Durvalumab or placebo plus gemcitabine and cisplatin in participants with advanced biliary tract cancer (TOPAZ-1): updated overall survival from a randomised phase 3 study.

BACKGROUND

In the preplanned interim analysis of the TOPAZ-1 study, durvalumab plus gemcitabine-cisplatin significantly improved overall survival versus placebo plus gemcitabine-cisplatin in participants with advanced biliary tract cancer. We aimed to report updated overall survival and safety data from TOPAZ-1 with additional follow-up and data maturity beyond the interim analysis.

METHODS

TOPAZ-1 was a phase 3, randomised, double-masked, placebo-controlled, global study done at 105 sites in 17 countries. Participants aged 18 years or older with unresectable, locally advanced, or metastatic biliary tract cancer were randomly assigned (1:1) to durvalumab plus gemcitabine-cisplatin or placebo plus gemcitabine-cisplatin using a computer-generated randomisation scheme, stratified by disease status and primary tumour location. Participants received durvalumab (1500 mg) or placebo on day 1 of each cycle every 3 weeks for up to eight cycles, plus gemcitabine (1000 mg/m

FINDINGS

From April 16, 2019, to Dec 11, 2020, 914 participants were enrolled, 685 of whom were randomly assigned (341 to the durvalumab plus gemcitabine-cisplatin group and 344 to the placebo plus gemcitabine-cisplatin group). 345 (50%) participants were male and 340 (50%) were female. Median follow-up at the updated data cutoff was 23·4 months (95% CI 20·6-25·2) in the durvalumab plus gemcitabine-cisplatin group and 22·4 months (21·4-23·8) in the placebo plus gemcitabine-cisplatin group. At the updated data cutoff, 248 (73%) participants in the durvalumab plus gemcitabine-cisplatin group and 279 (81%) participants in the placebo plus gemcitabine-cisplatin group had died (median overall survival 12·9 months [95% CI 11·6-14·1] vs 11·3 months [10·1-12·5]; hazard ratio 0·76 [95% CI 0·64-0·91]). Kaplan-Meier-estimated 24-month overall survival rates were 23·6% (95% CI 18·7-28·9) in the durvalumab plus gemcitabine-cisplatin group and 11·5% (7·6-16·2) in the placebo plus gemcitabine-cisplatin group. Maximum grade 3 or 4 adverse events occurred in 250 (74%) of 338 participants in the durvalumab plus gemcitabine-cisplatin group and 257 (75%) of 342 in the placebo plus gemcitabine-cisplatin group. The most common maximum grade 3 or 4 treatment-related adverse events were decreased neutrophil count (70 [21%] vs 86 [25%]), anaemia (64 [19%] vs 64 [19%]), and neutropenia (63 [19%] vs 68 [20%]).

INTERPRETATION

Durvalumab plus gemcitabine-cisplatin showed robust and sustained overall survival benefit with no new safety signals. Findings continue to support the regimen as a standard of care for people with untreated, advanced biliary tract cancer.

FUNDING

AstraZeneca.

Informations de copyright

2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.

