{"entity":{"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","aka":[],"tldr":"The follow-up that took the same test across 12 different cancers and found the same answer, producing the first drug approval in history based on a molecular feature rather than an organ.","summary":"Le, Durham, Smith and colleagues expanded the 2015 proof-of-concept study to evaluate PD-1 blockade in patients with advanced mismatch repair-deficient cancers across 12 different tumour types. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones reactive to mutant neopeptides found in the tumour.\n\nThe authors concluded that the large proportion of mutant neoantigens in mismatch repair-deficient cancers makes them sensitive to immune checkpoint blockade regardless of tissue of origin, the argument the United States Food and Drug Administration accepted in granting pembrolizumab its tissue-agnostic approval in May 2017.","asOf":"2026-09-24","links":[{"label":"Science 2017","url":"https://doi.org/10.1126/science.aan6733"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/28596308/"},{"label":"Europe PMC full text (PMC5576142)","url":"https://europepmc.org/article/MED/28596308"}],"tags":["colorectal-evidence"],"related":["paper-le-pd1-blockade-mismatch-repair-deficiency-nejm-2015","paper-keynote-158-pembrolizumab-msi-high-noncolorectal-jco-2020"],"cancers":["colorectal","msi-high-colorectal"],"sections":["immunotherapy"],"technologies":["checkpoint-inhibitor"],"targets":["pd1"],"drugs":["pembrolizumab"],"companies":[],"institutions":["johns-hopkins"],"pathways":[],"terms":["msi","mmr","tumour-agnostic","neoantigen"],"trials":[],"people":["dung-le","luis-diaz"],"bottlenecks":["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":["Objective radiographic responses in 53 percent of patients and complete responses in 21 percent, across 12 tumour types.","Responses were durable, with median progression-free and overall survival not reached.","Neoantigen-specific T cell clones reactive to mutant neopeptides expanded rapidly in vivo in a responding patient."],"whatItMeans":"The first tumour-agnostic approval, and the reason every patient with metastatic colorectal cancer has mismatch repair status tested regardless of where the tumour started.","caveats":["Single-arm across heterogeneous tumour types; the response rate mixes cancers with very different natural histories.","Mismatch repair testing quality determines who gets the drug, and immunohistochemistry, polymerase chain reaction and sequencing do not always agree.","Around half of mismatch repair-deficient tumours still do not respond, and why is not known."],"changedPractice":true},"route":"/key-papers/paper-le-mismatch-repair-deficiency-pd1-solid-tumours-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-pd1-blockade-mismatch-repair-deficiency-nejm-2015","kind":"paper","name":"PD-1 blockade in tumors with mismatch-repair deficiency","route":"/key-papers/paper-le-pd1-blockade-mismatch-repair-deficiency-nejm-2015/"}],"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/"}],"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/"}],"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":"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-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/"}],"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/"}]}}