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Clinical Trial
. 2025 Feb;6(2):253-258.
doi: 10.1038/s43018-024-00894-y. Epub 2025 Feb 20.

Pembrolizumab in microsatellite-instability-high and mismatch-repair-deficient advanced solid tumors: updated results of the KEYNOTE-158 trial

Aurelien Marabelle  1 , David M O'Malley  2   3 , Andrew E Hendifar  4 , Paolo A Ascierto  5 , Daniel Motola-Kuba  6 , Nicolas Penel  7 , Philippe A Cassier  8 , Giovanni Bariani  9 , Ana De Jesus-Acosta  10 , Toshihiko Doi  11 , Federico Longo  12 , Wilson H Miller Jr  13   14 , Do-Youn Oh  15   16 , Maya Gottfried  17 , Lili Yao  18 , Fan Jin  18 , Alexander Gozman  18 , Michele Maio  19   20
Affiliations
Clinical Trial

Pembrolizumab in microsatellite-instability-high and mismatch-repair-deficient advanced solid tumors: updated results of the KEYNOTE-158 trial

Aurelien Marabelle et al. Nat Cancer. 2025 Feb.

Abstract

The phase 2 trial KEYNOTE-158 ( NCT02628067 ) evaluated pembrolizumab in microsatellite-instability-high and mismatch-repair-deficient (MSI-H/dMMR) noncolorectal tumors. With 373 participants (95% with baseline MSI/dMMR documentation) and 4.5 years of follow-up, the primary endpoint of overall response rate was 33.8%. Secondary endpoints of duration of response, overall survival and progression-free survival were 63.2, 19.8 and 4.0 months, respectively. Grade ≥3 treatment-related adverse events occurred in 50 (13%) participants. These results further support pembrolizumab use in MSI-H/dMMR tumors.

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Conflict of interest statement

