{"entity":{"id":"paper-rizvi-targeted-ngs-immunotherapy-determinants-jco-2018","kind":"paper","name":"Molecular determinants of response to anti-PD-1 and anti-PD-L1 blockade in patients with non-small-cell lung cancer profiled with targeted next-generation sequencing","aka":[],"tldr":"The routine gene panel used in clinic can estimate how many mutations a lung cancer carries almost as well as sequencing the whole exome can, and tumours with more mutations were more likely to benefit from immunotherapy, independently of the PD-L1 stain.","summary":"Detailed clinical annotation and response data were collected for 240 patients with advanced non-small-cell lung cancer treated with anti-PD-1 or anti-PD-L1 therapy and profiled with a targeted next-generation sequencing panel. Durable clinical benefit was defined as partial response or stable disease lasting more than six months. Panel-based tumour mutation burden correlated well with whole-exome estimates in 49 patients (rho 0.86). Burden was greater in patients with durable benefit than in those without (p = 0.006). Durable benefit was more common and progression-free survival longer above the 50th percentile of burden (38.6% against 25.1%; hazard ratio 1.38). The fraction of copy number-altered genome was highest in patients without durable benefit. Variants in EGFR and STK11 were associated with a lack of benefit. Burden and PD-L1 expression were independent, and a composite of the two enriched further for benefit.","asOf":"2026-09-25","links":[{"label":"Rizvi et al., J Clin Oncol 2018: targeted sequencing of 240 non-small-cell lung cancers treated with PD-(L)1 blockade","url":"https://doi.org/10.1200/JCO.2017.75.3384"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/29337640/"},{"label":"cBioPortal study nsclc_pd1_msk_2018 (MSK, J Clin Oncol 2018; 240 non-small-cell lung cancers profiled before PD-(L)1 blockade)","url":"https://www.cbioportal.org/study/summary?id=nsclc_pd1_msk_2018"}],"tags":[],"related":["tmb-high","pd-l1-tps"],"cancers":["nsclc"],"sections":[],"technologies":["cgp","tmb-testing","wes-wgs","checkpoint-inhibitor"],"targets":["pdl1","pd1","egfr","stk11"],"drugs":[],"companies":[],"institutions":["mskcc"],"pathways":["cancer-immunity-cycle","pd1-checkpoint"],"terms":["tmb","ngs","neoantigen","stk11-keap1"],"trials":[],"people":["matthew-hellmann"],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2018,"doi":"10.1200/JCO.2017.75.3384","pmid":"29337640","authors":"Rizvi H, Sanchez-Vega F, La K, et al.","paperType":"observational","findings":["Panel-based and exome-based mutation burden correlate at rho 0.86.","Durable benefit 38.6% above against 25.1% below the median burden.","Burden and PD-L1 expression are independent variables with similar predictive power.","EGFR and STK11 alterations predicted a lack of benefit."],"whatItMeans":"It made tumour mutational burden measurable in routine practice and, in the same stroke, showed it is a second axis alongside PD-L1 rather than a replacement for it.","caveats":["Retrospective and single centre.","A percentile cut-off is cohort-dependent and does not transfer to another panel.","Durable clinical benefit is a surrogate endpoint."],"changedPractice":false,"participants":240},"route":"/key-papers/paper-rizvi-targeted-ngs-immunotherapy-determinants-jco-2018/","neighbours":{"biomarker":[{"id":"pd-l1-tps","kind":"biomarker","name":"PD-L1 TPS (tumour proportion score)","route":"/biomarkers/pd-l1-tps/"},{"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":"cgp","kind":"technology","name":"Comprehensive genomic profiling","route":"/technologies/cgp/"},{"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":"egfr","kind":"target","name":"EGFR","route":"/targets/egfr/"},{"id":"pd1","kind":"target","name":"PD-1","route":"/targets/pd1/"},{"id":"pdl1","kind":"target","name":"PD-L1","route":"/targets/pdl1/"},{"id":"stk11","kind":"target","name":"STK11","route":"/targets/stk11/"}],"institution":[{"id":"mskcc","kind":"institution","name":"Memorial Sloan Kettering Cancer Center","route":"/institutions/mskcc/"}],"pathway":[{"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":"neoantigen","kind":"term","name":"Neoantigen","route":"/terms/neoantigen/"},{"id":"ngs","kind":"term","name":"Next-generation sequencing (NGS)","route":"/terms/ngs/"},{"id":"stk11-keap1","kind":"term","name":"STK11 / KEAP1 co-mutations","route":"/terms/stk11-keap1/"},{"id":"tmb","kind":"term","name":"Tumour mutational burden (TMB)","route":"/terms/tmb/"}],"person":[{"id":"matthew-hellmann","kind":"person","name":"Matthew D. Hellmann","route":"/people/matthew-hellmann/"}],"journal":[{"id":"jco","kind":"journal","name":"Journal of Clinical Oncology","route":"/journals/jco/"}]}}