xml: <clinical_study>
    <!-- This xml conforms to an XML Schema at:
      https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
    <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/NCT06024941</url>
    </required_header>
    <id_info>
      <org_study_id>Re-Induce 2</org_study_id>
      <nct_id>NCT06024941</nct_id>
    </id_info>
    <brief_title>Re-induction of a Systemic Immune Response in Metastatic or Locally Recurrent Lung Cancer</brief_title>
    <acronym>Re-Induce 2</acronym>
    <official_title>Re-induction of a Systemic Immune Response After Initial Response With Immune Therapy With Single-dose Radiotherapy in Metastatic or Locally Recurrent Lung Cancer: A Prospective Phase II Trial (Re-Induce 2)</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Maastricht Radiation Oncology</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>Maastricht Radiation Oncology</source>
    <oversight_info>
      <has_dmc>Yes</has_dmc>
      <is_fda_regulated_drug>No</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
    </oversight_info>
    <brief_summary>
      <textblock>
        Patients with metastatic non-small cell lung cancer (NSCLC) who after an initial response to&#xD;
        immunotherapy of chemo-immunotherapy show diffuse disease progression are treated with&#xD;
        chemotherapy, with a median PFS of about 3 months and a high incidence of important toxicity&#xD;
        or by continuation of immune therapy when the growth rate of the tumours is low. In a&#xD;
        previous study, it was showed that irradiating a single metastatic lesion and continuation of&#xD;
        immune therapy resulted in a median PFS time was 4.9 months (95% CI, 3.0-7.0 months). At&#xD;
        three months of follow-up, the PFS rate was 62.5%, at six months 37.5% and at 12 months&#xD;
        17.9%. The median OS for all patients was 14.9 months (95% CI, 12.2-21.5 months). Toxicity&#xD;
        was hardly observed. This was obtained with a few fractions of radiotherapy. There is&#xD;
        biological rationale to deliver this radiation in a single fraction of 10 Gy.&#xD;
  &#xD;
        Objective: The primary objective is to investigate if a single fraction of 10 Gy is not&#xD;
        inferior to a more fractionated schedule, which would add to the convenience for the patient,&#xD;
        even less toxicity and costs.&#xD;
  &#xD;
        Study design: Prospective, single-arm phase II trial. Study population: Patients with stage&#xD;
        IV NSCLC who initially showed a partial or complete remission under immune therapy alone or&#xD;
        concurrent immune therapy and chemotherapy and now show progressive disease according to&#xD;
        RECIST 1.1 criteria. At least two different lesions should show progressive disease. Patients&#xD;
        should be able to continue the same immune therapy (i.e. no adverse events grade 3 or more).&#xD;
  &#xD;
        Intervention: Patients continue the same immune therapy they already received and get&#xD;
        radiotherapy to one progressing lesion. The lesion may or may not be symptomatic. The&#xD;
        preferred radiotherapy dose is 10 Gy in 1 fraction, but other fractionation schedules (e.g.&#xD;
        24 Gy/ 3 fractions, 30 Gy/ 10 fractions, 20 Gy/ 5 fractions, 20-24 Gy / 1 fraction for&#xD;
        stereotactic radiotherapy for brain metastases), including so-called isotoxic strategies are&#xD;
        allowed if these are standard for a certain location or palliative indication in the body.&#xD;
  &#xD;
        Main study parameters/endpoints: Progression-free survival (PFS).&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Metastatic non-small cell lung cancer (NSCLC) has always had a remarkably high mortality,&#xD;
        with a 5-year overall survival (OS) rate of only 6%.However, immune checkpoint inhibitors&#xD;
        (ICI) targeting the programmed death protein (PD-1)/programmed death-ligand 1 (PD-L1) axis&#xD;
        have changed this outcome significantly. Patients with NSCLC who have been treated with ICI,&#xD;
        either as monotherapy or in combination with chemotherapy, are surviving longer as compared&#xD;
        to patients receiving chemotherapy alone,5-14 with 5-year OS rates as high as 15-30%.This has&#xD;
        led to the implementation of ICI in clinical practice, namely in patients with metastatic&#xD;
        NSCLC without specific gene alterations.&#xD;
  &#xD;
        Despite overall improved survival rates, a considerable number of patients fail to achieve a&#xD;
        response when treated with ICI (primary resistance) or develop resistance after an initial&#xD;
        period of clinical and radiological response (acquired resistance). Resistance to ICI is&#xD;
        thought to be the result of tumor cell intrinsic factors and an immunosuppressive tumor&#xD;
        microenvironment, resulting in the suppression of effective anti-tumor immunity. Currently,&#xD;
        treatment options in case of resistance to PD1/PD-L1 blockade are limited, with chemotherapy&#xD;
        being standard of care outside clinical trials. The PFS and OS in fit patients receiving&#xD;
        double-agent chemotherapy after progression are approximately 5 and 12 months, while for&#xD;
