139MO - Tislelizumab (TIS) plus chemotherapy (Chemo) vs placebo (PBO) plus chemo as first-line (1L) treatment of advanced gastric or gastroesophageal junction adenocarcinoma (GC/GEJC): Final analysis results of the RATIONALE-305 study

Background

TIS (anti-PD-1 antibody) plus (+) chemo demonstrated significant overall survival (OS) benefit vs PBO + chemo as 1L treatment in patients (pts) with advanced GC/GEJC at a pre-specified interim analysis of the PD-L1-positive (tumor area positivity score ≥5%) population in the global, phase 3 RATIONALE-305 study (NCT03777657). Here, we present primary analysis results in the intent-to-treat (ITT) population at the pre-specified final analysis.

Methods

Adults with previously untreated, HER2-negative, locally advanced, unresectable, or metastatic GC/GEJC, regardless of PD-L1 expression status, were randomized (1:1) to receive TIS 200 mg or PBO IV once every 3 weeks plus investigator (INV)-choice of chemo (5-FU + cisplatin or capecitabine + oxaliplatin). The primary endpoints were OS in the PD-L1-positive and ITT populations. Secondary endpoints included progression-free survival, objective response rate, and duration of response by INV per RECIST v1.1, and safety.

Results

At data cutoff, 997 pts were randomized (501 pts to TIS + chemo; 496 pts to PBO + chemo). Minimum study follow-up was 24.6 mo. OS in the TIS arm was significantly improved compared with the PBO arm in the ITT population (median OS: 15.0 mo vs 12.9 mo, respectively; HR=0.80 [95% CI: 0.70, 0.92]; 1-sided P=0.0011). Additional main efficacy results are presented in the Table. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 268 (53.8%) pts in the TIS arm and 246 (49.8%) pts in the PBO arm; TRAEs led to treatment discontinuation in 16.1% vs 8.1% of pts, respectively, and death in 1.2% vs 0.4%, respectively. Table: 139MO

ITT population. Data cutoff: 28 February 2023. Chemo, chemotherapy; CI, confidence interval; HR, hazard ratio; ITT, intent-to-treat; mDoR, median duration of response; mo, months; ORR, objective response rate; OS, overall survival; PBO, placebo; PFS, progression-free survival; TIS, tislelizumab.

Conclusions

In the ITT population, TIS + chemo showed statistically significant and clinically meaningful improvement in OS vs PBO + chemo and was well tolerated. These data support the TIS + chemo combination as a potential 1L treatment option for pts with advanced GC/GEJC.

Clinical trial identification

NCT03777657 (first posted December 17, 2018).

Editorial acknowledgement

This study was sponsored by BeiGene, Ltd. Medical writing support, under the direction of the authors, was provided by Victoria Dagwell, MSc, and Gemma Walker, BSc, of Ashfield MedComms, an Inizio company, and was funded by BeiGene, Ltd.

Legal entity responsible for the study

BeiGene, Ltd.

Funding

BeiGene, Ltd.

