3 to receive placebo received talimogene laherparepvec; thus, the Safety Analysis Set consisted of 344 participants in the Talimogene Laherparepvec + Pembrolizumab group and 344 participants in the Placebo + Pembrolizumab group.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="21"/>
                <count group_id="O2" value="344"/>
                <count group_id="O3" value="344"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Any treatment-emergent adverse events</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="21"/>
                    <measurement group_id="O2" value="331"/>
                    <measurement group_id="O3" value="338"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Grade ≥ 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="20"/>
                    <measurement group_id="O2" value="279"/>
                    <measurement group_id="O3" value="306"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Grade ≥ 3</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="13"/>
                    <measurement group_id="O2" value="151"/>
                    <measurement group_id="O3" value="161"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Grade ≥ 4</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="29"/>
                    <measurement group_id="O3" value="33"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Serious adverse events</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8"/>
                    <measurement group_id="O2" value="141"/>
                    <measurement group_id="O3" value="154"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Leading to discontinuation of talimogene laherparepvec/Placebo</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="24"/>
                    <measurement group_id="O3" value="26"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Leading to discontinuation of pembrolizumab</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="41"/>
                    <measurement group_id="O3" value="43"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Fatal adverse events</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="42"/>
                    <measurement group_id="O3" value="45"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>All-cause mortality: From enrollment (Phase 1b) or randomization (Phase 3) to end of study, up to 75 months in Phase 1b and 58 months in Phase 3. SAEs: From first dose of study drug to 90 days after last dose or 30 days after last dose if new anticancer therapy was started. AEs: From first dose to 30 days after last dose; median (range) duration of exposure was 48 (5.1, 110) weeks in Phase 1b, 39 (0.1, 107) weeks in Placebo + Pembrolizumab and 56 (0.1, 110) weeks in T-VEC + Pembrolizumab arm.</time_frame>
      <desc>All-cause mortality is reported for all enrolled (Phase 1b) or randomized (Phase 3) participants.&#xD;
Adverse events are reported for all participants who received at least 1 dose of talimogene laherparepvec or pembrolizumab.&#xD;
One participant who was randomized in Phase 3 to receive placebo received talimogene laherparepvec; thus, the Safety Analysis Set consisted of 344 participants in the talimogene laherparepvec + pembrolizumab group and 344 participants in the placebo + pembrolizumab group.</desc>
      <group_list>
        <group group_id="E1">
          <title>Phase 1b: Talimogene Laherparepvec + Pembrolizumab</title>
          <description>Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ plaque-forming units (PFU)/mL by intralesional injection on day 1 of week 1. Subsequent doses of talimogene laherparepvec at up to 4 mL of 10⁸ PFU/mL began 3 weeks after the first dose and were administered every 2 weeks until disappearance of injectable lesions, complete response (CR), confirmed disease progression (PD) per modified Immune-related Response Criteria (irRC), intolerance of study treatment, 24 months from the date of the first dose of pembrolizumab, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 2 weeks starting at the time of the third dose of talimogene laherparepvec (week 6) until confirmed PD per modified irRC, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
        </group>
        <group group_id="E2">
          <title>Phase 3: Placebo + Pembrolizumab</title>
          <description>Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
        </group>
        <group group_id="E3">
          <title>Phase 3: Talimogene Laherparepvec + Pembrolizumab</title>
          <description>Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA 23.1</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="156" subjects_at_risk="346"/>
                <counts group_id="E3" subjects_affected="146" subjects_at_risk="346"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="141" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="154" subjects_at_risk="344"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anaemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="9" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Anaemia of malignant disease</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Febrile neutropenia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Granulomatous lymphadenitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Lymph node pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Lymphadenopathy</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Thrombocytopenia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Acute coronary syndrome</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Acute myocardial infarction</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Angina pectoris</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Atrial fibrillation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Atrial flutter</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Atrioventricular block second degree</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Cardiac arrest</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Cardiac failure</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Cardiac failure acute</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Cardiac failure congestive</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Cardiogenic shock</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Left ventricular failure</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Mitral valve prolapse</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Myocardial infarction</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Myocarditis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Supraventricular tachycardia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Vertigo</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="344"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Addison's disease</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Adrenal insufficiency</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Adrenocortical insufficiency acute</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Endocrine disorder</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Hyperthyroidism</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Hypophysitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Hypopituitarism</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Lymphocytic hypophysitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Thyroid mass</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Thyroiditis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Papilloedema</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Retinal oedema</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Uveitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Abdominal pain upper</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Ascites</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Autoimmune colitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Colitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="5" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Gastritis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Gastrointestinal haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Haematochezia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Haemoperitoneum</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Ileus</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Large intestine polyp</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Mechanical ileus</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Oesophageal motility disorder</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Pancreatitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Rectal haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Asthenia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Chest pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Condition aggravated</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Death</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Disease progression</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>General physical health deterioration</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Generalised oedema</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Inflammation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Influenza like illness</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Multiple organ dysfunction syndrome</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Performance status decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="7" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Sudden death</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Swelling</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Autoimmune hepatitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Cholecystitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Cholecystitis acute</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Cholelithiasis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Hepatic failure</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Hepatitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Jaundice</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Anaphylactic shock</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Cytokine release syndrome</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Abscess</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Anal abscess</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Appendicitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Atypical pneumonia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Bronchitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Bronchopulmonary aspergillosis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Cellulitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Chorioretinitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Dermo-hypodermitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Diverticulitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Encephalitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Erysipelas</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Escherichia sepsis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Extradural abscess</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Gastroenteritis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Herpes zoster</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Infected cyst</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Influenza</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Localised infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Lower respiratory tract infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Lymph gland infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Meningitis aseptic</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Nasopharyngitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Periorbital cellulitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Postoperative wound infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Pulmonary sepsis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Pyelonephritis chronic</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Respiratory tract infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Scrotal abscess</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Sinusitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Tooth abscess</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Tracheobronchitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Ureteritis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="5" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Urinary tract infection bacterial</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Urosepsis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Wound infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="344"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Bone contusion</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Contusion</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Femur fracture</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Hip fracture</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Humerus fracture</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Infusion related reaction</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Lumbar vertebral fracture</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Multiple fractures</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Overdose</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Pseudomeningocele</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Radius fracture</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Skin laceration</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Spinal compression fracture</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Synovial rupture</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Toxicity to various agents</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Traumatic arthritis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Upper limb fracture</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>General physical condition abnormal</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Decreased appetite</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Diabetes mellitus</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Diabetic ketoacidosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Hypercalcaemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Hyperglycaemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Hyperkalaemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Hyponatraemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Tumour lysis syndrome</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Type 1 diabetes mellitus</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Type 2 diabetes mellitus</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Arthritis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Arthropathy</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Intervertebral disc degeneration</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Intervertebral disc protrusion</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Joint effusion</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Lumbar spinal stenosis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Myositis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Osteoarthritis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Pathological fracture</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Polyarthritis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Psoriatic arthropathy</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Spinal pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Adenocarcinoma gastric</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Adenocarcinoma of colon</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Basal cell carcinoma</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Bladder adenocarcinoma stage unspecified</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Breast cancer</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Endometrial cancer</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Intraductal proliferative breast lesion</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Malignant melanoma</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="26" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="27" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Malignant neoplasm progression</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Melanoma recurrent</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Metastases to bone</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Metastases to central nervous system</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Metastases to lung</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Metastases to nervous system</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Metastatic malignant melanoma</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="10" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="7" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Squamous cell carcinoma of skin</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Transitional cell carcinoma</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Tumour associated fever</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Tumour haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="344"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Altered state of consciousness</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Basal ganglia infarction</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Carotid artery stenosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Central nervous system necrosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Cerebral haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Dementia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Embolic stroke</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Epilepsy</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Facial paralysis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Hemiparesis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Hydrocephalus</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Ischaemic cerebral infarction</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Ischaemic stroke</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Migraine</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Nervous system disorder</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Neurological symptom</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Paraesthesia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Paraparesis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Paraplegia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Seizure</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Speech disorder</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Spinal cord compression</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Syncope</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Transient ischaemic attack</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Completed suicide</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Confusional state</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Delirium</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Mental status changes</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Obsessive-compulsive disorder</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Somatic symptom disorder</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Acute kidney injury</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Haematuria</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Nephrotic syndrome</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Renal colic</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Renal failure</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Renal impairment</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Ureteric obstruction</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Urinary retention</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Benign prostatic hyperplasia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Gynaecomastia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Chronic obstructive pulmonary disease</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Dyspnoea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="5" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Immune-mediated pneumonitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Interstitial lung disease</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Lung infiltration</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Pleural effusion</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Pneumonitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="5" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Pneumothorax spontaneous</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Pulmonary embolism</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Pulmonary oedema</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Pulmonary sarcoidosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Respiratory failure</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Sleep apnoea syndrome</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Dermatitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Dermatitis bullous</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Drug eruption</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Eczema</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Skin hypopigmentation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Skin lesion</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Skin ulcer</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Stevens-Johnson syndrome</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Surgical and medical procedures</title>
            <event_list>
              <event>