        those receiving single-agent chemotherapy only 4 and 10 months, respectively. Therefore,&#xD;
        exploring treatments for overcoming ICI resistance is warranted.&#xD;
  &#xD;
        Radiation therapy (RT) is an effective and common treatment in advanced NSCLC, playing a&#xD;
        major role in symptom control, improving quality of life and potentially survival in&#xD;
        oligometastatic disease. Moderately hypofractionated RT to tumor or metastases, while sparing&#xD;
        lymphoid tissues such as lymph nodes, bone marrow and the circulating blood pool, was shown&#xD;
        to enhance the immune response with clinical benefit.&#xD;
  &#xD;
        Acquired immunotherapy resistance is a common event in NSCLC, with most patients exhibiting&#xD;
        progression within the first 6 months (20%) or the first year of treatment (35%). Clinical&#xD;
        trials directed at overcoming immunotherapy resistance in NSCLC have mainly focused on the&#xD;
        escalation of systemic therapy by dual checkpoint blockade or by addition of supporting&#xD;
        substances. A phase II trial investigated the role of durvalumab plus tremelimumab in this&#xD;
        setting and showed no benefit. In contrast, the randomized phase II study of ramucirumab and&#xD;
        pembrolizumab showed improved OS of 14.5 months versus 11.6 months with standard of care. In&#xD;
        other trials investigating chemotherapy plus immunotherapy after ICI-resistance, the&#xD;
        continuation of immunotherapy beyond disease progression also resulted in improved outcomes&#xD;
        compared to patients receiving chemotherapy alone.&#xD;
  &#xD;
        Since previous works have demonstrated that the combination of ICI with RT in&#xD;
        immunotherapy-naïve patients has a relevant impact on PFS, OS and rate of abscopal responses,&#xD;
        local radiation has also been considered a viable option for overcoming immunotherapy&#xD;
        resistance.&#xD;
  &#xD;
        In the predecessor of the current study, &quot;Re-induction of a systemic immune response after&#xD;
        initial response with immune therapy with radiotherapy in metastatic or locally recurrent&#xD;
        lung cancer: A prospective phase II trial&quot;, NCT03406468, the clinical benefit of adding&#xD;
        radiotherapy to immune therapy was investigated. The results of a similar study at the&#xD;
        University Hospital Freiburg, Germany, RadImmun-NSCLC (&quot;Evaluation of systemic effects of&#xD;
        combined palliative radiation therapy and immunotherapy in patients with metastatic non-small&#xD;
        cell lung cancer after insufficient response to immune checkpoint blockade&quot;, DRKS00013531),&#xD;
        were pooled [submitted manuscript].&#xD;
  &#xD;
        A total of 48 patients were enrolled between March 2018 and September 2021 in Freiburg and&#xD;
        Maastricht, 25 patients within the RadImmun-NSCLC trial and 23 patients within the&#xD;
        Re-Induction trial. All patients had stage IV NSCLC, with the majority having adenocarcinoma.&#xD;
  &#xD;
        Importantly, following progression, 21.9% of patients were salvaged again by using local&#xD;
        irradiation.&#xD;
  &#xD;
        The median PFS time was 4.9 months (95% CI, 3.0-7.0 months). At three months of follow-up,&#xD;
        the PFS rate was 62.5%, at six months 37.5% and at 12 months 17.9%.&#xD;
  &#xD;
        With 62.5% of patients having no tumor progression three months after RT, the results of the&#xD;
        trials exceeded the initial hypothesis and suggest that radiation can boost the systemic&#xD;
        immune response, at least temporarily. Moreover, the median OS following RT was 14.9 months,&#xD;
        which is significantly higher than historical data on chemotherapy in the same context. These&#xD;
        results are similar to those obtained by escalation of systemic treatment with dual&#xD;
        checkpoint blockade or the combination of ramucirumab and pembrolizumab. However, in contrast&#xD;
        to the strategy to add another pharmacological agent, the rate of high-grade adverse events&#xD;
        was minimized in the study by keeping the immune treatment unchanged (25% versus 34-42%). The&#xD;
        results are in line with previous studies showing low toxicity of the combination between&#xD;
        stereotactic RT and immunotherapy.&#xD;
  &#xD;
        Similar positive results were achieved by a prospective trial investigating the RT-ICI&#xD;
        combination in oligo progressive metastatic NSCLC and melanoma patients. As approximately 40%&#xD;
        of patients had malignant melanoma and 50% were primarily refractory to ICI, a clear&#xD;
        interpretation of the results in the context of acquired resistance in NSCLC is not possible.&#xD;
        Furthermore, patients were not classified as progressive in this trial as long as they could&#xD;
        be salvaged by further RT, which could explain the unexpectedly high median PFS of 14.2&#xD;
        months.&#xD;
  &#xD;
        In a multicenter randomized phase 2 trial evaluating durvalumab plus tremelimumab and RT for&#xD;
