***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 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Pre clinical data suggest that combining a checkpoint inhibition with immunomodulatory derivative can increase anticancer response . We design ed a dose-escalation study using a 3 + 3 design to determine the safety , maximum tolerated dose ( MTD ) or recommended phase II dose ( R2PD ) and dose-limiting toxicities ( DLT ) of the anti – CTLA-4 antibody ipilimumab ( 1.5–3 mg/kg intravenously every 28 days × 4 ) and lenalidomide ( 10–25 mg orally daily for 21 of 28 days until disease progression or unacceptable toxicity ) in advanced cancers . Total of 36 patients ( Hodgkin lymphoma , 7 ; melanoma , 5 ; leiomyosarcoma , 4 ; renal cancer , 3 ; thyroid cancer , 3 ; other cancers , 14 ; median of 3 prior therapies ) were enrolled . The MTD has not been reached and ipilimumab 3 mg/kg and lenalidomide 25 mg have been declared as R2PD . DLT were grade ( G ) 3 rash ( 3 patients ) and G3 pancreatitis ( 1 patient ) . G3/4 drug-related toxicities other than DLT were G3 anemia ( 5 patients ) , G3 thromboembolism ( 2 patients ) , G3 thrombocytopenia , G3 rash , G3 hypopituitarism , G3 pneumonitis , G3 transaminitis , and G4 hypopituitarism ( all in 1 patient ) . Eight patients had tumor shrinkage per immune-related response criteria ( −79 % to −2 % ) including a PR ( −79 % for 7.2 + months ) in a refractory Hodgkin lymphoma . Using comprehensive genomic profiling , a total mutation burden ( mutations/Mb ) was evaluated in 17 patients , with one of the patients achieving a PR demonstrated intermediate mutation burden . In conclusion , combination of ipilimumab and lenalidomide is well tolerated and demonstrated preliminary signals of activity in patients with refractory Hodgkin lymphoma and other advanced cancers . Mol Cancer Ther ; 17(3 ) ; 671–6 . © 2017 AACR The incidence of esophagogastric cancer is rapidly rising , but only a minority of patients derive durable benefit from current therapies . Chemotherapy as well as anti-HER2 and PD-1 antibodies are st and ard treatments . To identify predictive biomarkers of drug sensitivity and mechanisms of resistance , we implemented prospect i ve tumor sequencing of patients with metastatic esophagogastric cancer . There was no association between homologous recombination deficiency defects and response to platinum-based chemotherapy . Patients with microsatellite instability-high tumors were intrinsically resistant to chemotherapy but more likely to achieve durable responses to immunotherapy . The single Epstein-Barr virus-positive patient achieved a durable , complete response to immunotherapy . The level of ERBB2 amplification as determined by sequencing was predictive of trastuzumab benefit . Selection for a tumor subclone lacking ERBB2 amplification , deletion of ERBB2 exon 16 , and comutations in the receptor tyrosine kinase , RAS , and PI3 K pathways were associated with intrinsic and /or acquired trastuzumab resistance . Prospect i ve genomic profiling can identify patients most likely to derive durable benefit to immunotherapy and trastuzumab and guide strategies to overcome drug resistance . Significance : Clinical application of multiplex sequencing can identify biomarkers of treatment response to contemporary systemic therapies in metastatic esophagogastric cancer . This large prospect i ve analysis sheds light on the biological complexity and the dynamic nature of therapeutic resistance in metastatic esophagogastric cancers . Cancer Discov ; 8(1 ) ; 49 - 58 . © 2017 AACR.See related commentary by Sundar and Tan , p. 14See related article by Pectasides et al. , p. 37This article is highlighted in the In This Issue feature , p. 1 Purpose Alterations in DNA damage response and repair ( DDR ) genes are associated with increased mutation load and improved clinical outcomes in platinum-treated metastatic urothelial carcinoma . We examined the relationship between DDR alterations and response to PD-1/PD-L1 blockade . Methods Detailed demographic , treatment response , and long-term outcome data were collected on patients with metastatic urothelial carcinoma treated with atezolizumab or nivolumab who had targeted exon sequencing performed on pre-immunotherapy tumor specimens . Presence of DDR alterations was correlated