                <sub_title>Axillary lymphadenectomy</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Arteritis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Deep vein thrombosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Hypertensive crisis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Labile blood pressure</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Peripheral artery occlusion</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Subclavian vein thrombosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Thrombophlebitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Vena cava thrombosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA 23.1</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="21" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="305" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="317" subjects_at_risk="344"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anaemia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="26" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="33" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Leukopenia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Hyperthyroidism</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="20" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="22" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Hypothyroidism</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="49" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="48" subjects_at_risk="344"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Visual impairment</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="6" subjects_at_risk="344"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="24" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="23" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Abdominal pain upper</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="12" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="7" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="28" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="52" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="13" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="73" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="70" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Dry mouth</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="19" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="14" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Frequent bowel movements</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="61" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="92" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="29" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="56" subjects_at_risk="344"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Asthenia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="29" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="27" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="17" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="73" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Face oedema</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="15" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="94" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="137" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Influenza like illness</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="26" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="64" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Injection site pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="14" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="15" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Injection site reaction</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="10" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Oedema peripheral</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="22" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="27" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="18" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="24" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="33" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="128" subjects_at_risk="344"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Cellulitis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="14" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Influenza</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="9" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Nasopharyngitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="23" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="21" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Oral herpes</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="16" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="15" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Rhinitis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="11" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="7" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="17" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="17" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="17" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="22" subjects_at_risk="344"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Contusion</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Infusion related reaction</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Procedural pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="9" subjects_at_risk="344"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="23" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="26" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="16" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="20" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Blood alkaline phosphatase increased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="15" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Blood iron decreased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Decreased appetite</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="26" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="43" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Hyperglycaemia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="11" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="19" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Hyperkalaemia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Hypophosphataemia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="14" subjects_at_risk="344"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="66" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="82" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="30" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="35" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Muscle spasms</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="9" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="16" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="33" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="21" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="29" subjects_at_risk="344"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Squamous cell carcinoma</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="344"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="44" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="62" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Neuropathy peripheral</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Paraesthesia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="13" subjects_at_risk="344"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="11" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="27" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="23" subjects_at_risk="344"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="44" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="58" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Dyspnoea</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="24" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="23" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Pneumonitis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="18" subjects_at_risk="344"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Actinic keratosis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="6" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Alopecia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="10" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Erythema</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="15" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="15" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="55" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="61" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="42" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="61" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Rash erythematous</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Rash macular</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="6" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Rash maculo-papular</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="17" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="20" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Skin lesion</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="11" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Skin mass</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Urticaria</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="344"/>
              </event>
              <event>
                <sub_title>Vitiligo</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="32" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="44" subjects_at_risk="344"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="22" subjects_at_risk="344"/>
                <counts group_id="E3" subjects_affected="19" subjects_at_risk="344"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Study Director</name_or_title>
      <organization>Amgen Inc.</organization>
      <phone>866-572-6436</phone>
      <email>medinfo@amgen.com</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02263508
org study id: 20110265
secondary id: 2014-000185-22
secondary id: KEYNOTE-034
nct id: NCT02263508
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
The primary objectives of the Phase 1b part of the study are to evaluate the safety, as
      assessed by incidence of dose limiting toxicity (DLT), of talimogene laherparepvec in
      combination with pembrolizumab in adults with previously untreated, unresectable, stage IIIB
      to IVM1c melanoma.

      The primary objective of Phase 3 are to evaluate the efficacy of talimogene laherparepvec
      with pembrolizumab versus placebo with pembrolizumab, as assessed by progression-free
      survival (PFS) (response evaluation by blinded independent central review using modified
      Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) and overall survival (OS).
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Phase 1b was an open-label, single-arm study. Phase 3 was a randomized, double-blind, placebo-controlled study design.
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Phase 1b: Number of Participants With Dose-limiting Toxicities (DLTs)
time frame: The DLT evaluation period was 6 weeks from the initial administration of pembrolizumab (week 6 to 12).
description: A DLT was defined as any toxicity related to study drug which met any of the following criteria based on Common Terminology Criteria for Adverse Events (CTCAE) version 4.0:
Grade 4 non-hematologic toxicity.
Grade 3 or higher pneumonitis.
Grade 3 non-hematologic toxicity lasting > 3 days despite optimal supportive care, excluding grade 3 fatigue.
Any grade 3 or higher non-hematologic laboratory value if medical intervention was required, or the abnormality lead to hospitalization, or the abnormality persisted for > 1 week.
Febrile neutropenia grade 3 or grade 4.
Thrombocytopenia < 25 x 10^9/L if associated with a bleeding event which does not result in hemodynamic instability but required an elective platelet infusion, or a life-threatening bleeding event which resulted in urgent intervention and admission to intensive care unit.