        NSCLC in the same setting, neither low-dose nor hypofractionated RT could enhance the&#xD;
        systemic response compared to the dual checkpoint blockade alone. However, median PFS values&#xD;
        were generally higher in this trial (4-4.6 months) as compared to standard chemotherapy. In&#xD;
        the study, the initial ICI was maintained, and the addition of RT alone led to comparable PFS&#xD;
        values of 4.9 months, with about 18% of patients still having no further progression at 12&#xD;
        months.&#xD;
  &#xD;
        There is evidence that particular dose fractionations may lead to a more pronounced immune&#xD;
        modulation than others. Taking into consideration the heterogeneous dose regimens in our&#xD;
        pooled cohort, it appears that any type of hypofractionated RT might be efficient in&#xD;
        prolonging PFS. A recently published study suggests that this beneficial effect might be&#xD;
        dependent on tumor aneuploidy, which could be used as a prognostic biomarker. In Maastro's&#xD;
        trial, the aggressiveness of the tumor, characterized by its metastasis growth rate, seemed&#xD;
        to impact outcome, with slower-growing tumors having an improved PFS. Some studies also found&#xD;
        a significant correlation between pretherapeutic tumor growth and OS, however others have&#xD;
        not. Following RT, the lesion velocity decreased, attaining at least stable disease in over&#xD;
        90% of patients for a median of 6.2 months.&#xD;
  &#xD;
        In Maastro's trial, at least one metastasis had to be left untreated for follow-up.&#xD;
        Nevertheless, the incidental partial irradiation of all measurable lesions was noticed in 11&#xD;
        patients, who also showed an improved outcome. The partial irradiation of metastases in&#xD;
        combination with immunotherapy has been suggested to have good local efficacy, and the&#xD;
        irradiation of all lesions to improve outcome. However, this is only possible in&#xD;
        oligometastatic disease. The trial shows that all metastatic NSCLC patients benefit from RT&#xD;
        of selected lesions, presumably with improved results in those with a slower tumor dynamic.&#xD;
  &#xD;
        Studies in Maastricht and in Freiburg in patients with NSCLC are indicative that the immune&#xD;
        activation already occurs within days after a single fraction of radiotherapy, likely after&#xD;
        10 Gy. Therefore, a single dose of radiation might be as effective to stimulate the immune&#xD;
        system as a hypofractionated regimen such as 24 Gy/ 3 fractions in our previous study, while&#xD;
        improving the convenience of the treatment for patients, decrease the costs of the&#xD;
        intervention and even further reduce toxicity. A single fraction of 10 Gy has been&#xD;
        extensively investigated and used for palliative radiotherapy and has been shown to be safe.&#xD;
  &#xD;
        The aim of the present study is therefore to investigate if a single fraction of 10 Gy will&#xD;
        also lead to similar disease control rates in patients showing progressive disease after an&#xD;
        initial response of immunotherapy as 3x8 Gy fractionated radiotherapy.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">October 1, 2023</start_date>
    <completion_date type="Anticipated">October 1, 2026</completion_date>
    <primary_completion_date type="Anticipated">October 1, 2025</primary_completion_date>
    <phase>Phase 2</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>N/A</allocation>
      <intervention_model>Single Group Assignment</intervention_model>
      <primary_purpose>Treatment</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Progression-free</measure>
      <time_frame>3 months after radiotherapy</time_frame>
      <description>Progression-free survival (PFS)</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Regression</measure>
      <time_frame>3 months after radiotherapy</time_frame>
      <description>Number of patients who show regression of the irradiated lesion</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Remission rate</measure>
      <time_frame>3 months after radiotherapy</time_frame>
      <description>Number of patients who show remission (RECIST 1.1) of the non-irradiated lesion(s)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Toxicity</measure>
      <time_frame>3 months after radiotherapy</time_frame>
      <description>Number of participants with treatment-related adverse events as assessed by CTCAE v4.0Toxicity (CTCAE 4.0) of this combination of remission and regression</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Overall survival</measure>
      <time_frame>3 months after radiotherapy</time_frame>
      <description>Overall survival (OS)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>PFS second course</measure>
      <time_frame>3 months after radiotherapy</time_frame>
      <description>PFS of patients who received a second course of radiotherapy at the time of disease progression</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Number</measure>
      <time_frame>3 months after radiotherapy</time_frame>