Disclosure

R. Xu: Financial Interests, Personal, Invited Speaker: BMS, MSD; Financial Interests, Personal, Advisory Board: Henrui, BeiGene, Astellas, Merck, Junshi. D. Oh: Financial Interests, Personal, Advisory Board: AstraZeneca, Novartis, Genentech/Roche, Merck Serono, Bayer, Taiho, ASLAN, Halozyme, Zymeworks, BMS/Celgene, BeiGene, Basilea, Turning Point, Yuhan, Arcus Biosciences, IQVIA, MSD; Financial Interests, Institutional, Research Grant: AstraZeneca, Novartis, Array, Eli Lilly, Servier, BeiGene, MSD, Handok. K. Kato: Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical, Bristol Myers Squibb, Merck and Co; Financial Interests, Personal, Advisory Board: Ono Pharmaceutical, Bristol Myers Squibb, Merck and Co, Bayer, AstraZeneca, BeiGene, Taiho, Merck Biophrma, Amgen, Novartis, Daiichi Sankyo; Financial Interests, Institutional, Coordinating PI: Ono Pharmaceuticals, Merck & Co; Financial Interests, Institutional, Local PI: Bayer, AstraZeneca, BeiGene, Chugai, Taiho, Oncolys Biopharma, Janssen Pharmaceutical. H. Arkenau: Financial Interests, Personal, Speaker’s Bureau: iOnctura, lab genius; Financial Interests, Personal, Advisory Board: BeiGene. J. Tabernero: Financial Interests, Personal, Advisory Board, scientific consultancy role: Orion Biotechnology, Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc., HalioDX SAS, Ikena Oncology, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Servier, Taiho, Tessa Therapeutics, TheraMyc, Hutchinson MediPharma International, Scandion Oncology, Ona Therapeutics, Sotio Biotech, Inspirna Inc, Scorpion Therapeutics, Tolremo Therapeutics; Financial Interests, Personal, Invited Speaker, educational collaboration: Medscape Education, Physicians Education Resource (PER), PeerView Institute for Medical Education, Imedex / HMP; Financial Interests, Personal, Invited Speaker, educacional collaboration: MJH Life Sciences; Financial Interests, Personal, Advisory Board: Cardiff Oncology; Financial Interests, Personal, Stocks/Shares: Oniria Therapeuics; Financial Interests, Institutional, Research Grant, ACRCelerate: Colorectal Cancer Stratified: Fundación Científica de la Asociación Española Contra el Cáncer; Financial Interests, Institutional, Research Grant, OPTIMISTICC: Opportunity to Investigate the Microbiome’s Impact on Science and Treatment In Colorectal Cancer: Cancer Research UK; Financial Interests, Institutional, Funding, Clinical Trials & Research: Amgen Inc, Array Biopharma Inc, AstraZeneca Pharmaceuticals LP, Bristol Myers Squibb International Corporation, Celgene International SARL, Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc, Janssen-Cilag International NV, Merck Health KGAA, Merck, Sharp & Dohme de España, SA, Novartis Farmacéutica SA, PharmaMar SA, Sanofi-Aventis Recherche & Développement, Servier, Taiho Pharma USA, Inc, BeiGene, Boehringer Ingelheim, HalioDX SAS, Hutchinson Medipharma, MedImmune, Menarini, Merus N V, Pfizer, Mirati; Non-Financial Interests, Personal, Member of Board of Directors, Board of Directors: Cancer Core Europe, Spanish Association Against Cancer -AECC; Non-Financial Interests, Personal, Member of Board of Directors, General Assembly: Horizon Europe Cancer Mission; Non-Financial Interests, Personal, Leadership Role, External Scientific Committee: Institute for Health Research INCLIVA – Clinical Hospital of Valencia, IdiSNA –Universidad de Navarra; Non-Financial Interests, Personal, Leadership Role, Scientific Advisory Board: Spanish National Cancer Research Centre (CNIO); Non-Financial Interests, Personal, Advisory Role, International Scientific Evaluation Committee: Bosch Health Campus (BHC); Non-Financial Interests, Personal, Advisory Role, Review Board: National Decade Against Cancer (NCT) - German Consortium for Translational Cancer Research (DKTK); Non-Financial Interests, Personal, Advisory Role, Scientific Advisory Board: Karolinska Comprehensive Cancer Centre; Non-Financial Interests, Personal, Advisory Role, International Review Committee (IRC): Oncode Institute; Non-Financial Interests, Personal, Advisory Role, Scientific Advisory Board (SAB): Oslo University Hospital Comprehensive Cancer Centre (OUH CCC); Non-Financial Interests, Personal, Leadership Role, Governance Advisory Committee: European Organization for Research and Treatment of Cancer -EORTC; Non-Financial Interests, Personal, Leadership Role, Vice Chairman: World Innovative Networking (WIN) Consortium in Personalized Cancer Medicine; Non-Financial Interests, Personal, Other, Coordinating PI & Steering Committee Member. Clinical Trials & Research: Array Biopharma Inc., AstraZeneca Pharmaceutical LP, Boehringer Ingelheim, MedImmune, Menarini, Merck Healthcare KGAA, Merck, Sharp & Dohme de España SA, Pfizer, Servier; Non-Financial Interests, Personal, Principal Investigator, Clinical Trials & Research: Array Biopharma Inc., AstraZeneca Pharmaceutics LP, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb International Corporation, Celgene International SARL, Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc., HalioDX SAS, Hutchinson Medipharma, Janssen-Cilag International NV, MedImmune, Menarini, Merck Healthcare KGAA, Merck, Sharp & Dohme de España SA, Merus NV, Mirati, Novartis Farmacéutica SA, Pfizer, Sanofi-Aventis Recherche & Développement, Servier, Taiho Pharma