Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first line treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma: RATIONALE-305 randomised, double blind, phase 3 trial
- PMID: 38806195
- DOI: 10.1136/bmj-2023-078876
Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first line treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma: RATIONALE-305 randomised, double blind, phase 3 trial
Abstract
Objective: To evaluate the efficacy and safety of tislelizumab added to chemotherapy as first line (primary) treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma compared with placebo plus chemotherapy.
Design: Randomised, double blind, placebo controlled, phase 3 study.
Setting: 146 medical centres across Asia, Europe, and North America, between 13 December 2018 and 28 February 2023.
Participants: 1657 patients aged ≥18 years with human epidermal growth factor receptor 2 negative locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma, regardless of programmed death-ligand 1 (PD-L1) expression status, who had not received systemic anticancer therapy for advanced disease.
Interventions: Patients were randomly (1:1) assigned to receive either tislelizumab 200 mg or placebo intravenously every three weeks in combination with chemotherapy (investigator's choice of oxaliplatin and capecitabine, or cisplatin and 5-fluorouracil) and stratified by region, PD-L1 expression, presence or absence of peritoneal metastases, and investigator's choice of chemotherapy. Treatment continued until disease progression or unacceptable toxicity.
Main outcome measures: The primary endpoint was overall survival, both in patients with a PD-L1 tumour area positivity (TAP) score of ≥5% and in all randomised patients. Safety was assessed in all those who received at least one dose of study treatment.
Results: Of 1657 patients screened between 13 December 2018 and 9 February 2021, 660 were ineligible due to not meeting the eligibility criteria, withdrawal of consent, adverse events, or other reasons. Overall, 997 were randomly assigned to receive tislelizumab plus chemotherapy (n=501) or placebo plus chemotherapy (n=496). Tislelizumab plus chemotherapy showed statistically significant improvements in overall survival versus placebo plus chemotherapy in patients with a PD-L1 TAP score of ≥5% (median 17.2 months v 12.6 months; hazard ratio 0.74 (95% confidence interval 0.59 to 0.94); P=0.006 (interim analysis)) and in all randomised patients (median 15.0 months v 12.9 months; hazard ratio 0.80 (0.70 to 0.92); P=0.001 (final analysis)). Grade 3 or worse treatment related adverse events were observed in 54% (268/498) of patients in the tislelizumab plus chemotherapy arm versus 50% (246/494) in the placebo plus chemotherapy arm.
Conclusions: Tislelizumab added to chemotherapy as primary treatment for advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma provided superior overall survival with a manageable safety profile versus placebo plus chemotherapy in patients with a PD-L1 TAP score of ≥5%, and in all randomised patients.
Trial registration: ClinicalTrials.gov NCT03777657.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Conflict of interest statement
Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: support from BeiGene. D-YO has participated on a data safety monitoring board or advisory board for AstraZeneca, Novartis, Genentech/F Hoffmann-La Roche, Merck Serono, Bayer, Taiho, ASLAN, Halozyme, Zymeworks, Bristol Myers Squibb/Celgene, BeiGene, Basilea, Turning Point, Yuhan, Arcus Biosciences, IQVIA, and Merck Sharp and Dohme; and has received grants from AstraZeneca, Novartis, Array, Eli Lilly, Servier, BeiGene, Merck Sharp and Dohme, and Handok. KK has received consulting fees from Bristol Myers