      <description>Number of patients who received a second course of radiotherapy at the time of disease progression</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Relation between the growth rate of the fastest growing metastasis in the 3 months preceding radiotherapy and PFS</measure>
      <time_frame>3 months after radiotherapy</time_frame>
      <description>Relation between the growth rate of the fastest growing metastasis in the 3 months preceding radiotherapy and PFS</description>
    </secondary_outcome>
    <number_of_arms>1</number_of_arms>
    <enrollment type="Anticipated">82</enrollment>
    <condition>Lung Cancer Stage IV</condition>
    <arm_group>
      <arm_group_label>Radiation</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Radiation to one progressive lesion</description>
    </arm_group>
    <intervention>
      <intervention_type>Radiation</intervention_type>
      <intervention_name>Radiation</intervention_name>
      <description>Radiation to one or more progressive lesions. Preferably 1x10Gy, but also 3x8Gy, 10x 3Gy, 5x4Gy or 1x20-24Gy is possible.</description>
      <arm_group_label>Radiation</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Stage IV NSCLC&#xD;
  &#xD;
            -  An initial partial or complete remission under immune therapy alone or concurrent&#xD;
               immune therapy and chemotherapy&#xD;
  &#xD;
            -  Subsequently progressive disease according to RECIST 1.1 criteria&#xD;
  &#xD;
            -  Considered by the treating physician to be able to continue the same immune treatment&#xD;
               as standard of care&#xD;
  &#xD;
            -  At least two different lesions should show progressive disease&#xD;
  &#xD;
            -  At least one progressing lesion should be eligible for radiation&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  Patients with any grade 3 or higher toxicity from previous therapy&#xD;
  &#xD;
            -  Patients who are not eligible for continuation of the immune therapy according to&#xD;
               standard practice&#xD;
  &#xD;
            -  Corticosteroids in a dose above 10 mg prednisone or equivalent per day. Corticoids&#xD;
               used as supportive therapy for systemic or radiotherapy are allowed&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>N/A</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>Dirk De Ruysscher, MD, PhD</last_name>
      <role>Principal Investigator</role>
      <affiliation>Maastro</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Chantal Overhof</last_name>
      <phone>+31 88 4455863</phone>
      <email>chantal.overhof@maastro.nl</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Ann Claessens</last_name>
      <phone>+31 88 4455863</phone>
      <email>ann.claessens@maastro.nl</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>Maastricht Radiation Oncology (Maastro)</name>
        <address>
          <city>Maastricht</city>
          <zip>6229 ET</zip>
          <country>Netherlands</country>
        </address>
      </facility>
      <contact>
        <last_name>Chantal Overhof</last_name>
        <phone>+31 88 4455863</phone>
        <email>chantal.overhof@maastro.nl</email>
      </contact>
      <contact_backup>
        <last_name>Ann Claessens</last_name>
        <phone>+31 88 44 55 863</phone>
        <email>ann.claessens@maastro.nl</email>
      </contact_backup>
      <investigator>
        <last_name>Dirk De Ruysscher, MD, PhD</last_name>
        <role>Principal Investigator</role>
      </investigator>
    </location>
    <location_countries>
      <country>Netherlands</country>
    </location_countries>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>August 22, 2023</study_first_submitted>
    <study_first_submitted_qc>August 29, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">September 6, 2023</study_first_posted>
    <last_update_submitted>August 29, 2023</last_update_submitted>
    <last_update_submitted_qc>August 29, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">September 6, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Lung Neoplasms</mesh_term>
    </condition_browse>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT06024941
  org study id: Re-Induce 2
  nct id: NCT06024941
  lead sponsor: 
  has dmc: Yes
  is fda regulated drug: No
  is fda regulated device: No
  Patients with metastatic non-small cell lung cancer (NSCLC) who after an initial response to
        immunotherapy of chemo-immunotherapy show diffuse disease progression are treated with
        chemotherapy, with a median PFS of about 3 months and a high incidence of important toxicity
        or by continuation of immune therapy when the growth rate of the tumours is low. In a
        previous study, it was showed that irradiating a single metastatic lesion and continuation of
        immune therapy resulted in a median PFS time was 4.9 months (95% CI, 3.0-7.0 months). At
        three months of follow-up, the PFS rate was 62.5%, at six months 37.5% and at 12 months
        17.9%. The median OS for all patients was 14.9 months (95% CI, 12.2-21.5 months). Toxicity
        was hardly observed. This was obtained with a few fractions of radiotherapy. There is
        biological rationale to deliver this radiation in a single fraction of 10 Gy.
  
