{"entity":{"id":"paper-keynote-177-nejm-2020","kind":"paper","name":"KEYNOTE-177: pembrolizumab instead of chemotherapy as first treatment for mismatch-repair-deficient metastatic colorectal cancer","aka":[],"tldr":"For the roughly 5% of metastatic bowel cancers with defective DNA mismatch repair, pembrolizumab alone lengthened the time without progression compared with chemotherapy, with far fewer severe side effects, and 83% of responses lasted two years or more. It made first-line pembrolizumab the standard for this group.","summary":"Open-label phase 3 trial of 307 patients with untreated microsatellite-instability-high or mismatch-repair-deficient metastatic colorectal cancer randomised to pembrolizumab or investigator's choice chemotherapy (FOLFOX or FOLFIRI with or without bevacizumab or cetuximab). Primary endpoints were PFS and OS.\n\nMedian PFS was 16.5 vs 8.2 months (HR 0.60), with 43.8% vs 33.1% responding and 83% vs 35% of responses lasting two years or more. Overall survival was not significantly different (HR 0.74) because 60% of chemotherapy patients crossed over to immunotherapy. It made first-line pembrolizumab the standard for dMMR metastatic colorectal cancer and cemented mismatch repair testing for every colorectal cancer.","asOf":"2026-09-08","links":[{"label":"NEJM 2020","url":"https://doi.org/10.1056/NEJMoa2017699"},{"label":"ClinicalTrials.gov NCT02563002","url":"https://clinicaltrials.gov/study/NCT02563002"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/33264544/"},{"label":"Five-year follow-up (Ann Oncol 2024)","url":"https://www.annalsofoncology.org/article/S0923-7534(24)04949-4/fulltext"}],"tags":[],"related":["msi-high","dmmr-ihc","paper-le-mmr-deficiency-pd1-nejm-2015","paper-andre-checkmate-8hw-nivolumab-ipilimumab-nejm-2024"],"cancers":["colorectal","msi-high-colorectal"],"sections":["immunotherapy"],"technologies":["checkpoint-inhibitor","histopathology-ihc","msi-mmr-testing"],"targets":["pd1","mmr"],"drugs":["pembrolizumab"],"companies":["merck"],"institutions":[],"pathways":["mismatch-repair-msi","pd1-checkpoint"],"terms":["msi","pfs","os","first-line","tmb","tumour-agnostic","mmr"],"trials":["keynote-177"],"people":["kim-tae-won","elena-elez","dung-le","yoshino-takayuki","luis-diaz","thierry-andre","eric-van-cutsem"],"bottlenecks":["b-immunotherapy-response","b-trial-design","b-biomarker-validation"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2020,"doi":"10.1056/NEJMoa2017699","pmid":"33264544","authors":"Andre T, Shiu KK, Kim TW, et al.","paperType":"rct","findings":["Median PFS 16.5 vs 8.2 months; HR 0.60 (95% CI 0.45-0.80); 24-month PFS 48.3% vs 18.6%.","Objective response 43.8% vs 33.1%; complete response 11% vs 4%.","Grade 3 or higher treatment-related adverse events 22% vs 66%.","Overall survival (Lancet Oncology 2022): HR 0.74 (95% CI 0.53-1.03), not significant; median 77.5 vs 36.7 months; 60% of chemotherapy patients received subsequent anti-PD-1 therapy.","PFS curves crossed early: about 29% of pembrolizumab patients progressed by 4 months, suggesting a subgroup of primary resistance."],"whatItMeans":"Every colorectal cancer should be tested for mismatch repair deficiency, because patients whose metastatic tumour is dMMR should receive pembrolizumab rather than chemotherapy as first treatment, gaining a much better chance of durable remission with fewer side effects. About a third of dMMR tumours do not respond initially, so early scans are essential and chemotherapy remains available. The trial does not apply to the 95% of metastatic colorectal cancers that are mismatch-repair proficient (the deficient share is higher in localised disease, about 15%).","caveats":["OS was not significantly improved, mostly because of crossover; the design makes an OS benefit unprovable.","Early crossing of the PFS curves indicates a group with rapid progression on immunotherapy who might be better served by combinations (nivolumab plus ipilimumab in CheckMate 8HW).","Open-label design and a heterogeneous chemotherapy control arm.","Immunohistochemistry and PCR for mismatch