Competing interests: A.M.’s institution received financial support from MSD for the conduct of the KEYNOTE-158 study and other MSD-sponsored trials. His institution received drug supply from MSD for academic sponsored trials and also received a grant from the MSD Avenir Foundation for translational research not related to this study. A.M. benefitted from medical writing support from MSD for this manuscript preparation. D.M.O. reports receiving institutional grants from Abbvie, Advaxis Agenus, Alkermes, Aravive, Arcus Biosciences, AstraZeneca, BeiGene USA, Boston Biomedical, Bristol Myers Squibb, Clovis Oncology, Deciphera Pharma, Eisai, EMD Serono, Exelixis, Genentech, Genmab, GlaxoSmithKline, GOG Foundation, Hoffmann-La Roche, ImmunoGen, Incyte Corporation, IOVANCE Biotherapeutics, Karyopharm, Leap Therapeutics, Merck & Co, MSD, Mersana Therapeutics, Novartis, NovoCure, NRG Oncology, OncoC4, OncoQuest, Pfizer, Precision Therapeutics, Prelude Therapuetics, Regeneron Pharmaceuticals, RTOG, Rubius Therapeutics, SeaGen, Sutro Biopharma, SWOG, TESARO and Verastem and consulting fees from Abbvie, AdaptImmune, Agenus, Arquer Diagnostics, Arcus Biosciences, AstraZeneca, Atossa Therapeutics, Boston Biomedical, Cardiff Oncology, Celcuity, Clovis Oncology, Corcept Therapeutics, Duality Bio, Eisai, Exelixis, Genentech, Genelux, GlaxoSmithKline, GOG Foundation, Hoffmann-La Roche, ImmunoGen, Imvax, InterVenn, INXMED, IOVANCE Biotherapeutics, Janssen, Jazz Pharmaceutical, Laekna, Leap Therapeutics, Luzsana Biotechnology, Merck & Co., MSD, Mersana Therapeutics, Myriad, Novartis, NovoCure, OncoC4, Onconova, Regeneron Pharmaceuticals, RepImmune, R Pharm, Roche Diagnotics, SeaGen, Sorrento, Sutro Biopharma, Tarveda Therapeutics, Toray, Trillium, Umoja, Verastem, VBL Therapeutics, Vincerx Pharma, Xencor and Zentalis. A.E.H. reports receiving grants from Ipsen and NGM Biopharmaceuticals, travel expenses from Halozyme and consulting fees from Abbvie, Celgene, Eisai, Faraday Pharmaceuticals, Ipsen, Merus, Novartis, PANCAN, Perthera, Valar Labs and Varian Medical Systems. P.A.A. reports receiving grants from Bristol Myers Squibb, Pfizer/Array, Roche-Genentech and Sanofi, travel expenses from Bio-Al Health, Pfizer and RepImmune and consulting fees from Bayer, Bio-Al Health, Bristol Myers Squibb, Idera, Italfarmaco, Lunaphore, Medicenna, Merck Serono, MSD, Nektar, Novartis, Pierre Fabre, Pfizer/Array, RepImmune, Sandoz, Sanofi, Sun Pharma and ValoTx. D.M.-K. reports receiving travel expenses from AMGEN, AstraZeneca, Bayer, Merck, MSD, Novartis and Roche. N.P. reports grants from Bayer and travel expenses from Astellas Pharma and Janssen/Cilag. P.A.C. reports receiving grants from Astrazeneca, Abbvie, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Blueprint Medicines, Celgene, Eli Lilly, GlaxoSmithKline, Innate Pharma, Janssen, Loxo, MSD, Novartis, Plexxikon, Taiho Pharmaceutical, Toray Industries and Transgene, consulting fees from Bristol Myers Squibb/Celgene, Boehringer Ingelheim, Janssen Oncology and OSE Immunotherapeutics and travel expenses from OSE Immunotherapeutics and Roche. A.D.J.-A. reports receiving grants from AstraZeneca, Eli Lilly and Merck and consulting fees from MSD. T.D. reports receiving institutional grants from Abbvie, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharma, Daiichi Sankyo, Eisai, Eli Lilly, Janssen, Merck, Novartis, Pfizer, SHIONOGI, Sumitomo Dainippon and Taiho, consulting fees from Abbvie, A2 Health Care, Bayer, Chugai Pharma, KAKEN Pharma, KYOWA KIRIN, Noil Immune, Otsuka, PRA Health Science, Rakuten Medical, SHIONOGI, Sumitomo Dainippon, Taiho and Takeda and fees as a speaker from AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Ono Pharma and Rakuten Medical. F.L. reports speaker and/or advisory role fees from MSD, Bristol Myers Squibb, Lilly, Roche, Merck Serono, Amgen, Servier and Bayer. W.H.M.Jr. reports receiving institutional grants from Merck, CIHR, CRS, Terry Fox Research Institute, Samuel Waxman, Cancer Research Foundation and the Canadian Cancer Society Research Institute, consulting fees from Merck, BMS, Roche, GSK, Novartis, Amgen, Mylan, EMD Serono and Sanofi and fees as a speaker from McGill University, JGH, BMS, Merck, Roche, GSK, Novartis, Amgen, Mylan EMD Serono and Sanofi. D.-Y.O. reports receiving institutional grants from AstraZeneca, Novartis, Array, Eli Lilly, Servier, BeiGene, MSD and Handok. L.Y. is an employee of MSD. F.J. and M.G. are employees of MSD and stockholders of Merck & Co. M.M. reports being an advisor or board member for Roche, Bristol Myers Squibb, MSD, Incyte, AstraZeneca, Amgen, Pierre Fabre, Eli Lilly, GlaxoSmithKline, Sanofi, Alfasigma and Merck Serono, receiving honoraria for Roche, Bristol Myers Squibb, MSD, AstraZeneca, Amgen, Pierre Fabre, Eli Lilly, GlaxoSmithKline, Sciclone, Sanofi, Alfasigma and Merck Serono and owning stock in Epigen Therapeutics and Theravance.

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