Efficacy and safety of pembrolizumab for the treatment of advanced biliary cancer: Results from the KEYNOTE-158 and KEYNOTE-028 studies

Sarina A. Piha-Paul, Do Youn Oh, Makoto Ueno, David Malka, Hyun Cheol Chung, Adnan Nagrial, Robin K. Kelley, Willeke Ros, Antoine Italiano, Kazuhiko Nakagawa, Hope S. Rugo, Filippo de Braud, Andrea Iolanda Varga, Aaron Hansen, Hui Wang, Suba Krishnan, Kevin G. Norwood, Toshihiko Doi

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151 Citations (Scopus)


We present data from patients with advanced biliary tract cancer (BTC) receiving pembrolizumab in the KEYNOTE-158 (NCT02628067; phase 2) and KEYNOTE-028 (NCT02054806; phase 1b) studies. Eligible patients aged ≥18 years from both studies had histologically/cytologically confirmed incurable BTC that progressed after standard treatment regimen(s), measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, Eastern Cooperative Oncology Group performance status 0/1, and no prior immunotherapy. Programmed death ligand 1 (PD-L1)-positive tumors were required for eligibility in KEYNOTE-028 only. Patients received pembrolizumab 200 mg every three weeks (KEYNOTE-158) or 10 mg/kg every two weeks (KEYNOTE-028) for ≤2 years. Primary efficacy endpoint was objective response rate (ORR) by RECIST v1.1. Response assessed by independent central review is reported. KEYNOTE-158 enrolled 104 patients and KEYNOTE-028 enrolled 24 patients. Median (range) follow-up was 7.5 months (0.6-34.3) in KEYNOTE-158 and 5.7 months (0.6-55.4) in KEYNOTE-028. In KEYNOTE-158, ORR was 5.8% (6/104; 95% CI, 2.1%-12.1%); median duration of response (DOR) was not reached (NR) (range, 6.2-26.6+ months). Median (95% CI) OS and PFS were 7.4 (5.5-9.6) and 2.0 (1.9-2.1) months. Among PD-L1-expressers (n = 61) and PD-L1-nonexpressers (n = 34), respectively, ORR was 6.6% (4/61) and 2.9% (1/34). In KEYNOTE-028, ORR was 13.0% (3/23; 95% CI, 2.8%-33.6%); median DOR was NR (range, 21.5-53.2+ months). Median (95% CI) OS and PFS were 5.7 (3.1-9.8) and 1.8 (1.4-3.1) months. Grade 3 to 5 treatment-related adverse events occurred in 13.5% of patients in KEYNOTE-158 (no grade 4; grade 5 renal failure, n = 1) and 16.7% in KEYNOTE-028 (no grade 4/5). In summary, pembrolizumab provides durable antitumor activity in 6% to 13% of patients with advanced BTC, regardless of PD-L1 expression, and has manageable toxicity.

Original languageEnglish
Pages (from-to)2190-2198
Number of pages9
JournalInternational Journal of Cancer
Issue number8
Publication statusPublished - 2020 Oct 15

Bibliographical note

Funding Information:
Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (MSD). We thank the patients and their families and caregivers for participating in our study, along with all investigators and site personnel. Additional statistical support was provided by Lei Xu, PhD, and Chao Gao, PhD (former employee), and additional study support was provided by Melanie Leiby, PhD, of Merck & Co., Inc., Kenilworth, NJ, USA, and funded by MSD. Medical writing assistance was provided by Michael J. Theisen of C4 MedSolutions, LLC (Yardley, PA, USA), a CHC Group company. This assistance was funded by MSD.

