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We conducted a single-arm phase 2 study of nivolumab in 35 patients with dMMR uterine or ovarian cancers. Co-primary endpoints included objective response rate (ORR) and progression-free survival at 24\u2009weeks (PFS24). Secondary endpoints included overall survival (OS), disease control rate (DCR), duration of response (DOR) and safety. Exploratory endpoints included biomarkers and molecular correlates of response. The ORR was 58.8% (97.5% confidence interval (CI): 40.7\u2013100%), and the PFS24 rate was 64.7% (97.5% one-sided CI: 46.5\u2013100%), meeting the pre-specified endpoints. The DCR was 73.5% (95% CI: 55.6\u201387.1%). At the median follow-up of 42.1\u2009months (range, 8.9\u201359.8\u2009months), median OS was not reached. One-year OS rate was 79% (95% CI: 60.9\u201389.4%). Thirty-two patients (91%) had a treatment-related adverse event (TRAE), including arthralgia (<jats:italic>n<\/jats:italic>\u2009=\u200910, 29%), fatigue (<jats:italic>n<\/jats:italic>\u2009=\u200910, 29%), pain (<jats:italic>n<\/jats:italic>\u2009=\u200910, 29%) and pruritis (<jats:italic>n<\/jats:italic>\u2009=\u200910, 29%); most were grade 1 or grade 2. Ten patients (29%) reported a grade 3 or grade 4 TRAE; no grade 5 events occurred. Exploratory analyses show that the presence of dysfunctional (CD8<jats:sup>+<\/jats:sup>PD-1<jats:sup>+<\/jats:sup>) or terminally dysfunctional (CD8<jats:sup>+<\/jats:sup>PD-1<jats:sup>+<\/jats:sup>TOX<jats:sup>+<\/jats:sup>) T cells and their interaction with programmed death ligand-1 (PD-L1)<jats:sup>+<\/jats:sup> cells were independently associated with PFS24. PFS24 was associated with presence of <jats:italic>MEGF8<\/jats:italic> or <jats:italic>SETD1B<\/jats:italic> somatic mutations. This trial met its co-primary endpoints (ORR and PFS24) early, and our findings highlight several genetic and tumor microenvironment parameters associated with response to PD-1 blockade in dMMR cancers, generating rationale for their validation in larger cohorts.<\/jats:p><jats:p>ClinicalTrials.gov identifier: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/classic.clinicaltrials.gov\/ct2\/show\/NCT03241745\">NCT03241745<\/jats:ext-link>.<\/jats:p>","DOI":"10.1038\/s41591-024-02942-7","type":"journal-article","created":{"date-parts":[[2024,4,23]],"date-time":"2024-04-23T10:02:23Z","timestamp":1713866543000},"page":"1330-1338","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Nivolumab for mismatch-repair-deficient or hypermutated gynecologic cancers: a phase 2 trial with biomarker analyses"],"prefix":"10.1038","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2621-8553","authenticated-orcid":false,"given":"Claire F.","family":"Friedman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beryl L.","family":"Manning-Geist","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qin","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tara","family":"Soumerai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aliya","family":"Holland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7694-8760","authenticated-orcid":false,"given":"Arnaud","family":"Da Cruz Paula","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3944-6803","authenticated-orcid":false,"given":"Hunter","family":"Green","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melih Arda","family":"Ozsoy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexia","family":"Iasonos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Travis","family":"Hollmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"Mario M.","family":"Leitao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer J.","family":"Mueller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vicky","family":"Makker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William P.","family":"Tew","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8217-4554","authenticated-orcid":false,"given":"Roisin E.","family":"O\u2019Cearbhaill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying L.","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria M.","family":"Rubinstein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiffany","family":"Troso-Sandoval","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart M.","family":"Lichtman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6070-2413","authenticated-orcid":false,"given":"Alison","family":"Schram","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chrisann","family":"Kyi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel N.","family":"Grisham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela","family":"Causa Andrieu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0477-1956","authenticated-orcid":false,"given":"E. 