***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
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    Input: PURPOSE Programmed death-1 ( PD-1 ) , an inhibitory receptor expressed on activated T cells , may suppress antitumor immunity . This phase I study sought to determine the safety and tolerability of anti-PD-1 blockade in patients with treatment-refractory solid tumors and to preliminarily assess antitumor activity , pharmacodynamics , and immunologic correlates . PATIENTS AND METHODS Thirty-nine patients with advanced metastatic melanoma , colorectal cancer ( CRC ) , castrate-resistant prostate cancer , non-small-cell lung cancer ( NSCLC ) , or renal cell carcinoma ( RCC ) received a single intravenous infusion of  anti-PD-1 ( MDX-1106 ) in dose-escalating six-patient cohorts at 0.3 , 1 , 3 , or 10 mg/kg , followed by a 15-patient expansion cohort at 10 mg/kg . Patients with evidence of clinical benefit at 3 months were eligible for repeated therapy . RESULTS Anti-PD-1 was well tolerated : one serious adverse event , inflammatory colitis , was observed in a patient with melanoma who received five doses at 1 mg/kg . One durable complete response ( CRC ) and two partial responses ( PRs ; melanoma , RCC ) were seen . Two additional patients ( melanoma , NSCLC ) had significant lesional tumor regressions not meeting PR criteria . The serum half-life of anti-PD-1 was 12 to 20 days . However , pharmacodynamics indicated a sustained mean occupancy of > 70 % of PD-1 molecules on circulating T cells > or = 2 months following infusion , regardless of dose . In nine patients examined , tumor cell surface B7-H1 expression appeared to correlate with the likelihood of response to treatment . CONCLUSION Blocking the PD-1 immune checkpoint with intermittent antibody dosing is well tolerated and associated with evidence of antitumor activity . Exploration of alternative dosing regimens and combinatorial therapies with vaccines , targeted therapies , and /or other checkpoint inhibitors is warranted Therapies that target the programmed death-1 ( PD-1 ) receptor have shown unprecedented rates of durable clinical responses in patients with various cancer types . One mechanism by which cancer tissues limit the host immune response is via upregulation of PD-1 lig and ( PD-L1 ) and its ligation to PD-1 on antigen-specific CD8 + T cells ( termed adaptive immune resistance ) . Here we show that pre-existing CD8 + T cells distinctly located at the invasive tumour margin are associated with expression of the PD-1/PD-L1 immune inhibitory axis and may predict response to therapy . We analysed sample s from 46 patients with metastatic melanoma obtained before and during anti-PD-1 therapy ( pembrolizumab )  using quantitative immunohistochemistry , quantitative multiplex immunofluorescence , and next-generation sequencing for T-cell antigen receptors ( TCRs ) . In serially sample d tumours , patients responding to treatment showed proliferation of intratumoral CD8 + T cells that directly correlated with radiographic reduction in tumour size . Pre-treatment sample s obtained from responding patients showed higher numbers of CD8- , PD-1- and PD-L1-expressing cells at the invasive tumour margin and inside tumours , with close proximity between PD-1 and PD-L1 , and a more clonal TCR repertoire . Using multivariate analysis , we established a predictive model based on CD8 expression at the invasive margin and vali date d the model in an independent cohort of 15 patients . Our findings indicate that tumour regression after therapeutic PD-1 blockade requires pre-existing CD8 + T cells that are negatively regulated by PD-1/PD-L1-mediated adaptive immune resistance BACKGROUND Results from phase 2 and 3 trials in patients with advanced melanoma have shown significant improvements in the proportion of patients achieving an objective response and prolonged progression-free survival with the combination of nivolumab ( an anti-PD-1 antibody ) plus ipilimumab ( an anti-CTLA-4 antibody ) compared with ipilimumab alone . We report 2-year overall survival data from a r and omised controlled trial assessing this treatment in previously untreated