Funding Information:
S. P.‐P: Research funding paid to institution from AbbVie, Inc.; Alkermes; Aminex Therapeutics; Amphivena Therapeutics, Inc.; BioMarin Pharmaceutical, Inc.; Boehringer Ingelheim; Bristol‐Myers Squib; Cerulean Pharma Inc.; Chugai Pharmaceutical Co., Ltd; Curis, Inc.; Daiichi Sankyo; Eli Lilly; Five Prime Therapeutics; Genmab A/S; GlaxoSmithKline; Helix BioPharma Corp.; Incyte Corp.; Jacobio Pharmaceuticals Co., Ltd.; Medimmune, LLC.; Medivation, Inc.; Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA; NewLink Genetics Corporation/Blue Link Pharmaceuticals; Novartis Pharmaceuticals; Pieris Pharmaceuticals, Inc.; Pfizer; Principia Biopharma, Inc.; Puma Biotechnology, Inc.; Rapt Therapeutics, Inc.; Seattle Genetics; Taiho Oncology; Tesaro, Inc.; TransThera Bio; and XuanZhu Biopharma; P30CA016672 ‐ Core Grant (CCSG Shared Resources). M. U: Honararia from Taiho Pharmaceutical, Yakult Honsha, AstraZeneca, Novartis, Lilly, Teijin Pharma, Shire, Ono Pharmaceutical and Merck Biopharm; research funding from Taiho Pharmaceutical, Shire, Daiichi Sankyo, Eisai, AstraZeneca, Ono Pharmaceutical, MSD, Merck Biopharm, NanoCarrier, Dainippon Sumitomo Pharma, Incyte, ASLAN Pharmaceuticals and Yakult Honsha. D. M: Honoraria and non‐financial support from Amgen, Bayer, Ipsen, Merck, Merck Serono, Roche, Sanofi and Servier; honoraria from Shire, HalioDx and Agios. H. C. C: Grants/research support from Eli Lilly, GSK, MSD, Merck‐Serono, BMS/Ono and Taiho; honoraria from Merck‐Serono, Eli Lilly and Foundation Medicine; consultant to Taiho, Celltrion, MSD, Eli Lilly, Quintiles, BMS and Merck‐Serono. A. N: Research funding (to institution) from MSD, BMS, Novartis, Medimmune, AbbVie and Incyte; honoraria from MSD, BMS, Roche and AstraZeneca. R. K. K: Research funding (to institution) from Agios, Adaptimmune, AstraZeneca, Bayer, BMS, EMD Serono, Medimmune, Merck, Novartis, Partner Therapeutics, QED and Taiho; consulting/steering committee funding (to institution) from Agios, AstraZeneca and BMS; IDMC and advisory funding (to self) from Genentech/Roche; travel support for satellite symposium and advisory board (to self) from Ipsen. D.‐Y. O: Consultant and/or advisory board member for AstraZeneca, Novartis, Genentech/Roche, Merck Serono, Bayer, Taiho, Halozyme and Zymeworks; research grant from AstraZeneca, Novartis, Array, Eli Lilly and Green Cross. W. R: No conflict of interest. A. I: Research grant from MSD. K. N: Honoraria from Astellas Pharma Inc., AstraZeneca, Eli Lilly Japan K.K., EPS Associate Co. Ltd., MSD K.K., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Ono Pharma Co. Ltd. and Pfizer Japan Inc.; research funding from A2 Healthcare Corp., AC Medical Inc., Astellas Pharma Inc., Bristol‐Myers Squibb Company, Chugai Pharmaceutical Co. Ltd., ICON Japan K.K., inVentiv Health Japan, JCR, Kyowa Hakko Kirin Co. Ltd., MSD K.K., Nippon Boehringer Ingelheim Co. Ltd., Ono Pharma Co. Ltd., PAREXEL International Corp., Pfizer Japan Inc., PPD‐SNBL K.K., Quintiles Inc. and Takeda Pharmaceutical Co. Ltd. H. S. R: Research support for clinical trials (to institution) from Pfizer, Merck, Novartis, Eli Lilly, Genentech, OBI Pharma, Odonate Therapeutics, Daiichi Sankyo, Eisai, Seattle Genetics, MacroGenics and Immunomedics; travel support from Daiichi Sankyo, Mylan, Pfizer, Amgen, Merck, AstraZeneca, MacroGenics and Puma Biotechnology. F. B: Daiichi Sankyo, Ignyta, Amgen, Pfizer, Octimet Oncology, Incyte, Teofarma, Pierre Fabre, Roche, EMD Serono, BMS, NMS Nerviano and Sanofi. A. I. V: Research grants from Astrazeneca, BMS, Boehringer Ingelheim, Johnson & Johnson, Lilly, Medimmune, Merck, NH TherAGuiX, Pfizer and Roche; non‐financial support (drug supplied) from Astrazeneca, Bayer, BMS, Boringher Ingelheim, Johnson & Johnson, Lilly, Medimmune, Merck, NH TherAGuiX, Pfizer and Roche. A. H: Genetech, Hoffmann La Roche, Merck Serono, GSK, BMS, Novartis, Boston Biomedical, Boehringer Ingelheim, AstraZeneca, MedImmune and Pfizer. H. W, S. K, and K. N: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (employment). T. D: Grants from AbbVie, Astellas Pharma, Boehringer Ingelheim, Bristol‐Myers Squibb, Celgene, Chugai Pharma, Daiichi Sankyo, Dainippon Sumitomo, Eli Lilly, Janssen, Kyowa Hakko Kirin, Merck Serono, MSD, Novartis, Pfizer, Quintiles, Taiho and Takeda; personal fees from Amgen, Chugai Pharma, Daiichi Sankyo, Dainippon Sumitomo, Kyowa Hakko Kirin, Eli Lilly, MSD and Taiho.

Publisher Copyright:
© 2020 UICC

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research


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