PMID- 35680043 OWN - NLM STAT- MEDLINE DCOM- 20220913 LR - 20220915 IS - 1569-8041 (Electronic) IS - 0923-7534 (Linking) VI - 33 IP - 9 DP - 2022 Sep TI - Pembrolizumab in microsatellite instability high or mismatch repair deficient cancers: updated analysis from the phase II KEYNOTE-158 study. PG - 929-938 LID - S0923-7534(22)01720-3 [pii] LID - 10.1016/j.annonc.2022.05.519 [doi] AB - BACKGROUND: Pembrolizumab demonstrated durable antitumor activity in 233 patients with previously treated advanced microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) advanced solid tumors in the phase II multicohort KEYNOTE-158 (NCT02628067) study. Herein, we report safety and efficacy outcomes with longer follow-up for more patients with previously treated advanced MSI-H/dMMR noncolorectal cancers who were included in cohort K of the KEYNOTE-158 (NCT02628067) study. PATIENTS AND METHODS: Eligible patients with previously treated advanced noncolorectal MSI-H/dMMR solid tumors, measurable disease as per RECIST v1.1, and Eastern Cooperative Oncology Group performance status of 0 or 1 received pembrolizumab 200 mg Q3W for 35 cycles or until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) as per RECIST v1.1 by independent central radiologic review. RESULTS: Three hundred and fifty-one patients with various tumor types were enrolled in KEYNOTE-158 cohort K. The most common tumor types were endometrial (22.5%), gastric (14.5%), and small intestine (7.4%). Median time from first dose to database cut-off (5 October 2020) was 37.5 months (range, 0.2-55.6 months). ORR among 321 patients in the efficacy population (patients who received >/=1 dose of pembrolizumab enrolled >/=6 months before the data cut-off date) was 30.8% [95% confidence interval (CI) 25.8% to 36.2%]. Median duration of response was 47.5 months (range, 2.1+ to 51.1+ months; '+' indicates no progressive disease by the time of last disease assessment). Median progression-free survival was 3.5 months (95% CI 2.3-4.2 months) and median overall survival was 20.1 months (95% CI 14.1-27.1 months). Treatment-related adverse events (AEs) occurred in 227 patients (64.7%). Grade 3-4 treatment-related AEs occurred in 39 patients (11.1%); 3 (0.9%) had grade 5 treatment-related AEs (myocarditis, pneumonia, and Guillain-Barre syndrome, n = 1 each). CONCLUSIONS: Pembrolizumab demonstrated clinically meaningful and durable benefit, with a high ORR of 30.8%, long median duration of response of 47.5 months, and manageable safety across a range of heavily pretreated, advanced MSI-H/dMMR noncolorectal cancers, providing support for use of pembrolizumab in this setting. CI - Copyright (c) 2022 Merck Sharp & Dohme Corp., a subsidiary Merck & Co., Inc.,, The Author(s). Published by Elsevier Ltd.. All rights reserved. FAU - Maio, M AU - Maio M AD - University of Siena and Center for Immuno-Oncology, Department of Oncology, University Hospital, Siena, Italy. Electronic address: maio@unisi.it. FAU - Ascierto, P A AU - Ascierto PA AD - Unit of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori Istituto di Ricovero e Cura a Carattere Scientifico Fondazione Pascale, Naples, Italy. FAU - Manzyuk, L AU - Manzyuk L AD - Outpatient Medical Treatment Department, NN Blokhin National Medical Research Center of Oncology, Moscow, Russia. FAU - Motola-Kuba, D AU - Motola-Kuba D AD - COMOP A.C., Clinical Investigation, Mexico City, Mexico. FAU - Penel, N AU - Penel N AD - Medical Oncology Department, Centre Oscar Lambret and Lille University, Lille, France. FAU - Cassier, P A AU - Cassier PA AD - Department of Medical Oncology, Centre Leon Berard, Lyon, France. FAU - Bariani, G M AU - Bariani GM AD - Department of Radiology and Oncology, Instituto do Cancer do Estado de Sao Paulo, Universidade de Sao Paulo, Sao Paulo, Brazil. FAU - De Jesus Acosta, A AU - De Jesus Acosta A AD - Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, USA. FAU - Doi, T AU - Doi T AD - Experimental Therapeutics, National Cancer Center Hospital East, Kashiwa, Japan. FAU - Longo, F AU - Longo F AD - Medical Oncology Department, Ramon y Cajal University Hospital, IRYCIS, CIBERONC, Madrid, Spain. FAU - Miller, W H AU - Miller WH AD - Segal Cancer Centre, Jewish General