{"entity":{"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","aka":[],"tldr":"Across 86 patients with 12 different dMMR cancers, pembrolizumab produced responses in 53% and complete responses in 21%, prompting the first approval of a cancer drug based on a genetic marker rather than tumour site.","summary":"Extending the 2015 study, this report treated 86 patients with treatment-refractory, mismatch-repair-deficient cancers of 12 types (colorectal, endometrial, gastric, biliary, pancreatic, small bowel and others) with pembrolizumab. The objective response rate was 53% (46 of 86) with complete responses in 21% (18); disease control was 77%, and neither median PFS nor OS had been reached at a median follow-up of 12.5 months. Responses were seen in every tumour type. Functional analysis showed rapid in vivo expansion of neoantigen-specific T-cell clones. The FDA approved pembrolizumab for any unresectable or metastatic MSI-H/dMMR solid tumour in May 2017, the first tissue-agnostic cancer drug approval, and the randomised KEYNOTE-177 trial later confirmed first-line benefit in dMMR colorectal cancer (median PFS 16.5 versus 8.2 months).","asOf":"2026-09-08","links":[{"label":"Full text (DOI)","url":"https://doi.org/10.1126/science.aan6733"},{"label":"ClinicalTrials.gov NCT01876511","url":"https://clinicaltrials.gov/study/NCT01876511"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/28596308/"},{"label":"Europe PMC full text (PMC5576142)","url":"https://europepmc.org/article/MED/28596308"}],"tags":[],"related":["paper-le-mmr-deficiency-pd1-nejm-2015","paper-niche-2-nejm-2024","msi-high","dmmr-ihc","paper-keynote-158-pembrolizumab-msi-high-noncolorectal-jco-2020"],"cancers":["colorectal","pancreatic","msi-high-colorectal"],"sections":["immunotherapy"],"technologies":["checkpoint-inhibitor","msi-mmr-testing"],"targets":["pd1","mmr"],"drugs":["pembrolizumab","nivolumab","dostarlimab"],"companies":[],"institutions":["johns-hopkins"],"pathways":["mismatch-repair-msi"],"terms":["msi","tumour-agnostic","neoantigen","tmb","mmr"],"trials":["keynote-177","checkmate-8hw"],"people":["dung-le","luis-diaz"],"bottlenecks":["b-regulatory-fragmentation","b-biomarker-validation","b-immunotherapy-response","b-rare-cancers"],"keyPapers":[],"journals":["science"],"dependsOn":[],"notes":[],"journal":"Science","year":2017,"doi":"10.1126/science.aan6733","pmid":"28596308","authors":"Le DT, Durham JN, Smith KN, et al.","paperType":"translational","findings":["86 patients with dMMR cancers of 12 types; pembrolizumab 10 mg/kg every 2 weeks.","Objective response 53% (46 of 86); complete response 21% (18 of 86); disease control 77%.","Median PFS and OS not reached at 12.5 months median follow-up; responses in all 12 tumour types.","Neoantigen-specific T-cell clones expanded in blood within weeks of starting therapy.","Estimated that dMMR occurs in about 4% of advanced cancers, roughly 60,000 patients a year in the United States."],"whatItMeans":"This paper established a new regulatory paradigm: a drug approved for a molecular feature regardless of organ. It made MSI/MMR testing standard across advanced cancers and remains the clearest example of a biomarker that works across histologies. It also anchored the idea that mutation load, via neoantigens, is what makes tumours visible to T cells.","caveats":["Single-arm basket study; approvals rested on response rate and durability.","Heterogeneous prior therapies and tumour types; small numbers per type.","Roughly a quarter of dMMR tumours are primary resistant, and mechanisms (B2M loss, JAK mutations) are incompletely understood.","Later data suggest sensitivity varies by MSI assay and tumour type (for example, lower in some dMMR pancreatic and brain tumours)."],"changedPractice":true,"participants":86},"route":"/key-papers/paper-le-mmr-deficiency-science-2017/","neighbours":{"paper":[{"id":"paper-keynote-158-pembrolizumab-msi-high-noncolorectal-jco-2020","kind":"paper","name":"KEYNOTE-158: pembrolizumab in non-colorectal high microsatellite instability or mismatch repair-deficient cancer","route":"/key-papers/paper-keynote-158-pembrolizumab-msi-high-noncolorectal-jco-2020/"},{"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-niche-2-nejm-2024","kind":"paper","name":"NICHE-2: a month of nivolumab and ipilimumab before surgery clears mismatch-repair-deficient colon cancer in most patients","route":"/key-papers/paper-niche-2-nejm-2024/"}],"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/"}],"cancer":[{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"},{"id":"gastric-msi-high","kind":"cancer","name":"Microsatellite-unstable (MSI-high) gastric cancer","route":"/cancers/gastric-msi-high/"},{"id":"msi-high-pdac","kind":"cancer","name":"Mismatch repair deficient (MSI-high) pancreatic ductal adenocarcinoma","route":"/cancers/msi-high-pdac/"},{"id":"msi-high-colorectal","kind":"cancer","name":"Mismatch-repair deficient (MSI-high) colorectal cancer","route":"/cancers/msi-high-colorectal/"},{"id":"pancreatic","kind":"cancer","name":"Pancreatic ductal adenocarcinoma","route":"/cancers/pancreatic/"}],"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/"}],"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":"dostarlimab","kind":"drug","name":"Dostarlimab","route":"/drugs/dostarlimab/"},{"id":"nivolumab","kind":"drug","name":"Nivolumab","route":"/drugs/nivolumab/"},{"id":"pembrolizumab","kind":"drug","name":"Pembrolizumab","route":"/drugs/pembrolizumab/"}],"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/"}],"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":"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":"checkmate-8hw","kind":"trial","name":"CheckMate 8HW","route":"/trials/checkmate-8hw/"},{"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":"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/"},{"id":"b-rare-cancers","kind":"bottleneck","name":"Rare and paediatric cancers without markets","route":"/bottlenecks/b-rare-cancers/"},{"id":"b-regulatory-fragmentation","kind":"bottleneck","name":"Regulatory divergence between regions","route":"/bottlenecks/b-regulatory-fragmentation/"}],"journal":[{"id":"science","kind":"journal","name":"Science","route":"/journals/science/"}],"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/"}]}}