USA Inc; Non-Financial Interests, Personal, Other, Steering Committee Member. Clinical Trials & Research: Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc., HalioDX SAS, Hutchinson Medipharma, Janssen-Cilag International NV, Merus NV, Taiho Pharma USA Inc; Non-Financial Interests, Personal, Other, Coordinating PI. Clinical Trials & Research: Mirati; Non-Financial Interests, Personal, Member: AACR, ASCO, EACR, EORTC, SEOM; Other, Personal, Other, President: Oncology Master Plan – Catalonia Department of Health; Other, Personal, Other, Advisory Committee: Advisory Committee on Pharmaceutical Provision Financing under the Spanish National Health System. M. Cruz-Correa: Financial Interests, Institutional, Research Grant: Merck, SeaGen, BMS, Taiho, Pfizer, Janssen, AbbVie, Genentech, Incyte, HUYABIO, BeiGene. A.V. Zimina: Non-Financial Interests, Personal, Principal Investigator, Participation as PI in YUHAN LASER-301 trial.: YUHAN. K. Lee: Financial Interests, Personal, Advisory Board: BMS (Korea), Bayer (Korea), Daiichi Sankyo (Korea), Merck Sharp & Dohme (Korea), Metafines, Vifor pharma (Korea), Astellas (Korea); Financial Interests, Personal, Invited Speaker: Boryung Co.; Financial Interests, Institutional, Local PI: ABLBIO, ALX Oncology, Amgen, Arcus Biosciences, Astellas Pharma, AstraZeneca, BeiGene, Bolt therapeutics, Daiichi Sankyo, Exelixis, Genexine, Green Cross Corp, InventisBio, LSK BioPharma, Leap therapeutics, Macrogenics, MedPacto, Merck KGaA, Merck Sharp & Dohme, Oncologie, Ono pharmaceutical, Y-BIOLOGICS, Pfizer, Pharmacyclics, Seagen, Taiho Pharmaceutical, Trishula therapeutics, Zymeworks,; Non-Financial Interests, Personal, Leadership Role, SMC chair of ASPEN-06 study: ALX Oncology. H. Hirano: Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical, Ono Pharmaceutical, Teijin Phama, Novartis; Financial Interests, Personal, Writing Engagement: Nichi-Iko; Financial Interests, Institutional, Research Grant: Chugai Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Ono Pharmaceutical, Janssen Pharmaceutical, Merck Biopharma, Bristol Myers Squibb, Pfizer, Eisai, Amgen, Astellas, Seagen, MSD, Insyte, BeiGene, Novartis. D.R. Spigel: Financial Interests, Institutional, Other, Consulting: AstraZeneca, BeiGene, Bristol Myers Squibb, Evidera, GSK, Ipsen Biopharmaceuticals, Janssen, Jazz Pharmaceuticals, Lilly, Molecular Templates, Monte Rosa Therapeutics, Novartis, Pfizer, Regeneron, Sanofi-Aventis, AbbVie, Novocure, Roche/Genentech; Financial Interests, Institutional, Research Grant, Serve as PI: Amgen, Aeglea Biotherapeutics, Agios, Arrys Therapeutics, Astellas, AstraZeneca, Bayer, BeiGene, BIND Therapeutics, Blueprint Medicine, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celldex Therapeutics, Clovis, Daiichi Sankyo, Eisai, Lilly, Genentech/Roche, G1 Therapeutics, Gilead Sciences, GSK, GRAIL, Hutchinson MediPharma, ImClone Systems, Ipsen, Janssen, Loxo, MacroGenics, MedImmune, Merck, Nektar, Neon Therapeutics, Novartis, Novocure, Rgenix, SeaGen, Taiho Oncology, Tarveda, Tizona Therapeutics, Transgene, UT Southwestern, Verastem, Arcus Biosciences, Molecular Template, Cyteir Therapeutics, BioNTech, Apollomics, Pure Tech Health, Elevation Oncology, Repare Therapeutics, Razor Genomics, Denovo Biopharma, Erasca, Kronos Bio, Zai Laboratory, Faeth Therapeutics, Ascendis Pharma, Lyell Immunopharma, Synthekine, Shenzhen Chipscreen Biosciences, AbbVie, AnHeart Therapeutics, Calithera, Endeavor, FujiFilm Pharmaceuticals, Incyte, Jazz Pharmaceuticals, Millennium Pharmaceuticals, Moderna, Monte Rosa Therapeutics, Peloton Therapeutics, Stemline Therapeutics, Tango Therapeutics, Tesaro. L.S. Wyrwicz: Financial Interests, Personal, Advisory Board: BMS, Servier; Financial Interests, Personal and Institutional, Local PI: BMS, MSD, Servier, BeiGene, Roche, AstraZeneca; Financial Interests, Personal, Steering Committee Member: AstraZeneca. R.A. Pazo Cid: Financial Interests, Personal, Advisory Board: Roche, BMS, Servier, Ipsen, Lilly, AstraZeneca; Financial Interests, Personal, Invited Speaker: Servier, BMS, Roche, Eisai; Financial Interests, Personal and Institutional, Local PI, Support for manuscript presentation (funding, provision of study materials, medical writing, article processing charges): Ipsen, Astellas. L. Li: Financial Interests, Personal, Full or part-time Employment: BeiGene (Beijing) Co., Ltd.; Financial Interests, Personal, Stocks/Shares: BeiGene (Beijing) Co., Ltd.; Financial Interests, Personal, Training: BeiGene (Beijing) Co., Ltd. Y. Xu: Financial Interests, Personal, Full or part-time Employment: BeiGene (Shanghai) Co., Ltd; Financial Interests, Personal, Stocks/Shares: BGNE (NASDAQ). M.B. McHenry: Financial Interests, Personal, Full or part-time Employment: BeiGene; Financial Interests, Personal, Stocks/Shares, Stockholder: BeiGene. S. Yang: Financial Interests, Personal, Full or part-time Employment: BeiGene. M. Moehler: Financial Interests, Personal, Advisory Board: BMS, Servier, Amgen, Lilly, BeiGene, Novartis, Taiho, Daiichi, Amgen, MD; Financial Interests, Personal, Invited Speaker: MSD, BMS, Falk foundation, AIO, BeiGene, Amgen; Financial Interests, Institutional, Advisory Board: Bayer, Sanofi; Financial Interests, Personal, Other, Chair: EORTC. All other authors have declared no conflicts of interest.