Grade 5 toxicity (ie, death).
Any other intolerable toxicity leading to permanent discontinuation of talimogene laherparepvec or pembrolizumab.
measure: Phase 3: Progression Free Survival (PFS) by Blinded Independent Central Review (BICR) Assessed Using Modified RECIST 1.1
time frame: From randomization until the data-cut-off date of 02 March 2020; median (range) time on follow-up was 25.5 (0.6, 44.7) months in the Placebo + Pembrolizumab arm and 25.6 (0.3, 45.8) months in the Talimogene Laherparepvec + Pembrolizumab arm.
description: PFS per modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 is defined as the interval from randomization to the earlier event of progressive disease (PD) per modified RECIST 1.1 or death from any cause.
PD: Increase in size of target lesions from nadir by ≥ 20% and ≥ 5 mm absolute increase above nadir, or the appearance of a new lesion.
Median PFS was calculated using the Kaplan-Meier method. Participants without an event were censored at their last evaluable tumor assessment if available; otherwise on their randomization date.
The primary analysis of PFS was specified to be conducted when 407 PFS events had occurred (data cut-off date 02 March 2020).
measure: Phase 3: Overall Survival
time frame: From randomization until the end of study; median (range) time on follow-up was 34.8 (0.6, 58.3) months in the Placebo + Pembrolizumab arm and 36.8 (0.3, 58.4) months in the Talimogene Laherparepvec + Pembrolizumab arm.
description: Overall survival (OS) is defined as the interval from randomization to death from any cause.
Median overall survival was calculated using the Kaplan-Meier method. Participants without an event were censored at their last known alive date.
measure: Phase 1b: Objective Response Rate (ORR)
time frame: Tumor assessments were performed at week 6 (prior to initiation of pembrolizumab), week 18, and every 12 weeks thereafter until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 58.6 (1.4, 61.6) months.
description: ORR is defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) using the modified Immune-related Response Criteria (irRC), by Investigator assessment.
CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline, response must have been confirmed by a second, consecutive assessment at least 4 weeks apart.
Radiographic imaging for assessment of lesions was performed using computed tomography (CT), positron emission tomography (PET), magnetic resonance imaging (MRI), or ultrasound. Clinical measurement of cutaneous, subcutaneous, and palpable nodal tumor lesions was conducted with calipers.
measure: Phase 1b: Best Overall Response (BOR)
time frame: Tumor assessments were performed at week 6 (prior to initiation of pembrolizumab), week 18, and every 12 weeks thereafter until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 58.6 (1.4, 61.6) months.
description: Best overall response is defined as the best overall visit response in the following order: CR, PR, stable disease (SD), progressive disease (PD), or unevaluable (UE), based on investigator assessment using the modified irRC up to the start of any subsequent anti-cancer therapy.
CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline; PD was defined as an increase in tumor area ≥ 25% relative to nadir; and SD was defined as any outcome not meeting the criteria for response or PD with ≥ 77 days elapsed after enrollment. Responses and PD must have been confirmed by a second, consecutive assessment at least 4 weeks apart.
measure: Phase 1b: Durable Response Rate (DRR)
time frame: Tumor assessments were performed at week 6 (prior to initiation of pembrolizumab), week 18, and every 12 weeks thereafter until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 58.6 (1.4, 61.6) months.
description: DRR is defined as the percentage of participants with a best overall response of CR or PR using the modified irRC per Investigator assessment with a duration of response of at least 6 months.
CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline, response must have been confirmed by a second, consecutive assessment at least 4 weeks apart.
measure: Phase 1b: Duration of Response (DOR)
time frame: Tumor assessments were performed at week 6 (prior to initiation of pembrolizumab), week 18, and every 12 weeks thereafter until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 58.6 (1.4, 61.6) months.
description: Duration of response (DOR) is defined as the time from the date of an initial response (CR or PR) that is subsequently confirmed to the earlier of confirmed PD or death. Participants who had not ended their response at the time of analysis were censored at their last evaluable tumor assessment before start of the first subsequent anticancer therapy.
CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline; PD was defined as an increase in tumor area ≥ 25% relative to nadir. Response and PD must have been confirmed by a second, consecutive assessment at least 4 weeks apart.
measure: Phase 1b: Disease Control Rate (DCR)
time frame: Tumor assessments were performed at week 6 (prior to initiation of pembrolizumab), week 18, and every 12 weeks thereafter until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 58.6 (1.4, 61.6) months.
description: DCR is defined as the percentage of participants with a best overall response of CR, PR, or SD using the modified irRC per Investigator assessment.