        Objective: The primary objective is to investigate if a single fraction of 10 Gy is not
        inferior to a more fractionated schedule, which would add to the convenience for the patient,
        even less toxicity and costs.
  
        Study design: Prospective, single-arm phase II trial. Study population: Patients with stage
        IV NSCLC who initially showed a partial or complete remission under immune therapy alone or
        concurrent immune therapy and chemotherapy and now show progressive disease according to
        RECIST 1.1 criteria. At least two different lesions should show progressive disease. Patients
        should be able to continue the same immune therapy (i.e. no adverse events grade 3 or more).
  
        Intervention: Patients continue the same immune therapy they already received and get
        radiotherapy to one progressing lesion. The lesion may or may not be symptomatic. The
        preferred radiotherapy dose is 10 Gy in 1 fraction, but other fractionation schedules (e.g.
        24 Gy/ 3 fractions, 30 Gy/ 10 fractions, 20 Gy/ 5 fractions, 20-24 Gy / 1 fraction for
        stereotactic radiotherapy for brain metastases), including so-called isotoxic strategies are
        allowed if these are standard for a certain location or palliative indication in the body.
  
        Main study parameters/endpoints: Progression-free survival (PFS).
  Metastatic non-small cell lung cancer (NSCLC) has always had a remarkably high mortality,
        with a 5-year overall survival (OS) rate of only 6%.However, immune checkpoint inhibitors
        (ICI) targeting the programmed death protein (PD-1)/programmed death-ligand 1 (PD-L1) axis
        have changed this outcome significantly. Patients with NSCLC who have been treated with ICI,
        either as monotherapy or in combination with chemotherapy, are surviving longer as compared
        to patients receiving chemotherapy alone,5-14 with 5-year OS rates as high as 15-30%.This has
        led to the implementation of ICI in clinical practice, namely in patients with metastatic
        NSCLC without specific gene alterations.
  
        Despite overall improved survival rates, a considerable number of patients fail to achieve a
        response when treated with ICI (primary resistance) or develop resistance after an initial
        period of clinical and radiological response (acquired resistance). Resistance to ICI is
        thought to be the result of tumor cell intrinsic factors and an immunosuppressive tumor
        microenvironment, resulting in the suppression of effective anti-tumor immunity. Currently,
        treatment options in case of resistance to PD1/PD-L1 blockade are limited, with chemotherapy
        being standard of care outside clinical trials. The PFS and OS in fit patients receiving
        double-agent chemotherapy after progression are approximately 5 and 12 months, while for
        those receiving single-agent chemotherapy only 4 and 10 months, respectively. Therefore,
        exploring treatments for overcoming ICI resistance is warranted.
  
