{"entity":{"id":"paper-rizvi-mutational-landscape-pd1-science-2015","kind":"paper","name":"Rizvi 2015: the mutational landscape determines who responds to PD-1 blockade in lung cancer","aka":[],"tldr":"Lung cancers with more mutations, typically those caused by smoking, were more likely to respond to pembrolizumab, the study that established tumour mutational burden as a biomarker for immunotherapy.","summary":"Rizvi, Hellmann, Snyder and colleagues at Memorial Sloan Kettering sequenced the exomes of non-small-cell lung cancers from patients treated with pembrolizumab in a discovery cohort of 16 and a validation cohort of 18. A higher number of nonsynonymous mutations was associated with a higher response rate, more durable clinical benefit and longer progression-free survival. A molecular smoking signature, a higher predicted neoantigen burden and mutations in DNA repair genes also tracked with benefit, and in one responder the team detected T cells recognising a specific neoantigen.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1126/science.aaa1348"}],"tags":[],"related":["paper-pardoll-immune-checkpoint-blockade-nrc-2012","tmb-high"],"cancers":["nsclc"],"sections":[],"technologies":["checkpoint-inhibitor","wes-wgs","tmb-testing"],"targets":["pd1","pdl1","kras"],"drugs":["pembrolizumab"],"companies":[],"institutions":["mskcc"],"pathways":["cancer-immunity-cycle","mutagenesis-signatures","pd1-checkpoint"],"terms":["tmb","neoantigen","mutational-signature"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"journal":"Science","year":2015,"doi":"10.1126/science.aaa1348","authors":"Rizvi NA, Hellmann MD, Snyder A, et al.","paperType":"translational","findings":["Whole-exome sequencing of NSCLC from 16 patients (discovery) and 18 (validation) treated with pembrolizumab.","Higher nonsynonymous mutation burden was associated with durable clinical benefit (73% vs 13% in the discovery cohort) and longer progression-free survival.","A transversion-high smoking signature, predicted neoantigen burden and DNA repair pathway mutations were also associated with benefit.","Neoantigen-specific T cells were detected in a responding patient."],"whatItMeans":"This paper turned a hypothesis into a biomarker: tumour mutational burden is now measured by commercial panels and underpins the tissue-agnostic approval of pembrolizumab for TMB-high tumours. It also explains why smokers' lung cancers, long the hardest to treat, respond better to immunotherapy than never-smokers' cancers.","caveats":["Small cohorts; the mutation burden cut-off was set within the study.","TMB has proved a weaker and less consistent predictor in later, larger trials, and panel-based estimates differ between assays."],"changedPractice":true,"participants":34},"route":"/key-papers/paper-rizvi-mutational-landscape-pd1-science-2015/","neighbours":{"paper":[{"id":"paper-pardoll-immune-checkpoint-blockade-nrc-2012","kind":"paper","name":"Pardoll 2012: the blockade of immune checkpoints in cancer immunotherapy","route":"/key-papers/paper-pardoll-immune-checkpoint-blockade-nrc-2012/"},{"id":"paper-tumeh-pd1-adaptive-immune-resistance-nature-2014","kind":"paper","name":"Tumeh 2014: PD-1 blockade works by releasing T cells already present at the tumour edge","route":"/key-papers/paper-tumeh-pd1-adaptive-immune-resistance-nature-2014/"}],"biomarker":[{"id":"tmb-high","kind":"biomarker","name":"TMB-high (tumour mutational burden >= 10 mutations per megabase)","route":"/biomarkers/tmb-high/"}],"cancer":[{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"}],"technology":[{"id":"checkpoint-inhibitor","kind":"technology","name":"Immune checkpoint inhibitors","route":"/technologies/checkpoint-inhibitor/"},{"id":"tmb-testing","kind":"technology","name":"Tumour mutational burden testing","route":"/technologies/tmb-testing/"},{"id":"wes-wgs","kind":"technology","name":"Whole-exome & whole-genome sequencing","route":"/technologies/wes-wgs/"}],"target":[{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/"},{"id":"pd1","kind":"target","name":"PD-1","route":"/targets/pd1/"},{"id":"pdl1","kind":"target","name":"PD-L1","route":"/targets/pdl1/"}],"drug":[{"id":"pembrolizumab","kind":"drug","name":"Pembrolizumab","route":"/drugs/pembrolizumab/"}],"institution":[{"id":"mskcc","kind":"institution","name":"Memorial Sloan Kettering Cancer Center","route":"/institutions/mskcc/"}],"pathway":[{"id":"mutagenesis-signatures","kind":"pathway","name":"Mutagenesis & mutational signatures","route":"/pathways/mutagenesis-signatures/"},{"id":"pd1-checkpoint","kind":"pathway","name":"PD-1 / PD-L1 immune checkpoint & T-cell activation","route":"/pathways/pd1-checkpoint/"},{"id":"cancer-immunity-cycle","kind":"pathway","name":"The cancer-immunity cycle","route":"/pathways/cancer-immunity-cycle/"}],"term":[{"id":"mutational-signature","kind":"term","name":"Mutational signature","route":"/terms/mutational-signature/"},{"id":"neoantigen","kind":"term","name":"Neoantigen","route":"/terms/neoantigen/"},{"id":"tmb","kind":"term","name":"Tumour mutational burden (TMB)","route":"/terms/tmb/"}]}}