with best objective response per Response Evaluation Criteria in Solid Tumors ( RECIST ) and progression-free and overall survival . Results Sixty patients with urothelial cancer enrolled in prospect i ve trials of anti-PD-1/PD-L1 antibodies met inclusion criteria . Any DDR and known or likely deleterious DDR mutations were identified in 28 ( 47 % ) and 15 ( 25 % ) patients , respectively . The presence of any DDR alteration was associated with a higher response rate ( 67.9 % v 18.8 % ; P < .001 ) . A higher response rate was observed in patients whose tumors harbored known or likely deleterious DDR alterations ( 80 % ) compared with DDR alterations of unknown significance ( 54 % ) and in those whose tumors were wild-type for DDR genes ( 19 % ; P < .001 ) . The correlation remained significant in multivariable analysis that included presence of visceral metastases . DDR alterations also were associated with longer progression-free and overall survival . Conclusion DDR alterations are independently associated with response to PD-1/PD-L1 blockade in patients with metastatic urothelial carcinoma . These observations warrant additional study , including prospect i ve validation and exploration of the interaction between tumor DDR alteration and other tumor/host biomarkers of immunotherapy response Background Inhibition of programmed death-lig and 1 ( PD-L1 ) with atezolizumab can induce durable clinical benefit ( DCB ) in patients with metastatic urothelial cancers , including complete remissions in patients with chemotherapy refractory disease . Although mutation load and PD-L1 immune cell ( IC ) staining have been associated with response , they lack sufficient sensitivity and specificity for clinical use . Thus , there is a need to evaluate the peripheral blood immune environment and to conduct detailed analyses of mutation load , predicted neoantigens , and immune cellular infiltration in tumors to enhance our underst and ing of the biologic underpinnings of response and resistance . Methods and findings The goals of this study were to ( 1 ) evaluate the association of mutation load and predicted neoantigen load with therapeutic benefit and ( 2 ) determine whether intratumoral and peripheral blood T cell receptor ( TCR ) clonality inform clinical outcomes in urothelial carcinoma treated with atezolizumab .  We hypothesized that an elevated mutation load in combination with T cell clonal dominance among intratumoral lymphocytes prior to treatment or among peripheral T cells after treatment would be associated with effective tumor control upon treatment with anti-PD-L1 therapy . We performed whole exome sequencing ( WES ) , RNA sequencing ( RNA-seq ) , and T cell receptor sequencing ( TCR-seq ) of pretreatment tumor sample s as well as TCR-seq of matched , serially collected peripheral blood , collected before and after treatment with atezolizumab . These parameters were assessed for correlation with DCB ( defined as progression-free survival [ PFS ] > 6 months ) , PFS , and overall survival ( OS ) , both alone and in the context of clinical and intratumoral parameters known to be predictive of survival in this disease state . Patients with DCB displayed a higher proportion of tumor-infiltrating T lymphocytes ( TIL ) ( n = 24 , Mann-Whitney p = 0.047 ) . Pretreatment peripheral blood TCR clonality below the median was associated with improved PFS ( n = 29 , log-rank p = 0.048 ) and OS ( n = 29 , log-rank p = 0.011 ) . Patients with DCB also demonstrated more substantial expansion of tumor-associated TCR clones in the peripheral blood 3 weeks after starting treatment ( n = 22 , Mann-Whitney p = 0.022 ) . The combination of high pretreatment peripheral blood TCR clonality with elevated PD-L1 IC staining in tumor tissue was strongly associated with poor clinical outcomes ( n = 10 , hazard ratio ( HR ) ( mean ) = 89.88 , HR ( median ) = 23.41 , 95 % CI [ 2.43 , 506.94 ] , p(HR > 1 ) = 0.0014 ) . Marked variations in mutation loads were seen with different somatic variant calling method ologies , which , in turn , impacted associations with clinical outcomes . Missense mutation load , predicted neoantigen load , and expressed neoantigen load did not demonstrate significant association with DCB ( n = 25 , Mann-Whitney p = 0.22 , n = 25 , Mann-Whitney p = 0.55 , and n = 25 , Mann-Whitney p = 0.29 , respectively ) . Instead , we found evidence of time-varying effects of somatic mutation load on PFS in this cohort ( n = 25 , p = 0.044 ) . A limitation of our study is its small sample size ( n = 29 ) , a subset of the patients treated on IMvigor 210 ( NCT02108652 ) . Given the number of exploratory analyses performed , we intend for these results to be hypothesis-generating . Conclusions These results demonstrate the complex nature of immune response to checkpoint blockade and the compelling need for greater interrogation and data integration of both host and tumor factors . Incorporating these variables in prospect i ve studies will facilitate identification and treatment of resistant patients BACKGROUND Nivolumab plus ipilimumab showed promising efficacy for the treatment of non – small‐cell lung cancer ( NSCLC ) in a phase 1 trial , and tumor mutational burden has emerged as a potential biomarker of benefit . In this part of an open‐label , multipart , phase 3 trial , we examined progression‐free survival with nivolumab plus ipilimumab versus chemotherapy among patients with a high tumor mutational burden ( ≥10 mutations per megabase ) . METHODS We enrolled patients with stage IV or recurrent NSCLC that was not previously treated with chemotherapy . Those with a level of tumor programmed death lig and 1 ( PD‐L1 ) expression of at least 1 % were r and omly assigned , in a 1:1:1 ratio , to receive nivolumab plus ipilimumab , nivolumab monotherapy , or chemotherapy ; those with a tumor PD‐L1 expression level of less than 1 % were r and omly assigned , in a 1:1:1 ratio , to receive nivolumab plus ipilimumab , nivolumab plus chemotherapy , or chemotherapy .  Tumor mutational burden was determined by the FoundationOne CDx assay . RESULTS Progression‐free survival among patients with a high tumor mutational burden was significantly longer with nivolumab plus ipilimumab than with chemotherapy . The 1‐year progression‐free survival rate was 42.6 % with nivolumab plus ipilimumab versus 13.2 % with chemotherapy , and the median progression‐free survival was 7.2 months ( 95 % confidence interval [ CI ] , 5.5 to 13.2 ) versus 5.5 months ( 95 % CI , 4.4 to 5.8 ) ( hazard ratio for disease progression or death , 0.58 ; 97.5 % CI , 0.41 to 0.81 ; P<0.001 ) . The objective response rate was 45.3 % with nivolumab plus ipilimumab and 26.9 % with chemotherapy . The benefit of nivolumab plus ipilimumab over chemotherapy was broadly consistent within subgroups , including patients with a PD‐L1 expression level of at least 1 % and those with a level of less than 1 % . The rate of grade 3 or 4 treatment‐related adverse events was 31.2 % with nivolumab plus ipilimumab and 36.1 % with chemotherapy . CONCLUSIONS Progression‐free survival was significantly longer with first‐line nivolumab plus ipilimumab than with chemotherapy among patients with NSCLC and a high tumor mutational burden , irrespective of PD‐L1 expression level . The results vali date the benefit of nivolumab plus ipilimumab in NSCLC and the role of tumor mutational burden as a biomarker for patient selection . ( Funded by Bristol‐Myers Squibb and Ono Pharmaceutical ; CheckMate 227 Clinical Trials.gov number , NCT02477826 . BACKGROUND Nivolumab , a fully human IgG4 programmed death 1 ( PD-1 ) immune-checkpoint-inhibitor antibody , disrupts PD-1-mediated signaling and may restore antitumor immunity . METHODS In this r and omized , open-label , international phase 3 study , we assigned patients with nonsquamous non-small-cell lung cancer ( NSCLC ) that had progressed during or after platinum-based doublet chemotherapy  to receive nivolumab at a dose of 3 mg per kilogram of body 
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Subgroup analyses showed the predictive value of TMB was significant in non-small-cell lung cancer ( except for the OS ) and melanoma .
In addition , heterogeneity was substantial in targeted next generation sequencing group but tiny in whole exome sequencing group .
Furthermore , TMB and PD-L1 expression were capable to predict improved ORR of ICIs after stratification of each other , with tiny heterogeneity .
Moreover , tumor mutation burden and programmed cell death lig and 1 expression were independent factors on predicting efficacy of immune checkpoint inhibitors