{"entity":{"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","aka":[],"tldr":"Pembrolizumab shrank tumours in 40% of colorectal and 71% of other cancers with faulty DNA mismatch repair, but in none with intact repair, tying immunotherapy response to mutation burden.","summary":"This investigator-initiated phase 2 study tested the hypothesis that tumours with defective DNA mismatch repair (dMMR), which accumulate thousands of mutations and neoantigens, would respond to PD-1 blockade. Forty-one patients with treatment-refractory metastatic cancer were enrolled in three cohorts: dMMR colorectal cancer, MMR-proficient colorectal cancer, and dMMR non-colorectal cancers, all treated with pembrolizumab 10 mg/kg every two weeks. Immune-related objective response rates were 40% (4 of 10) in dMMR colorectal cancer, 0% (0 of 18) in MMR-proficient colorectal cancer and 71% (5 of 7) in dMMR non-colorectal cancers; 20-week PFS was 78% versus 11% in the two colorectal cohorts. Whole-exome sequencing showed a mean of 1782 somatic mutations in dMMR versus 73 in proficient tumours, and higher mutation load correlated with longer PFS.","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1056/NEJMoa1500596"},{"label":"ClinicalTrials.gov NCT01876511","url":"https://clinicaltrials.gov/study/NCT01876511"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/26028255/"},{"label":"Europe PMC full text (PMC4481136)","url":"https://europepmc.org/article/MED/26028255"}],"tags":[],"related":["paper-le-mmr-deficiency-science-2017","paper-cercek-dostarlimab-rectal-nejm-2022","msi-high","dmmr-ihc","tmb-high","paper-keynote-177-nejm-2020"],"cancers":["colorectal","msi-high-colorectal"],"sections":["immunotherapy"],"technologies":["checkpoint-inhibitor","msi-mmr-testing","wes-wgs"],"targets":["pd1","mmr"],"drugs":["pembrolizumab"],"companies":["merck"],"institutions":["johns-hopkins"],"pathways":["mismatch-repair-msi","pd1-checkpoint","cancer-immunity-cycle"],"terms":["msi","tmb","neoantigen","tumour-agnostic","mss-pmmr","mmr"],"trials":[],"people":["dung-le","luis-diaz","drew-pardoll","bert-vogelstein","kenneth-kinzler"],"bottlenecks":["b-biomarker-validation","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":"translational","findings":["41 patients: 11 dMMR colorectal, 21 MMR-proficient colorectal, 9 dMMR non-colorectal; pembrolizumab 10 mg/kg every 2 weeks.","Immune-related objective response: 40% dMMR colorectal, 0% proficient colorectal, 71% dMMR non-colorectal.","Immune-related PFS at 20 weeks: 78% (dMMR colorectal) vs 11% (proficient colorectal).","Mean somatic mutations per tumour 1782 (dMMR) vs 73 (proficient); higher load associated with longer PFS.","Benefit occurred in both Lynch-syndrome and sporadic dMMR tumours."],"whatItMeans":"This small trial explained why colorectal cancer had seemed immune-resistant (most is MMR-proficient) and established the principle that a genomic feature, not the tissue of origin, can predict immunotherapy response. It led directly to the 2017 tissue-agnostic approval of pembrolizumab and to routine MMR/MSI testing of many cancers. Every patient with advanced dMMR cancer should now be considered for checkpoint blockade.","caveats":["Very small cohorts; response rates have wide confidence intervals.","Dose of 10 mg/kg is higher than later standard dosing.","Single-arm; no randomised comparison until KEYNOTE-177.","Mutation burden as a biomarker beyond dMMR has proved less clean than this data suggested."],"changedPractice":true,"participants":41},"route":"/key-papers/paper-le-mmr-deficiency-pd1-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-cercek-dostarlimab-rectal-nejm-2022","kind":"paper","name":"Cercek 2022: six months of dostarlimab alone made rectal cancer disappear in every patient with mismatch-repair deficiency","route":"/key-papers/paper-cercek-dostarlimab-rectal-nejm-2022/"},{"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","route":"/key-papers/paper-keynote-177-nejm-2020/"},{"id":"paper-le-mmr-deficiency-science-2017","kind":"paper","name":"Le 2017: mismatch-repair deficiency predicts response to PD-1 blockade across twelve tumour types, leading to the first tissue-agnostic drug approval","route":"/key-papers/paper-le-mmr-deficiency-science-2017/"}],"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/"},{"id":"tmb-high","kind":"biomarker","name":"TMB-high (tumour mutational burden >= 10 mutations per megabase)","route":"/biomarkers/tmb-high/"}],"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":"msi-mmr-testing","kind":"technology","name":"MSI and mismatch-repair testing","route":"/technologies/msi-mmr-testing/"},{"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/"}],"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/"},{"id":"cancer-immunity-cycle","kind":"pathway","name":"The cancer-immunity cycle","route":"/pathways/cancer-immunity-cycle/"}],"term":[{"id":"msi","kind":"term","name":"Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)","route":"/terms/msi/"},{"id":"mss-pmmr","kind":"term","name":"Microsatellite-stable (MSS) / mismatch-repair proficient (pMMR)","route":"/terms/mss-pmmr/"},{"id":"neoantigen","kind":"term","name":"Neoantigen","route":"/terms/neoantigen/"},{"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/"}],"person":[{"id":"bert-vogelstein","kind":"person","name":"Bert Vogelstein","route":"/people/bert-vogelstein/"},{"id":"drew-pardoll","kind":"person","name":"Drew M. Pardoll","route":"/people/drew-pardoll/"},{"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-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/"}],"journal":[{"id":"nejm","kind":"journal","name":"New England Journal of Medicine","route":"/journals/nejm/"}],"trial":[{"id":"checkmate-8hw","kind":"trial","name":"CheckMate 8HW","route":"/trials/checkmate-8hw/"},{"id":"keynote-177","kind":"trial","name":"KEYNOTE-177","route":"/trials/keynote-177/"},{"id":"niche-2","kind":"trial","name":"NICHE-2","route":"/trials/niche-2/"}],"idea":[{"id":"idea-immunotherapy-mss-crc","kind":"idea","name":"Making microsatellite-stable colorectal cancer immunotherapy-responsive","route":"/ideas/idea-immunotherapy-mss-crc/"},{"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/"}],"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/"}]}}