advanced melanoma . METHODS In this multicentre , double-blind , r and omised , controlled , phase 2 trial ( CheckMate 069 ) we recruited patients from 19 specialist cancer centres in two countries ( France and the USA ) . Eligible patients were aged 18 years or older with previously untreated , unresectable stage III or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 . Patients were r and omly assigned 2:1 to receive an intravenous infusion of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or ipilimumab 3 mg/kg plus placebo , every 3 weeks for four doses . Subsequently , patients assigned to nivolumab plus ipilimumab received nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity , whereas patients allocated to ipilimumab alone received placebo every 2 weeks during this phase . R and omisation was done via an interactive voice response system with a permuted block schedule ( block size of six ) and stratification by BRAF mutation status . The study funder , patients , investigators , and study site staff were masked to treatment assignment . The primary endpoint , which has been reported previously , was the proportion of patients with BRAFV600 wild-type melanoma achieving an investigator-assessed objective response . Overall survival was an exploratory endpoint and is reported in this Article . Efficacy analyses were done on the intention-to-treat population , whereas safety was assessed in all treated patients who received at least one dose of study drug . This study is registered with Clinical Trials.gov , number NCT01927419 , and is ongoing but no longer enrolling patients . FINDINGS Between Sept 16 , 2013 , and Feb 6 , 2014 , we screened 179 patients and enrolled 142 , r and omly assigning 95 patients to nivolumab plus ipilimumab and 47 to ipilimumab alone . In each treatment group , one patient no longer met the study criteria following r and omisation and thus did not receive study drug . At a median follow-up of 24·5 months ( IQR 9·1 - 25·7 ) , 2-year overall survival was 63·8 % ( 95 % CI 53·3 - 72·6 ) for those assigned to nivolumab plus ipilimumab and 53·6 % ( 95 % CI 38·1 - 66·8 ) for those assigned to ipilimumab alone ; median overall survival had not been reached in either group ( hazard ratio 0·74 , 95 % CI 0·43 - 1·26 ; p=0·26 ) . Treatment-related grade 3 - 4 adverse events were reported in 51 ( 54 % ) of 94 patients who received nivolumab plus ipilimumab compared with nine ( 20 % ) of 46 patients who received ipilimumab alone . The most common treatment-related grade 3 - 4 adverse events were colitis ( 12 [ 13 % ] of 94 patients ) and increased alanine aminotransferase ( ten [ 11 % ] ) in the combination group and diarrhoea ( five [ 11 % ] of 46 patients ) and hypophysitis ( two [ 4 % ] ) in the ipilimumab alone group . Serious grade 3 - 4 treatment-related adverse events were reported in 34 ( 36 % ) of 94 patients who received nivolumab plus ipilimumab ( including colitis in ten [ 11 % ] of 94 patients , and diarrhoea in five [ 5 % ] ) compared with four ( 9 % ) of 46 patients who received ipilimumab alone ( including diarrhoea in two [ 4 % ] of 46 patients , colitis in one [ 2 % ] , and hypophysitis in one [ 2 % ] ) . No new types of treatment-related adverse events or treatment-related deaths occurred in this up date d analysis . INTERPRETATION Although follow-up of the patients in this study is ongoing , the results of this analysis suggest that the combination of first-line nivolumab plus ipilimumab might lead to improved outcomes compared with first-line ipilimumab alone in patients with advanced melanoma . The results suggest encouraging survival outcomes with immunotherapy in this population of patients . FUNDING Bristol-Myers Squibb BACKGROUND Limited evidence exists to show that adding a third agent to platinum-doublet chemotherapy improves efficacy in the first-line advanced non-small-cell lung cancer ( NSCLC ) setting . The anti-PD-1 antibody pembrolizumab has shown efficacy as monotherapy in patients with advanced NSCLC and has a non-overlapping toxicity profile with chemotherapy . We assessed whether the addition of pembrolizumab to platinum-doublet chemotherapy improves