Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND

Biliary tract cancers, which arise from the intrahepatic or extrahepatic bile ducts and the gallbladder, generally have a poor prognosis and are rising in incidence worldwide. The standard-of-care treatment for advanced biliary tract cancer is chemotherapy with gemcitabine and cisplatin. Because most biliary tract cancers have an immune-suppressed microenvironment, immune checkpoint inhibitor monotherapy is associated with a low objective response rate. We aimed to assess whether adding the immune checkpoint inhibitor pembrolizumab to gemcitabine and cisplatin would improve outcomes compared with gemcitabine and cisplatin alone in patients with advanced biliary tract cancer.

METHODS

KEYNOTE-966 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 175 medical centres globally. Eligible participants were aged 18 years or older; had previously untreated, unresectable, locally advanced or metastatic biliary tract cancer; had disease measurable per Response Evaluation Criteria in Solid Tumours version 1.1; and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible participants were randomly assigned (1:1) to pembrolizumab 200 mg or placebo, both administered intravenously every 3 weeks (maximum 35 cycles), in combination with gemcitabine (1000 mg/m

FINDINGS

Between Oct 4, 2019, and June 8, 2021, 1564 patients were screened for eligibility, 1069 of whom were randomly assigned to pembrolizumab plus gemcitabine and cisplatin (pembrolizumab group; n=533) or placebo plus gemcitabine and cisplatin (placebo group; n=536). Median study follow-up at final analysis was 25·6 months (IQR 21·7-30·4). Median overall survival was 12·7 months (95% CI 11·5-13·6) in the pembrolizumab group versus 10·9 months (9·9-11·6) in the placebo group (hazard ratio 0·83 [95% CI 0·72-0·95]; one-sided p=0·0034 [significance threshold, p=0·0200]). In the as-treated population, the maximum adverse event grade was 3 to 4 in 420 (79%) of 529 participants in the pembrolizumab group and 400 (75%) of 534 in the placebo group; 369 (70%) participants in the pembrolizumab group and 367 (69%) in the placebo group had treatment-related adverse events with a maximum grade of 3 to 4. 31 (6%) participants in the pembrolizumab group and 49 (9%) in the placebo group died due to adverse events, including eight (2%) in the pembrolizumab group and three (1%) in the placebo group who died due to treatment-related adverse events.

INTERPRETATION

Based on a statistically significant, clinically meaningful improvement in overall survival compared with gemcitabine and cisplatin without any new safety signals, pembrolizumab plus gemcitabine and cisplatin could be a new treatment option for patients with previously untreated metastatic or unresectable biliary tract cancer.