Déclaration de conflit d'intérêts

Declaration of interests D-YO reports advisory fees from Arcus Biosciences, Aslan Pharmaceuticals, AstraZeneca, Basilea, Bayer, BeiGene, Bristol Myers Squibb/Celgene, Genentech/Roche, Halozyme, IQVIA, Merck Serono, Novartis, Taiho Pharmaceutical, Turning Point Therapeutics, Yuhan, and Zymeworks; and institutional research funding from Array BioPharma, AstraZeneca, BeiGene, Eli Lilly, Handok, MSD, Novartis, and Servier. ARH reports consulting fees from AstraZeneca, Bristol Myers Squibb, and Genentech/Roche; research funding from Genentech and Merck; and speakers bureau fees from Eisai and Bristol Myers Squibb. MB reports consulting fees from AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Ipsen, MSD, Roche, and Sirtex Medical; speakers bureau fees from Bayer, Eisai, and Roche; and support for travel and attending meetings from AstraZeneca, Bayer, and Sirtex Medical. TO reports advisory fees from AstraZeneca, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eisai, Eli Lilly, Incyte, Meiji Seika Pharma, Mundipharma, Nihon Servier, Nippon Shinyaku, Pfizer, Taiho Pharmaceutical, and Takara Bio; and speaker fees from AstraZeneca, Baxter, Bayer, Bristol Myers Squibb, Chugai Pharma, Dainippon Sumitomo Pharma, Eisai, Eli Lilly, MSD, Nihon Servier, Novartis, Ono Pharmaceutical, Taiho Pharmaceutical, Teijin Pharma, and Yakult Honsha. L-TC reports personal speaker fees from Bristol Myers Squibb, CStone, Eli Lilly, Ipsen, Ono Pharmaceutical, Novartis, PharmaEngine, and TTY; fees for medical monitoring for clinical trials for Taivex; fees received as a data and safety monitoring committee member for clinical trials for OBI Pharma; advisory fees from AstraZeneca, MSD, and SynCoreBio; speaker fees from AstraZeneca, HuniLife Biotechnology, Ono Pharmaceutical, ScinoPharm Taiwan, SynCoreBio, and TTY; and research funding from Celgene. MK reports research funding from AbbVie and Takeda; and honoraria from EA Pharma and AstraZeneca. JWK reports research funding from inno.N and Jeil Pharmaceutical; and consulting fees from AstraZeneca, BeiGene, BeyondBio, Bristol Myers Squibb/Celgene, Eisai, GC Cell, MSD Ono, Sanofi-Aventis, Servier, and TCUBEit. TS reports speaker fees from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Baxter, Eli Lilly, Mundipharma (Thailand), Janssen, MSD, Novartis, Roche, and Takeda; and advisory fees from Novartis and Roche. MI reports grant or research support from Aslan Pharmaceuticals, AstraZeneca, Bayer, Bristol Myers Squibb, Chiome Bioscience, Chugai Pharma, Delta-Fly Pharma, EA Pharma, Eisai, Eli Lilly Japan, J-Pharma, Merck, Merus NV, Nihon Servier, Novartis, Ono Pharmaceutical, Pfizer, Takeda, and Yakult; fees or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Astellas Pharma, Bayer, Bristol Myers Squibb, Chugai Pharma, Eisai, Eli Lilly Japan, MSD, Nihon Servier, Novartis, Otsuka, Dainippon Sumitomo Pharma, Taiho Pharmaceutical, Takeda, Teijin Pharma, and Yakult; and fees for participation on a data safety monitoring board or advisory board from Aslan Pharmaceuticals, Bayer, Bristol Myers Squibb, Chugai Pharma, Eisai, Eli Lilly Japan, GlaxoSmithKline, Nihon Servier, Novartis, and Takeda. J-SC reports grant or research support from Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Janssen, Eli Lilly, Merck KGaA, MSD, MSD Oncology, Oncologie, Ono Pharmaceutical, Roche, Senhwa Biosciences, SynCore, and TTY; and consulting fees from Ono Pharmaceutical. PP reports personal fees for an advisory board from AstraZeneca, Sanofi-Aventis, Bristol Myers Squibb, Janssen Oncology, MSD, Pierre Fabre, Roche, and Servier; personal fees as an invited speaker from AstraZeneca, Ipsen, Pierre Fabre, and Merck; and being a principal investigator for AstraZeneca and Roche. HAB reports research funding from AbbVie, Agios, Arch Pharmalabs, ARMO BioSciences, Array BioPharma, Arvinas, AstraZeneca, Bayer, BIND Therapeutics, BioAtla, BioMed Valley Discoveries, Biotheryx, Boehringer Ingelheim, Bristol Myers Squibb, CALGB, CicloMed, Coordination Pharmaceuticals, CytomX, eFFECTOR Therapeutics, Eli Lilly, EMD Serono, Foundation Medicine, Gossamer Bio, Gilead Sciences, GlaxoSmithKline, Harpoon Therapeutics, Incyte, Infinity Pharmaceuticals, Janssen, Jiangsu Hengrui Pharmaceuticals, Jounce Therapeutics, Kymab, MacroGenics, MedImmune, Merck, Millennium/Takeda, miRNA Therapeutics, Moderna, NGM Bio, Novartis, Pfizer, Revolution Medicine, Roche/Genentech, Ryvu Therapeutics, Seattle Genetics, Tesaro, TG Therapeutics, Verastem Oncology, Vertex Pharmaceuticals, XBiotech, and