Squibb, Ono Pharmaceutical, Merck Sharp and Dohme, Bayer, BeiGene, AstraZeneca, Seagen/Pfizer, Servier, and Janssen; and has received honorariums from Bristol Myers Squibb, Ono Pharmaceutical, and Merck Sharp and Dohme. TA has participated on a data safety monitoring board or advisory board for BeiGene; and has received honorariums from iOnctura and LabGenius. JT has received consulting fees from Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiff Oncology, Chugai, Daiichi Sankyo, Genentech/F Hoffmann-La Roche, HalioDx, Hutchison MediPharma International, Ikena Oncology, Inspirna, IQVIA, Lilly, Menarini, Merck Serono, Merus, Merck Sharp and Dohme, Mirati, NeoPhore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Scandion Oncology, Scorpion Therapeutics, Seagen/Pfizer, Servier, Sotio Biotech, Taiho Pharmaceutical, TheraMyc, and Tolremo Therapeutics; has received honorariums from Imedex/HMP, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education, and Physicians Education Resource; and has stock in Oniria Therapeutics. MCC has received grants from BeiGene, AbbVie, Genentech/F Hoffmann-La Roche, Taiho, Seagen/Pfizer, Bristol Myers Squibb, Merck, Pfizer, Janssen, Mirati Therapeutics, Tempus, HUYABIO International, Regeneron, and DELFI. K-WL has received support for the present manuscript from BeiGene; has received grants to his institution for conducting clinical trials from AstraZeneca, Ono Pharmaceutical, Merck Sharp and Dohme, Merck KGaA, F Hoffmann-La Roche, Pfizer, Leap Therapeutics, ALX Oncology, Zymeworks, Astellas, Macrogenics, Amgen, Seagen/Pfizer, Bolt Therapeutics, Trishula Therapeutics, Oncologie, Pharmacyclics, MedPacto, Green Cross, ABL Bio, Y-BIOLOGICS, Daiichi Sankyo, Taiho Pharmaceutical, InventisBio, Elevar Therapeutics, Metafines, Idience, Genome and Company, and Exelixis; has received honorariums from Ono Pharmaceutical, Boryung, Daiichi Sankyo, Astellas, and Sanofi-Aventis; and has participated on a data safety monitoring board or advisory board for ALX Oncology and Metafines. SYR has received grants from AstraZeneca, Ono Pharmaceutical, Eisai, Ipsen, Merck Sharp and Dohme, Merck KGaA, Pfizer, BeiGene, Astellas Pharma, Amgen, ALX Oncology, Zymeworks, Macrogenics, Seagen/Pfizer, Bold Therapeutics, MedPacto, ABLBIO, Daiichi Sankyo, Taiho Pharmaceutical, Leap Therapeutics, and Arcus Biosciences; has received consulting fees from LG Biochem and Indivumed; has received honorariums from Merck Sharp and Dohme, Lilly, Daiichi Sankyo, and Eisai; and has participated on a data safety monitoring board or advisory board for Amgen. HH has received support for the present manuscript from BeiGene; has received grants from Amgen, Astellas, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Insyte, Janssen Pharmaceutical, Merck Biopharma, Merck Sharp and Dohme, Novartis, Ono Pharmaceutical, Pfizer, Seagen/Pfizer, and Taiho Pharmaceutical; and has received honorariums from Nichi-Iko, Novartis, Ono Pharmaceutical, Taiho Pharmaceutical, and Teijin Pharma. DS has received support for the present manuscript from BeiGene; has received grants from Genentech/F Hoffmann-La Roche, Novartis, Celgene, Bristol Myers Squibb, Lilly, AstraZeneca, University of Texas of SW Medical Center - Simmons Cancer Center, Merck, G1 Therapeutics, Neon Therapeutics, Nektar, Celldex, Clovis Oncology, Daiichi Sankyo, Astellas Pharma, GRAIL, Transgene, Aeglea Biotherapeutics, Ipsen, BIND Therapeutics, Eisai, ImClone Systems, Janssen Oncology, MedImmune, Agios, GlaxoSmithKline, Tesaro, Cyteir Therapeutics, Novocure, Elevation Oncology, Calithera Biosciences, Arcus Biosciences, Arrys Therapeutics, Bayer, BeiGene, Blueprint Medicine, Boehringer Ingelheim, Hutchinson MediPharma, Incyte, Kronos Bio, Loxo Oncology, MacroGenics, Molecular