        Radiation therapy (RT) is an effective and common treatment in advanced NSCLC, playing a
        major role in symptom control, improving quality of life and potentially survival in
        oligometastatic disease. Moderately hypofractionated RT to tumor or metastases, while sparing
        lymphoid tissues such as lymph nodes, bone marrow and the circulating blood pool, was shown
        to enhance the immune response with clinical benefit.
  
        Acquired immunotherapy resistance is a common event in NSCLC, with most patients exhibiting
        progression within the first 6 months (20%) or the first year of treatment (35%). Clinical
        trials directed at overcoming immunotherapy resistance in NSCLC have mainly focused on the
        escalation of systemic therapy by dual checkpoint blockade or by addition of supporting
        substances. A phase II trial investigated the role of durvalumab plus tremelimumab in this
        setting and showed no benefit. In contrast, the randomized phase II study of ramucirumab and
        pembrolizumab showed improved OS of 14.5 months versus 11.6 months with standard of care. In
        other trials investigating chemotherapy plus immunotherapy after ICI-resistance, the
        continuation of immunotherapy beyond disease progression also resulted in improved outcomes
        compared to patients receiving chemotherapy alone.
  
        Since previous works have demonstrated that the combination of ICI with RT in
        immunotherapy-naïve patients has a relevant impact on PFS, OS and rate of abscopal responses,
        local radiation has also been considered a viable option for overcoming immunotherapy
        resistance.
  
        In the predecessor of the current study, "Re-induction of a systemic immune response after
        initial response with immune therapy with radiotherapy in metastatic or locally recurrent
        lung cancer: A prospective phase II trial", NCT03406468, the clinical benefit of adding
        radiotherapy to immune therapy was investigated. The results of a similar study at the
        University Hospital Freiburg, Germany, RadImmun-NSCLC ("Evaluation of systemic effects of
        combined palliative radiation therapy and immunotherapy in patients with metastatic non-small
        cell lung cancer after insufficient response to immune checkpoint blockade", DRKS00013531),
        were pooled [submitted manuscript].
  
        A total of 48 patients were enrolled between March 2018 and September 2021 in Freiburg and
        Maastricht, 25 patients within the RadImmun-NSCLC trial and 23 patients within the
        Re-Induction trial. All patients had stage IV NSCLC, with the majority having adenocarcinoma.
  
        Importantly, following progression, 21.9% of patients were salvaged again by using local
        irradiation.
  
        The median PFS time was 4.9 months (95% CI, 3.0-7.0 months). At three months of follow-up,
        the PFS rate was 62.5%, at six months 37.5% and at 12 months 17.9%.
  
        With 62.5% of patients having no tumor progression three months after RT, the results of the
        trials exceeded the initial hypothesis and suggest that radiation can boost the systemic
        immune response, at least temporarily. Moreover, the median OS following RT was 14.9 months,
        which is significantly higher than historical data on chemotherapy in the same context. These
        results are similar to those obtained by escalation of systemic treatment with dual
        checkpoint blockade or the combination of ramucirumab and pembrolizumab. However, in contrast
        to the strategy to add another pharmacological agent, the rate of high-grade adverse events
        was minimized in the study by keeping the immune treatment unchanged (25% versus 34-42%). The
        results are in line with previous studies showing low toxicity of the combination between
        stereotactic RT and immunotherapy.
  
        Similar positive results were achieved by a prospective trial investigating the RT-ICI
        combination in oligo progressive metastatic NSCLC and melanoma patients. As approximately 40%
        of patients had malignant melanoma and 50% were primarily refractory to ICI, a clear
        interpretation of the results in the context of acquired resistance in NSCLC is not possible.
        Furthermore, patients were not classified as progressive in this trial as long as they could
        be salvaged by further RT, which could explain the unexpectedly high median PFS of 14.2
        months.
  
        In a multicenter randomized phase 2 trial evaluating durvalumab plus tremelimumab and RT for
        NSCLC in the same setting, neither low-dose nor hypofractionated RT could enhance the
        systemic response compared to the dual checkpoint blockade alone. However, median PFS values
        were generally higher in this trial (4-4.6 months) as compared to standard chemotherapy. In
        the study, the initial ICI was maintained, and the addition of RT alone led to comparable PFS
        values of 4.9 months, with about 18% of patients still having no further progression at 12
        months.
  