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A.I. reports consulting fees from Mylan. T.H. is currently employed by Bristol Myers Squibb and has received research funding from Calico Labs, Bristol Myers Squibb and PICI. M.M.L. reports research funding paid to the institution from KCI\/Acelity; ad hoc speaker for Intuitive Surgical; and advisory board participation for Johnson & Johnson\/Ethicon and Takeda. V.M. reports meeting\/travel support from Eisai and Merck; participation on data safety monitoring or advisory boards of Duality, Merck, Karyopharm, Exelexis, Eisai, Karyopharm, Bristol Myers Squibb, Clovis, Faeth Immunocore, Morphosys, AstraZeneca, Novartis, GlaxoSmithKline and Bayer (all uncompensated); and study support to the institution from Merck, Eisai, AztraZeneca, Faeth Immunocore, Karyopharm, Zymeworks, Duality, Clovis, Bayer and Takeda. R.E.O. reports personal fees from Tesaro\/GlaxoSmithKline, Regeneron, R-PHARM, Seattle Genetics, Fresenius Kabi, the Gynecologic Oncology Foundation, Bayer, Curio, Miltenyi, 2seventybio and Immunogen and Other from Hitech Health, all outside the submitted work. She is an uncompensated steering committee member for the PRIMA, Moonstone (Tesaro\/GlaxoSmithKline) and DUO-O (AstraZeneca) studies and an uncompensated advisor for Carina Biotech. Her institute receives funding for clinical research from Bayer\/Celgene\/Juno, Tesaro\/GlaxoSmithKline, Merck, the Ludwig Cancer Institute, AbbVie\/StemCentrx, Regeneron, TCR2 Therapeutics, Atara Biotherapeutics, MarkerTherapeutics, Syndax Pharmaceuticals, Genmab\/Seagen Therapeutics, Sellas Therapeutics, Genentech, Kite Pharma, Acrivon, Lyell Immunopharma and the Gynecologic Oncology Foundation. Y.L.L. reports institutional research funding from Repare Therapeutics, AstraZeneca and GlaxoSmithKline; honoraria from Total Health and Sarah Lawrence College; and travel\/meeting support by AstraZeneca, all outside the submitted work. M.M.R. reports research funding from Merk, Zentalis and AstraZeneca. A.S. reports advisory board participation with Relay Therapeutics, Mersana and Merus; consulting with Blueprint Bio and Flagship Pioneering; steering committee participation with Merus and Pfizer; research funding paid to the institution from AstraZeneca, ArQule, BeiGene\/Springworks, Black Diamond Therapeutics, Elevation Oncology, Kura, Eli Lilly, Merus, Northern Biologics, Pfizer, PMV Pharma, Relay, Repare Therapeutics, Revolution Medicine and Surface Oncology; and food and beverage from PUMA and Repare Therapeutics. C.K. reports grant funding from the Conquer Cancer Foundation; grant funding paid to the institution from Merus, Gritstone and Bristol Myers Squibb; and consulting fees from Scenic Immunology B.V. and OncLive. R.N.G. reports honoraria from GlaxoSmithKline, AstraZeneca, Natera, Springworks, Corcept, MJH and PER. C.A. reports clinical trial funding paid to the institution from AstraZeneca; consulting fees (advisory board) from Eisai\/Merck, Roche\/Genentech, AbbVie, AstraZeneca\/Merck and Repare Therapeutics; advisory board participation (uncompensated) for Blueprint Medicine; and leadership\/fiduciary roles for the GOG Foundation Board of Directors (travel cost reimbursement) and the NRG Oncology Board of Directors (uncompensated). B.W. reports a research grant from REPARE Therapeutics paid to the institution, outside the submitted work. M.L.H. reports advisory board participation at Aadi Bioscience, GlaxoSmithKline, Thrive Bioscience and Eli Lilly; an immediate family member who is employed by Sanofi; and service as a CME faculty speaker for Research to Practice. E.J.W. is a member of the Parker Institute for Cancer Immunotherapy, which supports research in the Wherry laboratory; an advisor for Danger Bio, Marengo, Janssen, NewLimit, Pluto Immunotherapeutics, Related Sciences, Santa Ana Bio, Synthekine and Surface Oncology; and is a founder of and holds stock in Surface Oncology, Danger Bio and Arsenal Biosciences. D.Z. reports institutional research support from AstraZeneca, Merck, Plexxikon, Synthekine and Genentech; consulting fees from AstraZeneca, Synthekine, Astellas, Tessa Therapeutics, Memgen, Celldex, Crown Biosciences, Hookipa Biotech, Kalivir, Xencor and GlaxoSmithKline; royalties from Merck; and stock options from Accurius Therapeutics, ImmunOS Therapeutics and Calidi Biotherapeutics, all outside the submitted work. The other authors do not have potential conflicts of interest to declare.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}