CR was defined as the disappearance of all lesions; PR was defined as a decrease in tumor area ≥ 50% relative to baseline, response must have been confirmed by a second, consecutive assessment at least 4 weeks apart; and SD was defined as any outcome not meeting the criteria for response or PD with ≥ 84 days elapsed after enrollment.
measure: Phase 1b: Progression-free Survival (PFS)
time frame: From first dose until the end of study; median (range) time on follow-up was 70.6 (1.4, 74.5) months.
description: Progression-free survival is defined as the time from first dose to the earlier event of confirmed PD per modified irRC or death from any cause. PFS was estimated using the Kaplan-Meier method. Participants without an event were censored at their last evaluable tumor assessment.
measure: Phase 1b: Overall Survival (OS)
time frame: From first dose until the end of study; median (range) time on follow-up was 70.6 (1.4, 74.5) months.
description: Overall survival is defined as the interval from first dose to death from any cause.
OS was estimated using the Kaplan-Meier method. Participants without an event were censored at their last known alive date.
measure: Phase 3: Complete Response Rate Assessed Using Modified irRC-RECIST (iCRR)
time frame: Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.
description: Complete response rate per modified Immune-related Response Criteria (irRC) simulating RECIST 1.1 (irRC-RECIST) is defined as the percentage of participants with a best overall response of complete response assessed using the modified irRC-RECIST (iCR) evaluated by blinded independent central review.
iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks after the criteria were first met. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.
Modifications to the irRC-RECIST 1.1 included an increase in the total number of target lesions and new measurable lesions to 10 with a maximum of 5 target lesions per organ, and target lesions must have been measurable by CT or MRI only.
measure: Phase 3: Progression Free Survival Assessed Using Modified irRC-RECIST (iPFS)
time frame: From randomization until the data cut-off date of 29 September 2020; median time on follow-up was 30.6 (0.6, 53.0) months in the Placebo + Pembrolizumab arm and 31.4 (0.3, 52.5) months in the Talimogene Laherparepvec + Pembrolizumab arm.
description: PFS per modified irRC-RECIST is defined as the interval from randomization to the earlier event of progressive disease assessed by modified irRC-RECIST (iPD) evaluated by blinded independent central review, or death from any cause.
iPD: Increase in tumor burden ≥ 20% and at least 5 mm absolute increase relative to nadir (minimum recorded tumor burden) confirmed by a repeat, consecutive assessment at least 4 weeks after the initial detection.
Median iPFS was calculated using the Kaplan-Meier method. Participants without an event were censored at their last evaluable tumor assessment if available; otherwise on their randomization date.
The primary analysis of iPFS was specified to be conducted when 256 iPFS events had occurred (data cut-off date 29 September 2020).
measure: Phase 3: Overall Survival Excluding Stage IVM1c Participants
time frame: From randomization until the end of study; median (range) time on follow-up was 34.8 (0.6, 58.3) months in the Placebo + Pembrolizumab arm and 36.8 (0.3, 58.4) months in the Talimogene Laherparepvec + Pembrolizumab arm.
description: Overall survival is defined as the interval from randomization to death from any cause.
Median OS was calculated using the Kaplan-Meier method. Participants without an event were censored at the last known alive date.
measure: Phase 3: Objective Response Rate Assessed Using Modified RECIST 1.1
time frame: Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.
description: ORR is defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) assessed using modified RECIST version 1.1, evaluated by blinded independent central review.
CR was defined as the disappearance of all lesions except lymph node short axis < 10 mm; PR was defined as a ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required.
Modifications to conventional RECIST 1.1 included the following: target lesions were measurable on CT or MRI; otherwise, they were considered as nontarget lesions. A maximum of 10 target lesions was allowed with up to 5 per organ.
measure: Phase 3: Best Overall Response Assessed Using Modified RECIST 1.1
time frame: Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.
description: BOR is defined as the best overall visit response up to and including the first overall visit response of PD in the following order: CR, PR, SD, non-CR/Non-PD (NN), PD or UE per modified RECIST 1.1, evaluated by BICR.
CR: Disappearance of all lesions except lymph node short axis < 10 mm; PR: ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required; NN: Persistence of ≥ 1 non-target lesions and/or maintenance of tumor marker level above normal limits; SD: Neither sufficient shrinkage of target lesions to qualify for CR or PR nor sufficient increase to qualify for PD and ≥ 84 days from randomization; PD: Increase from nadir by ≥ 20% or ≥ 5 mm of target lesions or any new lesion; Missing: No postbaseline assessment, or assessments on or after the start of first subsequent anticancer therapy, including complete or partial removal/reduction of any target lesion which contained melanoma on pathology evaluation or pathology results were unknown.
measure: Phase 3: Durable Response Rate (DRR) Assessed Using Modified RECIST 1.1
time frame: Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.
description: DRR is defined as the percentage of participants with a CR or PR per modified RECIST 1.1 evaluated by blinded independent central review, with a duration of response of ≥ 6 months.
