Pembrolizumab in patients with MSI-H advanced endometrial cancer from the KEYNOTE-158 study

Abstract

Background: Pembrolizumab (pembro) provides durable responses in patients (pts) with MSI-H cancers and is approved in the US/Japan for the treatment of MSI-H advanced solid tumors. MSI-H is expressed in ∼25% of endometrial cancers. An analysis of pts with MSI-H advanced endometrial cancer enrolled in cohorts D (advanced endometrial cancer) and K (pan-tumor MSI-H) of the phase 2 KEYNOTE-158 basket study (NCT02628067) is presented. Methods: Eligible pts had advanced endometrial cancer; progression on or intolerance to ≥ 1 line of standard therapy; measurable disease per RECIST v1.1; ECOG PS ≤ 1; and an MSI-H tumor sample determined retrospectively by centrally performed PCR (cohort D) or prospectively by locally performed IHC or PCR (cohort K). Pts received pembro 200 mg Q3W for up to 2 y or until PD or unacceptable toxicity. Tumor imaging was performed every 9 wk for the first 12 mo, and every 12 wk thereafter. Response was assessed per RECIST v1.1 by independent central radiologic review. The primary endpoint was ORR; secondary endpoints included DOR, PFS, OS and safety. Data cutoff was Dec 6, 2018. Results: 49 pts with MSI-H advanced endometrial cancer were enrolled in cohorts D (n = 11) and K (n = 38). Median age was 65 (range, 42-86) y; 51% had ECOG PS 1; 49% had received ≥2 lines of prior therapy; and histology was endometrioid in 53%, adenocarcinoma in 43%, clear cell in 2% and mucinous in 2% of pts. Median follow-up duration was 24 (range, 0.5-34) mo. ORR was 57% (95% CI, 42%-71%), with 8 (16%) CR and 20 (41%) PR. 8 pts (16%) had SD, and the DCR was 73%. Median DOR was not reached (NR; range, 3-27+ mo); 26 (93%) of the 28 responses were ongoing after ≥9 mo follow-up. Reduction in tumor size was observed in 37 (79%) of the 47 pts with ≥1 evaluable assessment. Median PFS was 26 (95% CI, 5-NR) mo. The 12-mo OS rate was 73%, with median OS not reached (95% CI, 27 mo-NR). Treatment-related AEs occurred in 39 (80%) pts; the most common events were fatigue (26%) and diarrhea (24%). 16% of pts had treatment-related grade 3-4 AEs; there were no grade 5 AEs. Conclusions: Pembro is associated with robust, durable antitumor activity with promising survival benefit and manageable safety in pts with heavily pretreated MSI-H advanced endometrial cancer. Clinical trial identification: NCT02628067. Editorial acknowledgement: Christine McCrary Sisk, funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Legal entity responsible for the study: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Funding: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Disclosure: D. O'Malley: Honoraria (self): AstraZeneca, Clovis, Tesaro, Immunogen, Ambry Genetics, Janssen/J&J, AbbVie, Amgen, Regeneron, Genentech/Roche, Novocure, GOG Foundation; Advisory / Consultancy: AstraZeneca, Clovis, Tesaro, Immunogen, Ambry Genetics, AbbVie, Amgen, Genentech/Roche, Novocure, Agenus; Research grant / Funding (institution): AstraZeneca, Clovis, Tesaro, Immunogen, Janssen/J&J, AbbVie, Regeneron, Amgen, Novocure, Genentech/Roche, VentiRx, Array Biopharma, EMD Serono, Ergomed, Ajinomoto Inc., Ludwig Cancer Research, Stemcentrx, Inc, Cerulean Pharma, GOG Group; Travel / Accommodation / Expenses: Agenus; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Bristol-Myers Squibb Co, Serono Inc, Tracon Pharmaceuticals Yale University, New Mexico Cancer Care Alliance, INC Research, Inc, inVentiv Health Clinical, Iovance Biotherapeutics, Inc, PRA Intl, Agenus. A. Marabelle: Advisory / Consultancy, Principal Investigator of Clinical Trials: Roche/Genentech, BMS, Merck (MSD), Pfizer, Lytix pharma, Eisai, AstraZeneca/Medimmune, Tesaro, Chugai; Advisory / Consultancy, Principal Investigator of Academic Trials: INCa, Ligue contre le Cancer, BMS, Unicancer, Transgene, Leon Berard Cancer Centre, BMS, Gustave Roussy, Boehringer Ingelheim; Advisory / Consultancy, Sub-Investigator of Clinical Trials: Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, AstraZeneca, Aveo, Bayer Healthcare Ag, Bbb Technologies Bv, Beigene, Bioalliance Pharma, Biontech Ag, Blueprint Medicines, Boehringer Ingelheim, Bristol; Research grant / Funding (self): AstraZeneca, BMS, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi; Research grant / Funding (institution), (drug supply): AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Johnson & Johnson, Lilly, Medimmune, Merck, NH TherAGuiX, Pfizer, Roche; Advisory / Consultancy, Member of Clinical Trial Scientific Committee: GSK, AstraZeneca; Advisory / Consultancy, Member of Data Safety and Monitoring Board: Oncovir, Inc.; Honoraria (self), Scientific Advisory Boards: Innate Pharma, Merck Serono, eTheRNA, Lytix pharma, Kyowa Kirin Pharma, Bayer, Novartis, BMS, Symphogen, Genmab, Amgen, Biothera, Nektar, GSK, Oncovir, Pfizer, Seattle Genetics, Flexus Bio, Roche/Genentech, OSE immunotherapeutics, Transgene, Gritstone; Speaker Bureau / Expert testimony: Roche/Genentech, BMS, Merck (MSD), Merck Serono, AstraZeneca/Medimmune, Amgen, Sanofi; Advisory / Consultancy, Scientific & Medical Consulting: Roche, Pierre Fabre, Onxeo, Eisai, Bayer, Genticel, Rigontec, Daichii Sankyo, Imaxio, Sanofi, BioNTech, Corvus, GLG, Deerfield, Guidepoint Global, Edimark, System Analytics, imCheck, Sotio, Bioncotech, Molecular Partners, Pillar Partners, Boehringer Ingel; Travel / Accommodation / Expenses: AstraZeneca, BMS, Merck (MSD), Roche; Shareholder / Stockholder / Stock options, Co-founder and Share Holder: Pegascy SAS (Gustave Roussy Spin Off for Drug Repositioning); Licensing / Royalties, Patent Issued (not licensed yet): “Humanized and Chimeric Monoclonal Antibodies to CD81”, Stanford Office of Technology Licensing, 3000 El Camino Real, Bldg. 5, Suite 300, Palo Alto, CA 94306-2100. U.S. Application Serial No. 62/351,054.; Research grant / Funding (institution): Merus, BMS, Boehringer Ingelheim, Transgene, Fondation MSD Avenir; Officer / Board of Directors, Supervisory Board Member: Gustave Roussy Foundation; Advisory / Consultancy, Member of the Steering Committee of the Immuno-Oncology Task Force: Unicancer; Advisory / Consultancy, Sub-investigator of Clinical Trials: Bristol-Myers Squibb, Ca, Celgene Corporation, Chugai Pharmaceutical Co., Clovis Oncology, Daiichi Sankyo, Debiopharm S.A., Eisai, Exelixis, Forma, Gamamabs, Genentech, Inc., Gilead Sciences, Inc, GlaxoSmithKline, Glenmark Pharmaceuticals, H3 Biomedicine; Advisory / Consultancy, Sub-investigator of Clinical Trials: Hoffmann La Roche Ag, Incyte