repair can disagree; misclassification of pMMR tumours as dMMR leads to ineffective treatment."],"changedPractice":true,"participants":307},"route":"/key-papers/paper-keynote-177-nejm-2020/","neighbours":{"biomarker":[{"id":"dmmr-ihc","kind":"biomarker","name":"dMMR (mismatch repair deficiency by IHC)","route":"/biomarkers/dmmr-ihc/"},{"id":"msi-high","kind":"biomarker","name":"MSI-high (microsatellite instability by PCR or sequencing)","route":"/biomarkers/msi-high/"}],"paper":[{"id":"paper-le-mmr-deficiency-pd1-nejm-2015","kind":"paper","name":"Le 2015: PD-1 blockade works in tumours with mismatch-repair deficiency, whatever the organ","route":"/key-papers/paper-le-mmr-deficiency-pd1-nejm-2015/"},{"id":"paper-andre-checkmate-8hw-nivolumab-ipilimumab-nejm-2024","kind":"paper","name":"Nivolumab plus ipilimumab in microsatellite-instability-high metastatic colorectal cancer (CheckMate 8HW)","route":"/key-papers/paper-andre-checkmate-8hw-nivolumab-ipilimumab-nejm-2024/"}],"cancer":[{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"},{"id":"msi-high-colorectal","kind":"cancer","name":"Mismatch-repair deficient (MSI-high) colorectal cancer","route":"/cancers/msi-high-colorectal/"}],"section":[{"id":"immunotherapy","kind":"section","name":"Immunotherapy","route":"/fronts/immunotherapy/"}],"technology":[{"id":"histopathology-ihc","kind":"technology","name":"Histopathology & immunohistochemistry","route":"/technologies/histopathology-ihc/"},{"id":"checkpoint-inhibitor","kind":"technology","name":"Immune checkpoint inhibitors","route":"/technologies/checkpoint-inhibitor/"},{"id":"msi-mmr-testing","kind":"technology","name":"MSI and mismatch-repair testing","route":"/technologies/msi-mmr-testing/"}],"target":[{"id":"mmr","kind":"target","name":"Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2)","route":"/targets/mmr/"},{"id":"pd1","kind":"target","name":"PD-1","route":"/targets/pd1/"}],"drug":[{"id":"pembrolizumab","kind":"drug","name":"Pembrolizumab","route":"/drugs/pembrolizumab/"}],"company":[{"id":"merck","kind":"company","name":"Merck & Co. (MSD)","route":"/companies/merck/"}],"pathway":[{"id":"mismatch-repair-msi","kind":"pathway","name":"Mismatch repair & microsatellite instability","route":"/pathways/mismatch-repair-msi/"},{"id":"pd1-checkpoint","kind":"pathway","name":"PD-1 / PD-L1 immune checkpoint & T-cell activation","route":"/pathways/pd1-checkpoint/"}],"term":[{"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/"},{"id":"tmb","kind":"term","name":"Tumour mutational burden (TMB)","route":"/terms/tmb/"},{"id":"tumour-agnostic","kind":"term","name":"Tumour-agnostic (tissue-agnostic) approval","route":"/terms/tumour-agnostic/"}],"trial":[{"id":"keynote-177","kind":"trial","name":"KEYNOTE-177","route":"/trials/keynote-177/"}],"person":[{"id":"dung-le","kind":"person","name":"Dung T. Le","route":"/people/dung-le/"},{"id":"elena-elez","kind":"person","name":"Elena Élez","route":"/people/elena-elez/"},{"id":"eric-van-cutsem","kind":"person","name":"Eric Van Cutsem","route":"/people/eric-van-cutsem/"},{"id":"luis-diaz","kind":"person","name":"Luis A. Diaz Jr.","route":"/people/luis-diaz/"},{"id":"kim-tae-won","kind":"person","name":"Tae Won Kim","route":"/people/kim-tae-won/"},{"id":"yoshino-takayuki","kind":"person","name":"Takayuki Yoshino","route":"/people/yoshino-takayuki/"},{"id":"thierry-andre","kind":"person","name":"Thierry André","route":"/people/thierry-andre/"}],"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-trial-design","kind":"bottleneck","name":"Trial design, endpoints and cost","route":"/bottlenecks/b-trial-design/"}],"journal":[{"id":"nejm","kind":"journal","name":"New England Journal of Medicine","route":"/journals/nejm/"}],"roadmap":[{"id":"colorectal-roadmap","kind":"roadmap","name":"Colorectal cancer roadmap: from the adenoma-carcinoma sequence and the first screening trials to total mesorectal excision, oxaliplatin, RAS testing, immunotherapy for mismatch repair-deficient disease, ctDNA-guided treatment and organ preservation","route":"/roadmaps/colorectal-roadmap/"}]}}