CR was defined as the disappearance of all lesions except lymph node short axis < 10 mm; PR was defined as a ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required.
measure: Phase 3: Duration of Response (DOR) Assessed Using Modified RECIST 1.1
time frame: From randomization until the data cut-off date of 29 September 2020; median time on follow-up was 30.6 (0.6, 53.0) months in the Placebo + Pembrolizumab arm and 31.4 (0.3, 52.5) months in the Talimogene Laherparepvec + Pembrolizumab arm.
description: Duration of response (DOR) is defined as the time from the date of an initial response of CR or PR to the earlier of PD per modified RECIST 1.1, or death. Participants who had not ended their response at the time of analysis were censored at their last evaluable tumor assessment date before start of the first subsequent anticancer therapy.
CR was defined as the disappearance of all lesions except lymph node short axis < 10 mm; PR was defined as a ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required. PD was defined as an increase from nadir by ≥ 20% or ≥ 5 mm absolute increase above nadir of target lesions or appearance of any new lesion.
measure: Phase 3: Disease Control Rate (DCR) Assessed Using RECIST 1.1
time frame: Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.
description: Disease control rate (DCR) per modified RECIST 1.1 is defined as the percentage of participants with a best overall response of CR, PR or SD evaluated by blinded independent central review.
CR was defined as the disappearance of all lesions except lymph node short axis < 10 mm; PR was defined as a ≥ 30% reduction in sum of diameters in target lesions. Confirmation of CR or PR was not required. SD was defined as neither sufficient shrinkage of target lesions to qualify for CR or PR nor sufficient increase to qualify for PD with ≥ 84 days elapsed after randomization.
measure: Phase 3: Objective Response Rate Assessed Using Modified irRC-RECIST (iORR)
time frame: Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.
description: Objective response rate per modified irRC-RECIST is defined as the percentage of participants with a best overall response of iCR or partial response assessed using modified irRC-RECIST (iPR) evaluated by blinded independent central review.
iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.
iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation.
Modifications to the irRC-RECIST 1.1 included an increase in the total number of target lesions and new measurable lesions to 10 with a maximum of 5 target lesions per organ, and target lesions must be measurable by CT or MRI only.
measure: Phase 3: Best Overall Response Assessed Using Modified irRC-RECIST
time frame: Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.
description: BOR is defined as the best overall visit response in the following order: iCR, iPR, stable disease per modified irRC-RECIST (iSD), iPD, or UE per modified irRC-RECIST (iUE), evaluated by BICR.
iCR: Disappearance of all lesions confirmed by consecutive assessment ≥ 4 weeks from the date first documented. Reduction of any pathological lymph node to <10 mm.
iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed ≥ 4 weeks after first documentation.
iPD: Increase in tumor burden ≥ 20 % and at least 5 mm absolute increase relative to nadir confirmed ≥ 4 weeks from initial detection.
iSD: Neither sufficient shrinkage to qualify for iCR or iPR nor sufficient increase to qualify for iPD and ≥ 84 days from randomization.
Missing: No postbaseline assessment, or assessments after start of first subsequent anticancer therapy, including complete or partial removal/reduction of any target lesion which contained melanoma on pathology evaluation or pathology results were unknown.
measure: Phase 3: Durable Response Rate Assessed Using Modified irRC-RECIST (iDRR)
time frame: Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.
description: Durable response rate per modified irRC-RECIST is defined as the percentage of participants with a best overall response of iCR or iPR per modified irRC-RECIST evaluated by blinded independent central review with a duration of response ≥ 6 months.
iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.
iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation.
measure: Phase 3: Duration of Response Assessed Using Modified irRC-RECIST (iDOR)
time frame: From randomization until the data cut-off date of 29 September 2020; median time on follow-up was 30.6 (0.6, 53.0) months in the Placebo + Pembrolizumab arm and 31.4 (0.3, 52.5) months in the Talimogene Laherparepvec + Pembrolizumab arm.
description: Duration of response per modified irRC-RECIST is defined as the time from the date of an initial response of iCR or iPR that was subsequently confirmed to the earlier of iPD per modified irRC-RECIST evaluated by blinded independent central review, or death. Participants who had not ended their response at the time of analysis were censored at their last evaluable tumor assessment date before the start of the first subsequent anticancer therapy.
iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.
iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation.
measure: Phase 3: Disease Control Rate Assessed Using Modified irRC-RECIST (iDCR)
time frame: Tumor assessments were performed every 12 weeks after initiation of treatment until confirmed PD or start of new anticancer treatment; median (range) time on follow-up was 30.6 (0.6, 53.0) months and 31.4 (0.3, 52.5) months in each group, respectively.
description: Disease control rate per modified irRC-RECIST is defined as the percentage of participants with a best overall response of iCR, iCR, or iSD assessed using modified irRC-RECIST evaluated by blinded independent central review.
iCR: Disappearance of all lesions (whether measurable or not and whether baseline or new) and confirmation by a repeat, consecutive assessment at least 4 weeks from the date first documented. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.
iPR: Decrease in tumor burden ≥ 30% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation.
iSD: Neither sufficient shrinkage to qualify for iCR or iPR nor sufficient increase to qualify for iPD with ≥ 84 days elapsed after randomization.
measure: Phase 3: Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Core Module (EORTC QLQ-C30) Global Health Status (GHS)/Quality of Life (QOL) Score
time frame: Baseline and day 1 of weeks 3, 6, 9, 12, then every 6 weeks until end of study treatment; median (range) duration of treatment was 39.0 (0.1, 107.3) weeks in Placebo + Pembrolizumab and 54.1 (0.1, 109.6) weeks in Talimogene Laherparepvec + Pembrolizumab.
description: The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status/quality of life scale, 5 functional scales, and 9 symptom scales/items.
The global health/QoL scale consists of 2 questions that ask participants to rate their overall health and overall quality of life during the past week on a scale from 1 (very poor) to 7 (excellent). The GHS/QoL subscale score was derived as the mean of each score then transformed to a scale from 0 to 100 where higher scores represent a better health status and a positive change from baseline indicates improvement.
The overall change from baseline (calculated from all on-treatment visits) was calculated using a restricted maximum likelihood-based mixed model for repeated measures (MMRM) (see model details in statistical analysis section).
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs)
time frame: From first dose to 30 days after last dose (90 days for SAEs); median (range) duration was 48 (5.1, 110.1) weeks in Phase 1b, 39 (0.1, 107.3) weeks in Placebo + Pembrolizumab and 56 (0.1, 109.6) weeks in Phase 3 Talimogene Laherparepvec + Pembrolizumab.
description: An adverse event (AE) is any untoward medical occurrence in a clinical trial subject, including worsening of a pre-existing medical condition. The event does not necessarily have a causal relationship with study treatment. TEAEs include AEs from the first dose of study drug to 30 days after the last dose.
A serious adverse event (SAE) is an AE that met at least 1 of the following criteria:
fatal
life threatening
required in-patient hospitalization or prolongation of existing hospitalization
resulted in persistent or significant disability/incapacity
congenital anomaly/birth defect
other medically important serious event. Treatment-emergent SAEs are any SAE occurring from first dose of study drug through 90 days after the last dose or 30 days after the last dose if new anticancer therapy was started, whichever was earlier.
AEs were graded for severity using CTCAE version 4.0, where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Life-threatening; Grade 5 = Fatal.
arm group label: Phase 1b: Talimogene Laherparepvec + Pembrolizumab
arm group type: Experimental
description: Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ plaque-forming units (PFU)/mL by intralesional injection. Subsequent doses of talimogene laherparepvec at up to 4 mL of 10⁸ PFU/mL began 3 weeks after the first dose and were administered every 2 weeks until disappearance of injectable lesions, complete response (CR), confirmed disease progression (PD) per modified Immune-related Response Criteria (irRC), intolerance of study treatment, 24 months from the date of the first dose of pembrolizumab, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 2 weeks starting at the time of the third dose of talimogene laherparepvec (week 6) until confirmed PD per modified irRC, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.
arm group label: Phase 3 : Placebo + Pembrolizumab
arm group type: Placebo Comparator
description: Participants received up to 4 mL placebo to talimogene laherparepvec by intralesional injection on day 1 of week 0. Subsequent doses of placebo (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, complete response per modified Immune-related Response Criteria simulating Response Evaluation Criteria in Solid Tumors (irRC-RECIST) (iCR), confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of placebo, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.