FUNDING

Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

Informations de copyright

Copyright © 2023 Elsevier Ltd. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests RKK, MU, CY, RSF, JF, ZR, TY, H-JK, SLC, MO, CV, MB, JOP, OB, UP, JWV, JE, and AV report funding to their institution from Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA (MSD), to support conduct of this study. All authors received medical writing and editorial support for the preparation of this manuscript from MSD. RKK additionally reports advisory committee membership for MSD; grants or contracts to their institution from Agios, AstraZeneca, Bayer, BMS, Eli Lilly, EMD Serono, Genentech/Roche, Loxo Oncology, MSD, Novartis, Partner Therapeutics, QED, Relay Therapeutics, Surface Oncology, and Taiho; consulting fees (advisory board payments) to themself from Compass Therapeutics, Kinnate, Exact Sciences, Regeneron, and Tyra Biosciences; consulting fees (advisory board or steering committee payments) to their institution from Agios, AstraZeneca, Exelixis, Ipsen, and MSD; travel support from AstraZeneca and MSD; participation on a data safety monitoring board (uncompensated) for Genentech/Roche and MSD; being a scientific and medical advisory board co-chair (uncompensated) for the Cholangiocarcinoma Foundation; and member of governance board (uncompensated) for the International Liver Cancer Association. MU additionally reports grants or contracts to their institution from Taiho Pharmaceutical, AstraZeneca, Merck Biopharma, MSD, Astellas Pharma, Eisai, Ono Pharmaceutical, Daiichi Sankyo, Novartis, Boehringer Ingelheim, and J-pharma; and payment or honoraria to themself from Taiho Pharmaceutical, AstraZeneca, Yakult Honsha, MSD, Nihon Servier, Ono Pharmaceutical, Incyte, Chugai Pharmaceutical, Boehringer Ingelheim, J-pharma, Takeda Pharmaceutical, Mylan EPD, Delta-Fly Pharma, and Novartis. CY additionally reports grants or contracts to themself from Servier, Bayer, AstraZeneca, Ono Pharmaceuticals, Celgene, Ipsen, Boryung Pharmaceuticals, Ildong Pharmaceuticals, CKD Pharmaceuticals, and HK inno.N; consulting fees to themself from Servier, Bayer, AstraZeneca, MSD, Eisai, Celgene, Bristol Myers Squibb, Debiopharm, Ipsen, Kyowa Kirin, Novartis, Boryung Pharmaceuticals, Merck Serono, Mundipharma, Roche, and Janssen; and payment or honoraria to themself from Servier, Bayer, AstraZeneca, MSD, Eisai, Celgene, Bristol Myers Squibb, Debiopharm, Ipsen, Kyowa Kirin, Novartis, Boryung Pharmaceuticals, Merck Serono, Mundipharma, Roche, and Janssen. RSF additionally reports grants or contracts to their institution from Adaptimmune, Bayer, Bristol Myers Squibb, Eisai, Eli Lilly, Pfizer, Roche, and Genentech; consulting fees to themself from AstraZeneca, Bayer, Bristol Myers Squibb, Exelixis, Cstone, Hengrui, Eisai, Eli Lilly, MSD, Pfizer, Roche, and Genentech; payment or honoraria to themself from Genentech; and participation on a data safety monitoring or advisory board from AstraZeneca, and Hengrui. JF additionally reports grants or contracts from Astellas, AstraZeneca, Incyte Biosciences Japan, Eisai, MSD, Ono Pharmaceutical, Sanofi, J-Pharma, Daiichi Sankyo, Sumitomo Dainippon, Taiho Pharmaceutical, Takeda, Delta-Fly Pharma, and Chugai Pharma; payment or honoraria from Ono Pharmaceutical, Chugai Pharmaceutical, Incyte Biosciences Japan, Eisai, Eli Lilly Japan, AstraZeneca, Yakult Honsha, Servier Japan, MSD, Novartis Pharma, Takeda, Bayer, Taiho Pharmaceutical, EA Pharma, Teijin Pharma, Daiichi Sankyo, and Terumo; and participation on a data safety monitoring board or advisory board from Onco Therapy Science, Chugai Pharma, Astellas, AstraZeneca, Takara Bio, Merck Bio, MSD, and Taiho Pharmaceutical. ZR additionally reports consulting fees from MSD, AstraZeneca, and Roche and payment or honoraria for lectures from Bayer, MSD, and Roche. TY additionally reports consulting fees from BMS, MSD, AstraZeneca, Eisai, and Ipsen; support for attending meetings or travel from Roche and Bayer; stock or stock options in Moderna; medical writing support from Taiho and Ispen; and payments to their institution for clinical trial investigatorship from BMS, MSD, Exelixis, Eli Lilly, AstraZeneca, Roche, and Taiho. H-JK additionally reports payment or honoraria to their institution from MEDtalks and Ipsen and payments made to their institution for participation on an advisory board from AstraZeneca, Janssen, MSD, and Ipsen. SLC additionally reports consulting fees to themself from MSD, AstraZeneca, Eisai, Roche, and Bayer; payment or honoraria to themself from MSD, AstraZeneca, Eisai, Roche, and Bristol Myers Squibb; and support for attending meetings or travel from Ipsen and Novartis. MO additionally reports payment or honoraria from Taiho Pharmaceutical, Yakult Honsha, MSD, Ono Pharmaceutical, Nihon, Servier, Bayer, and Pfizer. CV additionally reports consulting fees from Bayer, MSD, Roche, Ipsen, and AstraZeneca; and payment or honoraria from Bayer, MSD, Roche, Ipsen, and AstraZeneca. MB additionally reports consulting fees from Bayer Pharma, MSD, Eisai, Sirtex Medical, BMS, Roche, and AstraZeneca; and payment or honoraria from Bayer Pharma, MSD, Sirtex Medical, BMS, Roche, and AstraZeneca. JOP additionally reports grants or contracts from BMS (Celgene), Servier, MedPacto, Eutilex, and ABL Bio; support for attending meetings or travel from Minneamrita Therapeutics; and participation on a data safety monitoring board or advisory board for AstraZeneca, Adicet, and Merck Serono. JWV additionally reports consulting fees to themself from Ipsen, Novartis, AstraZeneca, Merck, Pfizer, PCI Biotech, Incyte, Keocyt, QED Therapeutics, Pieris Pharmaceuticals, Genoscience Pharma, Mundipharma, Wren Laboratories, Nucana, Debiopharm Group, Imaging Equipment Limited, Hutchison MediPharma, Zymeworks, Aptitude Health, Sirtex Medical, Baxter, Medivir, Cantargia AB, Autem Medical, Taiho Oncology, Servier, and Boehringer Ingelheim; payments to themself for speakers bureaus from Novartis, Ipsen, Nucana, Imaging Equipment Limited, Mylan, Incyte, Servier, and Delcath Systems; and support for attending meetings or travel from Nucana, Lilly, Roche, and AstraZeneca/MedImmune. LY reports salary for full-time employment from MSD. UM reports salary for full-time employment from MSD and stock ownership in Merck & Co, Rahway, NJ, USA. ABS reports salary for full-time employment from MSD and stock ownership in Merck & Co, Rahway, NJ, USA. JE additionally reports grants or contracts from BMS, Beigene, and Boston Scientific; and payment or honoraria from MSD, Eisai, BMS, AstraZeneca, Bayer, Roche, Ipsen, Basilea, Merck Serono, Incyte, Servier, Beigene, Taiho, and Boston Scientific. AV additionally reports consulting fees to themself from AstraZeneca, Amgen, Beigene, Böhringer Mannheim, BMS, BTG, Daiichi Sankyo, Eisai, Incyte, Ipsen, MSD, Pierre Fabre, Roche, Servier, Sirtex, Taiho, and Terumo; payment or honoraria to themself from AstraZeneca, Amgen, Beigene, Böhringer Mannheim, BMS, BTG, Daiichi Sankyo, Eisai, GSK, Imaging Equipment (AAA), Incyte, Ipsen, Jiangsu Hengrui Medicines, MSD, Pierre Fabre, Roche, Servier, Sirtex, Taiho, and Terumo; and participation on a data safety monitoring board or advisory board from AstraZeneca, Amgen, Beigene, Böhringer Mannheim, BMS, BTG, Daiichi Sankyo, Eisai, Incyte, Ipsen, MSD, Pierre Fabre, Roche, Servier, Sirtex, Taiho, and Terumo. OB and UP report no additional competing interests.