Zymeworks; and consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Forma Therapeutics, Grail, Incyte, Novartis, Pfizer, and Vincerx Pharma. VO reports grant or research support from Dr Reddy's Laboratories and Zydus Cadila; institutional fees for advisory board participation from AstraZeneca, Panacea Biotec, Dr Reddy's Laboratories, and Zydus Cadila; travel reimbursement as an invited speaker from AstraZeneca; other institutional financial interests with Alkem Laboratories, Eisai, Intas Pharmaceuticals, and Micro Labs; and non-financial interests with the Indian Association of Supportive Care in Cancer. ST reports honoraria from AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, MSD, Novartis, and Roche; speaker fees from Bristol Myers Squibb, Ipsen, and Novartis; and non-financial interests with AstraZeneca, Bristol Myers Squibb, Ipsen, Janssen, and Roche. CM reports institutional grant or research support from AstraZeneca, Daiichi Sankyo, Eisai, J-Pharma, Hitachi, Merck BioReliance, MSD, Kyowa Kirin, Ono Pharmaceutical, Taiho Pharmaceutical, and Yakult Honsha; personal fees for advisory board participation from AstraZeneca, Boehringer Ingelheim, Merck BioReliance, MSD, Servier, Taiho Pharmaceutical, and Yakult; and personal fees received as an invited speaker from AstraZeneca, Eisai, Kyowa Kirin, MSD, Novartis, Servier, Taiho Pharmaceutical, Teijin Pharma, and Yakult Honsha. REZ reports speaker fees from Bristol Myers Squibb, Ipsen, and Novartis; and travel grants from Pierre Fabre. MGM reports grant or research support from Ipsen, NuCana, and Servier; consulting fees from AstraZeneca and Incyte; and honoraria from Advanced Accelerator Applications and AstraZeneca. AA reports research funding from Amgen, Bayer, and Bristol Myers Squibb; and advisory fees from AstraZeneca, Amgen, Eisai, and MSD. JEC reports advisory fees from MSD; and fees as an invited speaker for AstraZeneca, Boehringer Ingelheim, Takeda, and Roche. VB reports consulting fees from Bayer, Bristol Myers Squibb Russia, Eisai, MSD, Novartis, Pfizer, Roche Russia, and Takeda; and travel expenses from Bayer, Bristol Myers Squibb Russia, MSD, and Roche Russia. BT reports research funding from Adaptimmune, AstraZeneca, Bristol Myers Squibb, and Exelixis. SS reports grant or research support from Delta-Fly Pharma and Incyte. DT reports personal fees for advisory board participation from Amgen, AstraZeneca, MSD, Pierre Fabre, Roche, Sanofi, and Servier. LE reports personal fees for advisory board participation from Amgen, Merk, MSD, and Servier. MP reports personal fees for advisory board participation from Roche and Servier; personal fees as an invited speaker from AstraZeneca, Ewopharma, and Takeda; and non-financial interests with AstraZeneca and Sanofi. DBZ reports advisory fees from Cornerstone Pharmaceuticals, Ipsen, Jazz Pharmaceuticals/Zymeworks, and QED Therapeutics; and research funding from AstraZeneca, Bayer, Bristol Meyers Squibb, Cornerstone Pharmaceuticals, Daiichi Sankyo, Eli Lily, Ipsen, Roche/Genentech, Legend Biotech, Merck, and Seagen. VGG holds stock in RPG Life Sciences and Zydus Lifesciences. FD reports grant or research support from Amgen, AstraZeneca, Bristol Myers Squibb, Exelixis, Genentech, Ipsen, Signatera, and Taiho Pharmaceutical; consulting fees from AstraZeneca, Eisai, Exelixis, Genentech, and Ipsen; and payment or honoraria from Astellas, Eisai, Exelixis, Ipsen, Servier, and Sirtex Medical. JOP reports advisory board fees from Adicet Bio, AstraZeneca, Bristol Myers Squibb (Celgene), MediRama, MedPacto, Merck Serono, and Servier; support for travel to meetings from Minneamrita Therapeutics; and grant or research support from ABL Bio, Bristol Myers Squibb (Celgene), Eutilex, MedPacto, and Servier. HK, CM, and MŻ are employees of AstraZeneca. JW and NR are employees of and hold stock in AstraZeneca. AV reports speaker fees from BeiGene, Bristol Myers Squibb, Eisai, Imaging Equipment, Incyte, Ipsen, Jiangsu Hengrui Pharmaceuticals, Eli Lilly, MSD, Novartis, Pierre Fabre, and Roche; and advisory fees from AstraZeneca, Bayer, Bristol Myers Squibb, Boston Scientific, Daiichi Sankyo, Eisai, Ipsen, Incyte, Lilly, MSD, Pierre Fabre, Roche, and Sirtex Medical. JWV reports advisory fees from Agios, AstraZeneca, Autem Therapeutics, Baxter, Hutchison MediPharma, Image Equipment, NuCana, QED Therapeutics, Sirtex Medical, Servier, and Zymeworks; speaker fees from Incyte, Ipsen, and Mylan; and research funding from AstraZeneca and Redx. All other authors declare no competing interests.