Hospital, Montreal, Canada; Department of Medicine, McGill University, Montreal, Canada. FAU - Oh, D-Y AU - Oh DY AD - Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea; Integrated Major in Innovative Medical Science, Seoul National University Graduate School, Seoul, South Korea. FAU - Gottfried, M AU - Gottfried M AD - Department of Medical Oncology, Meir Medical Center, Kfar Saba, Israel. FAU - Xu, L AU - Xu L AD - Merck & Co., Inc., Rahway, USA. FAU - Jin, F AU - Jin F AD - Merck & Co., Inc., Rahway, USA. FAU - Norwood, K AU - Norwood K AD - Merck & Co., Inc., Rahway, USA. FAU - Marabelle, A AU - Marabelle A AD - Department of Therapeutic Innovation and Early Trials, Gustave Roussy, Institut National de la Sante et de la Recherche Medicale U1015/CIC1428, Universite Paris Saclay, Villejuif, France. LA - eng SI - ClinicalTrials.gov/NCT02628067 PT - Clinical Trial, Phase II PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220606 PL - England TA - Ann Oncol JT - Annals of oncology : official journal of the European Society for Medical Oncology JID - 9007735 RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Antineoplastic Agents, Immunological) RN - DPT0O3T46P (pembrolizumab) SB - IM MH - Antibodies, Monoclonal, Humanized MH - *Antineoplastic Agents, Immunological/adverse effects MH - DNA Mismatch Repair/genetics MH - Humans MH - Microsatellite Instability MH - *Neoplasms/chemically induced/drug therapy/genetics OTO - NOTNLM OT - biomarker OT - cancer OT - immunotherapy OT - microsatellite instability OT - mismatch repair deficiency OT - tumor-agnostic COIS- Disclosure MM: advisor/board member for Roche; Bristol Myers Squibb; Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD); Incyte; AstraZeneca; Amgen; Pierre Fabre; Eli Lilly; GlaxoSmithKline; Sanofi; Alfasigma; Merck Serono; Honoraria for Roche; Bristol Myers Squibb; MSD; AstraZeneca; Amgen; Pierre Fabre; Eli Lilly; GlaxoSmithKline; Sciclone; Sanofi; Alfasigma; Merck Serono; owns stock in Epigen Therapeutics and Theravance; study funding to the institution from MSD to support study conduct. PAA: research funding from Bristol Myers Squibb; Roche/Genentech; Array BioPharma; and Sanofi. Served as a consultant/advisor for Bristol Myers Squibb; Roche/Genentech; MSD; Array BioPharma; Novartis; Merck Serono; Pierre Fabre; Incyte; MedImmune; AstraZeneca; Syndax; Sun Pharma; Sanofi; Idera; Ultimovacs; Sandoz; Immunocore; 4SC; Alkermes; Nektar; Italfarmaco; Boehringer Ingelheim; Eisai; Regeneron; Daiichi Sankyo; Pfizer; Oncosec; Nouscom; Takis; Lunaphore; and Seagen. Travel support from MSD. Unpaid consultant for Takis. Study funding to the institution from MSD to support study conduct. LM: study funding to the institution from MSD to support study conduct. DMK: research funding from Roche/Genentech; Novartis; Amgen; Bristol Myers Squibb; GlaxoSmithKline; Janssen; Eli Lilly; AstraZeneca; MSD; study funding to the institution from MSD to support study conduct. NP: study funding to the institution from MSD to support study conduct. PAC: research funding from Roche/Genentech; Novartis; Amgen; Bristol Myers Squibb; Blueprint Medicines; GlaxoSmithKline; Janssen; Eli Lilly; Taiho Pharmaceutical; AstraZeneca; MSD; Celgene; AbbVie; Toray Industries; Transgene; Innate Pharma; and Loxo. Personal fees from Roche/Genentech; Novartis; Amgen; Merck Serono; and AstraZeneca. Nonfinancial support from Roche/Genentech; Novartis; AstraZeneca; MSD; and Plexxikon. Travel accommodations from NETRIS Pharma. Study funding to the institution from MSD to support study conduct. GMB: research funding from mAbxience; MSD; Bristol Myers Squibb. Advisory role: Libbs. Study funding to the institution from MSD to support study conduct. ADJA: research funding from AstraZeneca; Merck & Co., Inc., Rahway, NJ, USA. Consultancy for Merck & Co., Inc., Rahway, NJ, USA. Study funding to the institution from MSD to support study conduct. TD: research funding from AbbVie; Boehringer Ingelheim; Bristol Myers Squibb; Chugai Pharma; Daiichi Sankyo; Eli Lilly; Eisai; IQVIA; Janssen Pharmaceuticals; Merck Serono; MSD; Novartis; Pfizer; Sumitomo Dainippon; Taiho; personal fees from Bristol Myers Squibb; Ono Pharmaceutical; served as consultant/advisor for