arm group label: Phase 3: Talimogene Laherparepvec + Pembrolizumab
arm group type: Experimental
description: Participants received talimogene laherparepvec at an initial dose of up to 4 mL 10⁶ PFU/mL by intralesional injection on day 1. Subsequent doses of talimogene laherparepvec at 10⁸ PFU/mL (up to 4 mL) began 3 weeks after the first dose and were administered every 2 weeks until the fifth injection of talimogene laherparepvec (week 9), and then synchronously with pembrolizumab thereafter every 3 weeks until disappearance of injectable lesions, iCR, confirmed iPD per modified irRC-RECIST, intolerance of study treatment, 24 months from the date of the first dose of talimogene laherparepvec, or end of study, whichever occurred first. Participants also received 200 mg pembrolizumab administered intravenously every 3 weeks starting on day 1 of week 0, until confirmed iPD per modified irRC-RECIST, treatment intolerance, 24 months from the first dose, or end of study, whichever occurred first.
intervention type: Drug
intervention name: Talimogene Laherparepvec
description: Talimogene laherparepvec administered by intratumoral injection
arm group label: Phase 1b: Talimogene Laherparepvec + Pembrolizumab
arm group label: Phase 3: Talimogene Laherparepvec + Pembrolizumab
other name: IMLYGIC®
other name: OncoVEX^GM-CSF
other name: T-VEC
intervention type: Drug
intervention name: Pembrolizumab
description: Administered at a dose of 200 mg as an intravenous infusion over approximately 30 minutes.
arm group label: Phase 1b: Talimogene Laherparepvec + Pembrolizumab
arm group label: Phase 3 : Placebo + Pembrolizumab
arm group label: Phase 3: Talimogene Laherparepvec + Pembrolizumab
other name: MK-3475
other name: Keytruda®
intervention type: Drug
intervention name: Placebo
description: Administered by intratumoral injection
arm group label: Phase 3 : Placebo + Pembrolizumab
criteria: 
gender: All
minimum age: 18 Years
maximum age: 95 Years
healthy volunteers: No
last name: MD
role: Study Director
affiliation: Amgen
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country: Australia
country: Austria
country: Belgium
country: Canada
country: Czechia
country: Finland
country: France
country: Germany
country: Greece
country: Hungary
country: Italy
country: Korea, Republic of
country: Netherlands
country: Poland
country: Portugal
country: Russian Federation
country: South Africa
country: Spain
country: Switzerland
country: United Kingdom
country: United States
country: Czech Republic
url: http://www.amgentrials.com
description: AmgenTrials clinical trials website
citation: Ribas A, Dummer R, Puzanov I, VanderWalde A, Andtbacka RHI, Michielin O, Olszanski AJ, Malvehy J, Cebon J, Fernandez E, Kirkwood JM, Gajewski TF, Chen L, Gorski KS, Anderson AA, Diede SJ, Lassman ME, Gansert J, Hodi FS, Long GV. Oncolytic Virotherapy Promotes Intratumoral T Cell Infiltration and Improves Anti-PD-1 Immunotherapy. Cell. 2017 Sep 7;170(6):1109-1119.e10. doi: 10.1016/j.cell.2017.08.027. Erratum In: Cell. 2018 Aug 9;174(4):1031-1032.
PMID: 28886381
citation: Dummer R, Hoeller C, Gruter IP, Michielin O. Combining talimogene laherparepvec with immunotherapies in melanoma and other solid tumors. Cancer Immunol Immunother. 2017 Jun;66(6):683-695. doi: 10.1007/s00262-017-1967-1. Epub 2017 Feb 25.
PMID: 28238174
citation: Chesney JA, Ribas A, Long GV, Kirkwood JM, Dummer R, Puzanov I, Hoeller C, Gajewski TF, Gutzmer R, Rutkowski P, Demidov L, Arenberger P, Shin SJ, Ferrucci PF, Haydon A, Hyngstrom J, van Thienen JV, Haferkamp S, Guilera JM, Rapoport BL, VanderWalde A, Diede SJ, Anderson JR, Treichel S, Chan EL, Bhatta S, Gansert J, Hodi FS, Gogas H. Randomized, Double-Blind, Placebo-Controlled, Global Phase III Trial of Talimogene Laherparepvec Combined With Pembrolizumab for Advanced Melanoma. J Clin Oncol. 2023 Jan 20;41(3):528-540. doi: 10.1200/JCO.22.00343. Epub 2022 Aug 23.
PMID: 35998300
responsible party type: Sponsor
mesh term: Melanoma
mesh term: Pembrolizumab
mesh term: Talimogene laherparepvec
sharing ipd: Yes
ipd description: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd info type: Clinical Study Report (CSR)
ipd time frame: Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication (or other new use) have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.
ipd access criteria: Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors, and if not approved, may be further arbitrated by a Data Sharing Independent Review Panel. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the link below.
ipd url: https://www.amgen.com/datasharing
provided document: 
provided document: 
participant flow: 
baseline: 
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reported events: 
certain agreements: 
point of contact: 