Templates, Pure Tech Health, Razor Genomics, Repare Therapeutics, Rgenix, Tizona Therapeutics, Verastem, BioNTech, AbbVie, Amgen, Anheart Therapeutics, Ascendis Pharma, Endeavour BioMedicines, Erasca, Faeth Therapeutics, FujiFilm, Gilead Sciences, Jazz Pharmaceuticals, Lyell Immunopharma, Millennium, Moderna Therapeutics, Monte Rosa Therapeutics, Peloton Therapeutics, Shenzhen Chipscreen Biosciences, Stemline Therapeutics, Synthekine, Taiho Oncology, Tango Therapeutics, Tarveda Therapeutics, Zai Laboratory, Apollomics, Strata Oncology, and Asher Biotherapeutics; and has received consulting fees from Genentech/F Hoffmann-La Roche, Novartis, Bristol Myers Squibb, AstraZeneca, GlaxoSmithKline, Molecular Templates, Jazz Pharmaceuticals, Sanofi-Aventis, Regeneron, Lilly, BeiGene, Ipsen, Monte Rosa Therapeutics, AbbVie, Lyell Immunopharma, and Novocure. KY has received support for the present manuscript from BeiGene; has received grants from Taiho Pharmaceutical; and has received honorariums from Daiichi Sankyo, Chugai Pharmaceutical, Bristol Myers Squibb K.K., Eli Lilly Japan K.K., Taiho Pharmaceutical, Ono Pharmaceutical, Takeda Pharmaceutical, and Merck Biopharm. RPC has received grants from Astellas and Ipsen; has received honorariums from Eisai, F Hoffmann-La Roche, and Bristol Myers Squibb; has received payment for expert testimony from AstraZeneca and Lilly; and has received support for attending meetings and/or travel from Lilly, F Hoffmann-La Roche and Bristol Myers Squibb. LF has received grants from AstraZeneca; has received consulting fees from AstraZeneca, Merck Sharp and Dohme, Eli Lilly, and Servier; has received honorariums from Merck Sharp and Dohme, Eli Lilly, and Bristol Myers Squibb; and has participated on a data safety monitoring board or advisory board for Merck Sharp and Dohme, Bristol Myers Squibb, Daiichi Sankyo, Servier, Taiho Oncology, and AstraZeneca. LE has received consulting fees from Merck Sharp and Dohme, Bristol Myers Squibb, and Amgen; has received honorariums from Merck Sharp and Dohme, Bristol Myers Squibb, and Servier; and has received support for attending meetings and/or travel from Servier and Merck Serono. HW is an employee of BeiGene and has stock or stock options in BeiGene. YX, JL, TS, and SY are employees of BeiGene and have no additional competing interests. LL is an employee of BeiGene (Beijing); has received support for attending meetings and/or travel from BeiGene (Beijing); and has stock or stock options with BeiGene (Beijing). MM has received grants from Amgen, Leap Therapeutics, Merck Serono, AstraZeneca, and Merck Sharp and Dohme; has received consulting fees from Bayer, Merck Sharp and Dohme, Merck Serono, Amgen, Taiho Pharmaceutical, Pfizer, F Hoffmann-La Roche, Lilly, Servier, BeiGene, Bristol Myers Squibb, and AstraZeneca; has received honorariums from Amgen, Genentech/F Hoffmann-La Roche, Merck Serono, Merck Sharp and Dohme Oncology, Bristol Myers Squibb, AstraZeneca/MedImmune, Servier, Pierre Fabre, and Sanofi; and has received support for attending meetings and/or travel from Amgen, Merck Serono, F Hoffmann-La Roche, Bayer, ASCO, German Cancer Society, Merck Sharp and Dohme, ESMO, and BeiGene. R-HX has received consulting fees from Hutchison, Hengrui, Junshi, Qilu, CPPC, F Hoffmann-La Roche, Merck Serono; and has participated on data safety monitoring boards or advisory boards for Astellas, Merck Sharp and Dohme, AstraZeneca, Junshi, Hengrui, BeiGene, Innovent, CPPC, and Keymed Biosience. All other authors declare no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.
Publication types
MeSH terms
Substances
Supplementary concepts
Associated data
LinkOut - more resources
Full Text Sources
Medical
Research Materials
Miscellaneous
