{"entity":{"id":"paper-le-pd1-blockade-mismatch-repair-deficiency-nejm-2015","kind":"paper","name":"PD-1 blockade in tumors with mismatch-repair deficiency","aka":[],"tldr":"Forty-one patients settled a decade of argument: colorectal cancers with a broken DNA spell-checker responded to immunotherapy in 40 percent of cases, and those without responded in none.","summary":"Le, Uram, Wang and colleagues conducted a phase 2 study of pembrolizumab at 10 mg per kilogram every 14 days in 41 patients with progressive metastatic carcinoma, in three cohorts: mismatch repair-deficient colorectal cancers, mismatch repair-proficient colorectal cancers, and mismatch repair-deficient cancers that were not colorectal. The co-primary end points were the immune-related objective response rate and the 20-week immune-related progression-free survival rate.\n\nWhole-exome sequencing showed a mean of 1,782 somatic mutations per tumour in mismatch repair-deficient tumours against 73 in proficient ones (p=0.007), and high somatic mutation loads were associated with prolonged progression-free survival (p=0.02).","asOf":"2026-09-24","links":[{"label":"N Engl J Med 2015","url":"https://doi.org/10.1056/NEJMoa1500596"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/26028255/"},{"label":"Europe PMC full text (PMC4481136)","url":"https://europepmc.org/article/MED/26028255"}],"tags":["colorectal-evidence"],"related":["paper-le-mismatch-repair-deficiency-pd1-solid-tumours-science-2017","paper-andre-keynote-177-pembrolizumab-msi-high-nejm-2020"],"cancers":["colorectal","msi-high-colorectal"],"sections":["immunotherapy"],"technologies":["checkpoint-inhibitor","wes-wgs"],"targets":["pd1"],"drugs":["pembrolizumab"],"companies":["merck"],"institutions":["johns-hopkins"],"pathways":[],"terms":["msi","mmr","tumour-agnostic","neoantigen"],"trials":[],"people":["dung-le","luis-diaz","bert-vogelstein","kenneth-kinzler"],"bottlenecks":["b-immunotherapy-response"],"keyPapers":[],"journals":["nejm"],"dependsOn":[],"notes":[],"journal":"New England Journal of Medicine","year":2015,"doi":"10.1056/NEJMoa1500596","pmid":"26028255","authors":"Le DT, Uram JN, Wang H, et al.","paperType":"rct","findings":["Immune-related objective response 40 percent (4 of 10) and 20-week progression-free survival 78 percent (7 of 9) in mismatch repair-deficient colorectal cancer.","0 percent (0 of 18) and 11 percent (2 of 18) in mismatch repair-proficient colorectal cancer.","Median progression-free and overall survival not reached in the deficient cohort against 2.2 and 5.0 months in the proficient cohort (hazard ratios 0.10, p<0.001, and 0.22, p=0.05).","In mismatch repair-deficient non-colorectal cancers, response 71 percent (5 of 7).","Mean 1,782 somatic mutations per tumour in deficient against 73 in proficient tumours (p=0.007)."],"whatItMeans":"The paper that split colorectal cancer into two diseases for immunotherapy purposes, and the direct ancestor of the first tumour-agnostic drug approval two years later.","caveats":["Ten patients in the key cohort; the effect size is large but the estimate is not precise.","Single-arm phase 2 with immune-related response criteria rather than standard RECIST.","It said nothing about how to treat the 95 percent of metastatic colorectal cancers that are mismatch repair-proficient, and that question is still open."],"changedPractice":true,"participants":41},"route":"/key-papers/paper-le-pd1-blockade-mismatch-repair-deficiency-nejm-2015/","neighbours":{"paper":[{"id":"paper-bullock-botensilimab-balstilimab-mss-colorectal-nat-med-2024","kind":"paper","name":"Botensilimab plus balstilimab in relapsed/refractory microsatellite stable metastatic colorectal cancer: a phase 1 trial","route":"/key-papers/paper-bullock-botensilimab-balstilimab-mss-colorectal-nat-med-2024/"},{"id":"paper-le-mismatch-repair-deficiency-pd1-solid-tumours-science-2017","kind":"paper","name":"Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade","route":"/key-papers/paper-le-mismatch-repair-deficiency-pd1-solid-tumours-science-2017/"},{"id":"paper-andre-keynote-177-pembrolizumab-msi-high-nejm-2020","kind":"paper","name":"Pembrolizumab in microsatellite-instability-high advanced colorectal cancer (KEYNOTE-177)","route":"/key-papers/paper-andre-keynote-177-pembrolizumab-msi-high-nejm-2020/"}],"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":"checkpoint-inhibitor","kind":"technology","name":"Immune checkpoint inhibitors","route":"/technologies/checkpoint-inhibitor/"},{"id":"wes-wgs","kind":"technology","name":"Whole-exome & whole-genome sequencing","route":"/technologies/wes-wgs/"}],"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/"}],"institution":[{"id":"johns-hopkins","kind":"institution","name":"Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center","route":"/institutions/johns-hopkins/"}],"term":[{"id":"msi","kind":"term","name":"Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)","route":"/terms/msi/"},{"id":"neoantigen","kind":"term","name":"Neoantigen","route":"/terms/neoantigen/"},{"id":"tumour-agnostic","kind":"term","name":"Tumour-agnostic (tissue-agnostic) approval","route":"/terms/tumour-agnostic/"}],"person":[{"id":"bert-vogelstein","kind":"person","name":"Bert Vogelstein","route":"/people/bert-vogelstein/"},{"id":"dung-le","kind":"person","name":"Dung T. Le","route":"/people/dung-le/"},{"id":"kenneth-kinzler","kind":"person","name":"Kenneth W. Kinzler","route":"/people/kenneth-kinzler/"},{"id":"luis-diaz","kind":"person","name":"Luis A. Diaz Jr.","route":"/people/luis-diaz/"}],"bottleneck":[{"id":"b-immunotherapy-response","kind":"bottleneck","name":"No one can predict who responds to immunotherapy","route":"/bottlenecks/b-immunotherapy-response/"}],"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/"}],"idea":[{"id":"idea-crc-mss-immunotherapy-by-biomarker-not-by-line","kind":"idea","name":"Select microsatellite stable patients for immunotherapy by a measured immune biomarker, not by how many treatments they have already failed","route":"/ideas/idea-crc-mss-immunotherapy-by-biomarker-not-by-line/"}]}}