efficacy in patients with advanced non-squamous NSCLC . METHODS In this r and omised , open-label , phase 2 cohort of a multicohort study ( KEYNOTE-021 ) , patients were enrolled at 26 medical centres in the USA and Taiwan . Patients with chemotherapy-naive , stage IIIB or IV , non-squamous NSCLC without targetable EGFR or ALK genetic aberrations were r and omly assigned ( 1:1 ) in blocks of four stratified by PD-L1 tumour proportion score ( < 1 % vs ≥1 % ) using an interactive voice-response system to 4 cycles of pembrolizumab 200 mg plus carboplatin area under curve 5 mg/mL per min and pemetrexed 500 mg/m2 every 3 weeks followed by pembrolizumab for 24 months and indefinite pemetrexed maintenance therapy or to 4 cycles of carboplatin and pemetrexed alone followed by indefinite pemetrexed maintenance therapy . The primary endpoint was the proportion of patients who achieved an objective response , defined as the percentage of patients with radiologically confirmed complete or partial response according to Response Evaluation Criteria in Solid Tumors version 1.1 assessed by masked , independent central review , in the intention-to-treat population , defined as all patients who were allocated to study treatment . Significance threshold was p<0·025 ( one sided ) . Safety was assessed in the as-treated population , defined as all patients who received at least one dose of the assigned study treatment . This trial , which is closed for enrolment but continuing for follow-up , is registered with Clinical Trials.gov , number NCT02039674 . FINDINGS Between Nov 25 , 2014 , and Jan 25 , 2016 , 123 patients were enrolled ; 60 were r and omly assigned to the pembrolizumab plus chemotherapy group and 63 to the chemotherapy alone group . 33 ( 55 % ; 95 % CI 42 - 68 ) of 60 patients in the pembrolizumab plus chemotherapy group achieved an objective response compared with 18 ( 29 % ; 18 - 41 ) of 63 patients in the chemotherapy alone group ( estimated treatment difference 26 % [ 95 % CI 9 - 42 % ] ; p=0·0016 ) . The incidence of grade 3 or worse treatment-related adverse events was similar between groups ( 23 [ 39 % ] of 59 patients in the pembrolizumab plus chemotherapy group and 16 [ 26 % ] of 62 in the chemotherapy alone group ) . The most common grade 3 or worse treatment-related adverse events in the pembrolizumab plus chemotherapy group were anaemia ( seven [ 12 % ] of 59 ) and decreased neutrophil count ( three [ 5 % ] ) ; an additional six events each occurred in two ( 3 % ) for acute kidney injury , decreased lymphocyte count , fatigue , neutropenia , and sepsis , and thrombocytopenia . In the chemotherapy alone group , the most common grade 3 or worse events were anaemia ( nine [ 15 % ] of 62 ) and decreased neutrophil count , pancytopenia , and thrombocytopenia ( two [ 3 % ] each ) . One ( 2 % ) of 59 patients in the pembrolizumab plus chemotherapy group experienced treatment-related death because of sepsis compared with two ( 3 % ) of 62 patients in the chemotherapy group : one because of sepsis and one because of pancytopenia . INTERPRETATION Combination of pembrolizumab , carboplatin , and pemetrexed could be an effective and tolerable first-line treatment option for patients with advanced non-squamous NSCLC . This finding is being further explored in an ongoing international , r and omised , double-blind , phase 3 study . FUNDING Merck & BACKGROUND Atezolizumab is a humanised antiprogrammed death-lig and 1 ( PD-L1 ) monoclonal antibody that inhibits PD-L1 and programmed death-1 ( PD-1 ) and PD-L1 and B7 - 1 interactions , reinvigorating anticancer immunity . We assessed its efficacy and safety versus docetaxel in previously treated patients with non-small-cell lung cancer . METHODS We did a r and omised , open-label , phase 3 trial ( OAK ) in 194 academic or community oncology centres in 31 
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Conclusion : The incidence risk of diarrhea associated with PD-1/-PD-L1 inhibitor monotherapy was significantly lower than that of docetaxel monotherapy group .
However it was higher in PD-1/PD-L1 inhibitor combined with chemotherapy group compared with the chemotherapy alone group