        There is evidence that particular dose fractionations may lead to a more pronounced immune
        modulation than others. Taking into consideration the heterogeneous dose regimens in our
        pooled cohort, it appears that any type of hypofractionated RT might be efficient in
        prolonging PFS. A recently published study suggests that this beneficial effect might be
        dependent on tumor aneuploidy, which could be used as a prognostic biomarker. In Maastro's
        trial, the aggressiveness of the tumor, characterized by its metastasis growth rate, seemed
        to impact outcome, with slower-growing tumors having an improved PFS. Some studies also found
        a significant correlation between pretherapeutic tumor growth and OS, however others have
        not. Following RT, the lesion velocity decreased, attaining at least stable disease in over
        90% of patients for a median of 6.2 months.
  
        In Maastro's trial, at least one metastasis had to be left untreated for follow-up.
        Nevertheless, the incidental partial irradiation of all measurable lesions was noticed in 11
        patients, who also showed an improved outcome. The partial irradiation of metastases in
        combination with immunotherapy has been suggested to have good local efficacy, and the
        irradiation of all lesions to improve outcome. However, this is only possible in
        oligometastatic disease. The trial shows that all metastatic NSCLC patients benefit from RT
        of selected lesions, presumably with improved results in those with a slower tumor dynamic.
  
        Studies in Maastricht and in Freiburg in patients with NSCLC are indicative that the immune
        activation already occurs within days after a single fraction of radiotherapy, likely after
        10 Gy. Therefore, a single dose of radiation might be as effective to stimulate the immune
        system as a hypofractionated regimen such as 24 Gy/ 3 fractions in our previous study, while
        improving the convenience of the treatment for patients, decrease the costs of the
        intervention and even further reduce toxicity. A single fraction of 10 Gy has been
        extensively investigated and used for palliative radiotherapy and has been shown to be safe.
  
        The aim of the present study is therefore to investigate if a single fraction of 10 Gy will
        also lead to similar disease control rates in patients showing progressive disease after an
        initial response of immunotherapy as 3x8 Gy fractionated radiotherapy.
  allocation: N/A
  intervention model: Single Group Assignment
  primary purpose: Treatment
  masking: None (Open Label)
  measure: Progression-free
  time frame: 3 months after radiotherapy
  description: Progression-free survival (PFS)
  measure: Regression
  time frame: 3 months after radiotherapy
  description: Number of patients who show regression of the irradiated lesion
  measure: Remission rate
  time frame: 3 months after radiotherapy
  description: Number of patients who show remission (RECIST 1.1) of the non-irradiated lesion(s)
  measure: Toxicity
  time frame: 3 months after radiotherapy
  description: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0Toxicity (CTCAE 4.0) of this combination of remission and regression
  measure: Overall survival
  time frame: 3 months after radiotherapy
  description: Overall survival (OS)
  measure: PFS second course
  time frame: 3 months after radiotherapy
  description: PFS of patients who received a second course of radiotherapy at the time of disease progression
  measure: Number
  time frame: 3 months after radiotherapy
  description: Number of patients who received a second course of radiotherapy at the time of disease progression
  measure: Relation between the growth rate of the fastest growing metastasis in the 3 months preceding radiotherapy and PFS
  time frame: 3 months after radiotherapy
  description: Relation between the growth rate of the fastest growing metastasis in the 3 months preceding radiotherapy and PFS
  arm group label: Radiation
  arm group type: Experimental
  description: Radiation to one progressive lesion
  intervention type: Radiation
  intervention name: Radiation
  description: Radiation to one or more progressive lesions. Preferably 1x10Gy, but also 3x8Gy, 10x 3Gy, 5x4Gy or 1x20-24Gy is possible.
  arm group label: Radiation
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: N/A
  healthy volunteers: No
  last name: Dirk De Ruysscher, MD, PhD
  role: Principal Investigator
  affiliation: Maastro
  last name: Chantal Overhof
  phone: +31 88 4455863
  email: chantal.overhof@maastro.nl
  last name: Ann Claessens
  phone: +31 88 4455863
  email: ann.claessens@maastro.nl
  facility: 
  contact: 
  contact backup: 
  investigator: 
  country: Netherlands
  responsible party type: Sponsor
  mesh term: Lung Neoplasms