Corporation, Innate Pharma, Iris Servier, Janssen, Kura Oncology, Kyowa Kirin Pharm, Lilly, Loxo Oncology, Lytix Biopharma As, Medimmune, Menarini Ricerche, Merck Sharp & Dohme Chibret, Merrimack Pharmaceuticals, Merus; Advisory / Consultancy, Sub-investigator of Clinical Trials: Millennium Pharmaceuticals, Nanobiotix, Nektar Therapeutics, Novartis Pharma, Octimet Oncology Nv, Oncoethix, Oncomed, Oncopeptides, Onyx Therapeutics, Orion Pharma, Oryzon Genomics, Pfizer, Pharma Mar, Pierre Fabre, Rigontec Gmbh, Roche; Advisory / Consultancy, Sub-investigator of Clinical Trials: Sanofi Aventis, Sierra Oncology, Taiho Pharma, Tesaro, Inc, Tioma Therapeutics, Inc., Xencor; Honoraria (self), Scientific Advisory Boards: Merck (MSD), Cerenis, Innate pharma, Protagen, Partner Therapeutics, Servier, Sanofi, Pierre Fabre, Molecular Partners, Innate Pharma. A. De Jesus-Acosta: Advisory / Consultancy: Merck & Co., Inc.; Research grant / Funding (self): Merck & Co., Inc., AZ; Research grant / Funding (institution): Merck & Co., Inc. S.A. Piha-Paul: Research grant / Funding (institution): AbbVie, Inc.; Aminex Therapeutics; BioMarin Pharmaceutical, Inc; Boehringer Ingelheim; Bristol Myers Squib; Cerulean Pharma Inc.; Chugai Pharmaceutical Co., Ltd; Curis, Inc.; Five Prime Therapeutics; Flex Bio, Inc.; Genmab A/S; GlaxoSmithKline; Research grant / Funding (institution): Helix BioPharma Corp.; Incyte Corp.; Jacobio Pharmaceuticals Co., Ltd.; Medimmune, LLC.; Medivation, Inc.; Merck Sharp and Dohme Corp.; NewLink Genetics Corporation/Blue Link Pharmaceuticals; Novartis Pharmaceuticals; Pieris Pharmaceuticals, Inc.; Pfizer; Research grant / Funding (institution): Principia Biopharma, Inc.; Puma Biotechnology, Inc.; Seattle Genetics; Taiho Oncology; Tesaro, Inc.; TransThera Bio; XuanZhu Biopharma. A. Arkhipov: Research grant / Funding (institution): MSD. F. Longo: Research grant / Funding (institution): MSD. D. Motola-Kuba: Speaker Bureau / Expert testimony: Pfizer, MSD, Eli Lilly, AstraZeneca, Roche, BMS, Asopharma; Research grant / Funding (institution): MSD. R. Shapira-Frommer: Honoraria (self): MSD, BMS, Roche, Novartis, Medison; Advisory / Consultancy: MSD, Clovis oncology; Research grant / Funding (institution): MSD. R. Geva: Speaker Bureau / Expert testimony, Lecture: MSD, Novartis, Roche, Janssen, Takeda, Pfizer; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses, Lecture & Travel: BMS, Medison, Merck; Research grant / Funding (institution): MSD. B.J. Rimel: Advisory / Consultancy: Tesaro, Clovis, AstraZeneca, Genentech, Deep 6 AI; Research grant / Funding (institution): Merck. J.A. Lopez-Martin: Advisory / Consultancy: MSD, BMS, Roche, Pierre-Fabre, Celgene, Amgen, Novartis, Lilly, PharmaMar, Chobani; Research grant / Funding (institution): MSD, BMS, Roche, Novartis, PharmaMar, Lilly; Travel / Accommodation / Expenses: MSD, Roche, BMS, Lilly, PharmaMar; Shareholder / Stockholder / Stock options: PharmaMar. A.R. Hansen: Advisory / Consultancy, Research grant / Funding (self): Genentech/Roche, Merck, GSK, Bristol-Myers Squibb, Novartis, Boston Biomedical, Boehringer-Ingelheim, AstraZeneca, Medimmune; Research grant / Funding (institution): Merck. J.M. Mehnert: Advisory / Consultancy: Merck, Boehringer Ingelheim, Array Biopharma, Amgen; Research grant / F