AbbVie; Amgen; Boehringer Ingelheim; Daiichi Sankyo; Janssen Pharmaceuticals; Kyowa Kirin; MSD; Otsuka Pharmaceutical; Rakuten Medical; Sumitomo Dainippon; Takeda Pharmaceutical; study funding to the institution from MSD to support study conduct. FL: honoraria/consulting or advisory role/travel and accommodations from MSD; BMS; Roche; Merck Serono; Amgen; Lilly; Sanofi; Servier; Bayer; and Ferrer Pharma. Study funding to the institution from MSD to support study conduct. WHM: personal fees for serving as a consultant for BMS, Merck & Co., Inc., Rahway, NJ, USA; Roche; Novartis; Amgen; GSK; Amgen Mylan; and EMD Serono. Grants or contracts from any entity (to the institution): Merck; CIHR; CRS; Terry Fox Research Institute; Samuel Waxman Cancer Research Foundation; and CCSI. Study funding to the institution from MSD to support study conduct. DYO: consultant/advisory board for AstraZeneca; Novartis; Genentech/Roche; Merck Serono; Bayer; Taiho; ASLAN; Halozyme; Zymeworks; BMS/Celgene; BeiGene; Basilea; Turning Point. Research funding/grant from AstraZeneca; Novartis; Array; Eli Lilly; Servier; BeiGene; MSD; Handok. Study funding to the institution from MSD to support study conduct. MG: study funding to the institution from MSD to support study conduct. LX, FJ, and KN: employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and stockholders of Merck & Co., Inc., Rahway, NJ, USA. AM: reports funding to the institution from MSD to support study conduct; honorarium from MSD for a scientific advisory board on other compound and different clinical situation than the present study; research grant from Fondation MSD Avenir and Bristol Myers Squibb on immunotherapy topics other than the present study; and personal fees for speakers bureau from Bristol Myers Squibb and MSD on topics not related to the present study. Data sharing Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD) is committed to providing qualified scientific researchers access to anonymized data and clinical study reports from the company's clinical trials for the purpose of conducting legitimate scientific research. MSD is also obligated to protect the rights and privacy of trial participants and, as such, has a procedure in place for evaluating and fulfilling requests for sharing company clinical trial data with qualified external scientific researchers. The MSD data-sharing website (available at: http://engagezone.msd.com/ds_documentation.php) outlines the process and requirements for submitting a data request. Applications will be promptly assessed for completeness and policy compliance. Feasible requests will be reviewed by a committee of MSD subject matter experts to assess the scientific validity of the request and the qualifications of the requestors. In line with data privacy legislation, submitters of approved requests must enter into a standard data-sharing agreement with MSD before data access is granted. Data will be made available for request after product approval in the US and EU or after product development is discontinued. There are circumstances that may prevent MSD from sharing requested data, including country- or region-specific regulations. If the request is declined, it will be communicated to the investigator. Access to genetic or exploratory biomarker data requires a detailed, hypothesis-driven statistical analysis plan that is collaboratively developed by the requestor and MSD subject matter experts; after approval of the statistical analysis plan and execution of a data-sharing agreement, MSD will either perform the proposed analyses and share the results with the requestor or will construct biomarker covariates and add them to a file with clinical data that is uploaded to an analysis portal so that the requestor can perform the proposed analyses. EDAT- 2022/06/10 06:00 MHDA- 2022/09/14 06:00 CRDT- 2022/06/09 19:26 PHST- 2021/12/14 00:00 [received] PHST- 2022/04/21 00:00 [revised] PHST- 2022/05/29 00:00 [accepted] PHST- 2022/06/10 06:00 [pubmed] PHST- 2022/09/14 06:00 [medline] PHST- 2022/06/09 19:26 [entrez] AID - S0923-7534(22)01720-3 [pii] AID - 10.1016/j.annonc.2022.05.519 [doi] PST - ppublish SO - Ann Oncol. 2022 Sep;33(9):929-938. doi: 10.1016/j.annonc.2022.05.519. Epub 2022 Jun 6.