{"entity":{"id":"paper-checkmate-649-lancet-2021","kind":"paper","name":"CheckMate 649: nivolumab plus chemotherapy as first treatment for advanced gastric, gastro-oesophageal junction and oesophageal adenocarcinoma","aka":[],"tldr":"Adding the immunotherapy nivolumab to first-line chemotherapy helped patients with advanced stomach and oesophageal adenocarcinoma live longer, especially when the tumour showed PD-L1, making chemo-immunotherapy the new standard.","summary":"Open-label phase 3 trial of 1,581 patients with untreated, HER2-negative advanced gastric, gastro-oesophageal junction or oesophageal adenocarcinoma randomised to nivolumab plus chemotherapy (XELOX or FOLFOX) or chemotherapy alone (a third arm tested nivolumab plus ipilimumab). Primary endpoints were OS and PFS in patients with PD-L1 combined positive score (CPS) of 5 or more.\n\nIn CPS 5 or more, median OS was 14.4 vs 11.1 months (HR 0.71) and PFS 7.7 vs 6.0 months (HR 0.68); in all randomised patients OS was 13.8 vs 11.6 months (HR 0.80). It was the first immunotherapy to improve first-line survival in gastric cancer and it made PD-L1 CPS testing standard, though regulators disagreed about the CPS threshold for use.","asOf":"2026-09-08","links":[{"label":"PubMed search: CheckMate 649 Lancet 2021","url":"https://pubmed.ncbi.nlm.nih.gov/?term=CheckMate+649+nivolumab+chemotherapy+gastric+Janjigian+Lancet+2021"},{"label":"ClinicalTrials.gov NCT02872116","url":"https://clinicaltrials.gov/study/NCT02872116"}],"tags":[],"related":[],"cancers":["gastric","esophageal"],"sections":[],"technologies":["checkpoint-inhibitor","cytotoxic-chemotherapy","platinum"],"targets":["pd1","pdl1"],"drugs":["nivolumab","ipilimumab"],"companies":["bms"],"institutions":["mskcc"],"pathways":[],"terms":["cps","os","pfs","first-line","msi"],"trials":[],"people":["yelena-janjigian","shitara-kohei","shen-lin"],"bottlenecks":["b-biomarker-validation","b-immunotherapy-response","b-regulatory-fragmentation"],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2021,"doi":"10.1016/S0140-6736(21)00797-2","pmid":"34102137","authors":"Janjigian YY, Shitara K, Moehler M, et al.","paperType":"rct","findings":["CPS 5 or more: median OS 14.4 vs 11.1 months, HR 0.71 (98.4% CI 0.59-0.86); median PFS 7.7 vs 6.0 months, HR 0.68.","All randomised patients: median OS 13.8 vs 11.6 months, HR 0.80 (99.3% CI 0.68-0.94).","Objective response in CPS 5 or more: 60% vs 45%.","Exploratory analysis showed little benefit in CPS below 5, and the EMA restricted the label to CPS 5 or more while the FDA initially approved it regardless of PD-L1 (later narrowed to CPS 1 or more).","Grade 3-4 treatment-related adverse events 59% vs 44%."],"whatItMeans":"Patients with newly diagnosed advanced stomach or oesophageal adenocarcinoma whose tumour is HER2-negative and PD-L1 positive (CPS 5 or more, or at least 1 in some regions) should receive chemotherapy with nivolumab (or pembrolizumab, from KEYNOTE-859), which adds about three months of median survival and doubles the chance of being alive at three years. The benefit in PD-L1-negative tumours is doubtful, and these patients may be better served by chemotherapy alone or by trials.","caveats":["Benefit is concentrated in PD-L1-positive tumours; the ITT result is driven by the CPS 5 or more subgroup.","Open-label design; CPS scoring reproducibility is imperfect.","Microsatellite-instability-high tumours (about 3%) derived very large benefit and inflate pooled estimates.","The nivolumab plus ipilimumab chemotherapy-free arm failed to improve OS."],"changedPractice":true,"participants":1581},"route":"/key-papers/paper-checkmate-649-lancet-2021/","neighbours":{"cancer":[{"id":"gastric","kind":"cancer","name":"Gastric & gastro-oesophageal junction cancer","route":"/cancers/gastric/"},{"id":"oesophageal-adenocarcinoma","kind":"cancer","name":"Oesophageal and junctional adenocarcinoma","route":"/cancers/oesophageal-adenocarcinoma/"},{"id":"esophageal","kind":"cancer","name":"Oesophageal cancer","route":"/cancers/esophageal/"},{"id":"gastric-pdl1-high","kind":"cancer","name":"PD-L1-high gastric cancer","route":"/cancers/gastric-pdl1-high/"}],"technology":[{"id":"cytotoxic-chemotherapy","kind":"technology","name":"Cytotoxic chemotherapy","route":"/technologies/cytotoxic-chemotherapy/"},{"id":"checkpoint-inhibitor","kind":"technology","name":"Immune checkpoint inhibitors","route":"/technologies/checkpoint-inhibitor/"},{"id":"platinum","kind":"technology","name":"Platinum agents","route":"/technologies/platinum/"}],"target":[{"id":"pd1","kind":"target","name":"PD-1","route":"/targets/pd1/"},{"id":"pdl1","kind":"target","name":"PD-L1","route":"/targets/pdl1/"}],"drug":[{"id":"ipilimumab","kind":"drug","name":"Ipilimumab","route":"/drugs/ipilimumab/"},{"id":"nivolumab","kind":"drug","name":"Nivolumab","route":"/drugs/nivolumab/"}],"company":[{"id":"bms","kind":"company","name":"Bristol Myers Squibb","route":"/companies/bms/"}],"institution":[{"id":"mskcc","kind":"institution","name":"Memorial Sloan Kettering Cancer Center","route":"/institutions/mskcc/"}],"term":[{"id":"cps","kind":"term","name":"Combined positive score (CPS)","route":"/terms/cps/"},{"id":"first-line","kind":"term","name":"Lines of therapy","route":"/terms/first-line/"},{"id":"msi","kind":"term","name":"Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)","route":"/terms/msi/"},{"id":"os","kind":"term","name":"Overall survival (OS)","route":"/terms/os/"},{"id":"pfs","kind":"term","name":"Progression-free survival (PFS)","route":"/terms/pfs/"}],"person":[{"id":"jaffer-ajani","kind":"person","name":"Jaffer A. Ajani","route":"/people/jaffer-ajani/"},{"id":"shitara-kohei","kind":"person","name":"Kohei Shitara","route":"/people/shitara-kohei/"},{"id":"shen-lin","kind":"person","name":"Lin Shen","route":"/people/shen-lin/"},{"id":"yelena-janjigian","kind":"person","name":"Yelena Y. Janjigian","route":"/people/yelena-janjigian/"}],"bottleneck":[{"id":"b-biomarker-validation","kind":"bottleneck","name":"Biomarkers are not validated or standardised","route":"/bottlenecks/b-biomarker-validation/"},{"id":"b-immunotherapy-response","kind":"bottleneck","name":"No one can predict who responds to immunotherapy","route":"/bottlenecks/b-immunotherapy-response/"},{"id":"b-regulatory-fragmentation","kind":"bottleneck","name":"Regulatory divergence between regions","route":"/bottlenecks/b-regulatory-fragmentation/"}],"journal":[{"id":"lancet","kind":"journal","name":"The Lancet","route":"/journals/lancet/"}]}}