PMID- 37796513 OWN - NLM STAT- MEDLINE DCOM- 20231222 LR - 20240102 IS - 2374-2445 (Electronic) IS - 2374-2437 (Print) IS - 2374-2437 (Linking) VI - 9 IP - 12 DP - 2023 Dec 1 TI - Tislelizumab vs Sorafenib as First-Line Treatment for Unresectable Hepatocellular Carcinoma: A Phase 3 Randomized Clinical Trial. PG - 1651-1659 LID - 10.1001/jamaoncol.2023.4003 [doi] AB - IMPORTANCE: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, and additional first-line treatments are needed. The programmed cell death protein 1 inhibitor tislelizumab demonstrated efficacy and a tolerable safety profile as second-line HCC treatment. OBJECTIVE: To investigate efficacy and safety of tislelizumab vs sorafenib tosylate for first-line treatment of unresectable HCC. DESIGN, SETTING, AND PARTICIPANTS: The open-label, global, multiregional phase 3 RATIONALE-301 randomized clinical trial enrolled systemic therapy-naive adults with histologically confirmed HCC, Barcelona Clinic Liver Cancer stage B or C disease, disease progression following (or patient was not amenable to) locoregional therapy, Eastern Cooperative Oncology Group performance status of 1 or less, and Child-Pugh class A, between December 27, 2017, and October 2, 2019. Data cutoff was July 11, 2022. INTERVENTION: Patients were randomized 1:1 to receive tislelizumab, 200 mg intravenously every 3 weeks, or sorafenib tosylate, 400 mg orally twice daily. MAIN OUTCOMES AND MEASURES: The primary end point was overall survival (OS); secondary end points included objective response rate, progression-free survival, duration of response, and safety. RESULTS: A total of 674 patients were included in the analysis (570 men [84.6%]; median age, 61 years [range, 23-86 years]). As of July 11, 2022, minimum study follow-up was 33 months. The primary end point of OS noninferiority of tislelizumab vs sorafenib was met in the intention-to-treat population (n = 674); median overall survival was 15.9 (95% CI, 13.2-19.7) months vs 14.1 (95% CI, 12.6-17.4) months, respectively (hazard ratio [HR], 0.85 [95.003% CI, 0.71-1.02]), and superiority of tislelizumab vs sorafenib was not met. The objective response rate was 14.3% (n = 49) for tislelizumab vs 5.4% (n = 18) for sorafenib, and median duration of response was 36.1 (95% CI, 16.8 to not evaluable) months vs 11.0 (95% CI, 6.2-14.7) months, respectively. Median progression-free survival was 2.1 (95% CI, 2.1-3.5) months vs 3.4 (95% CI, 2.2-4.1) months with tislelizumab vs sorafenib (HR, 1.11 [95% CI, 0.92-1.33]). The incidence of treatment-emergent adverse events (AEs) was 96.2% (325 of 338 patients) for tislelizumab and 100% (n = 324) for sorafenib. Grade 3 or greater treatment-related AEs were reported in 75 patients (22.2%) receiving tislelizumab and 173 (53.4%) receiving sorafenib. There was a lower incidence of treatment-related AEs leading to drug discontinuation (21 [6.2%] vs 33 [10.2%]) and drug modification (68 [20.1%] vs 187 [57.7%]) with tislelizumab vs sorafenib. CONCLUSIONS AND RELEVANCE: In RATIONALE-301, tislelizumab demonstrated OS benefit that was noninferior vs sorafenib, with a higher objective response rate and more durable responses, while median progression-free survival was longer with sorafenib. Tislelizumab demonstrated a favorable safety profile vs sorafenib. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03412773. FAU - Qin, Shukui AU - Qin S AD - Nanjing Tianyinshang Hospital of China Pharmaceutical University, Nanjing, China. FAU - Kudo, Masatoshi AU - Kudo M AD - Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan. FAU - Meyer, Tim AU - Meyer T AD - Academic Department of Oncology, Royal Free Hospital NHS Trust and University College London, London, United Kingdom. FAU - Bai, Yuxian AU - Bai Y AD - Department of Gastrointestinal Oncology, Harbin Medical University Cancer Hospital, Harbin, China. FAU - Guo, Yabing AU - Guo Y AD - Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China. FAU - Meng, Zhiqiang AU - Meng Z AD - Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China. FAU - Satoh, Taroh AU - Satoh T AD - Department of Frontier Science for Cancer and Chemotherapy, Osaka University, Osaka, Japan. FAU - Marino, Donatella AU - Marino D AD - Department of Oncology, Ordine Mauriziano Hospital, Turin, Italy. FAU - Assenat, Eric AU - Assenat E AD - Department of Oncology, Montpellier University Hospital, Montpellier, France. FAU - Li, Songzi AU - Li S AD - Biometrics, BeiGene Ltd, Ridgefield Park, New Jersey. FAU - Chen, Yaxi AU - Chen Y AD - Clinical Science, BeiGene (Beijing) Co, Ltd, Beijing, China. FAU - Boisserie, Frederic AU - Boisserie F AD - Clinical Science, BeiGene Ltd, Ridgefield Park, New Jersey. FAU - Abdrashitov, Ramil AU - Abdrashitov R AD - Clinical Development, BeiGene USA, Inc, Fulton, Maryland. FAU - Finn, Richard S AU - Finn RS AD - Division of Hematology/Oncology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California. FAU - Vogel, Arndt AU - Vogel A AD - Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. FAU - Zhu, Andrew X AU - Zhu AX AD - Jiahui International Cancer Center, Jiahui Health, Shanghai, China. AD - Massachusetts General Hospital, Harvard Medical School, Boston. LA - eng SI - ClinicalTrials.gov/NCT03412773 PT - Clinical Trial, Phase III PT - Journal Article PT - Randomized Controlled Trial PL - United States TA - JAMA Oncol JT - JAMA oncology JID - 101652861 RN - 9ZOQ3TZI87 (Sorafenib) RN - 0KVO411B3N (tislelizumab) RN - 0 (Antineoplastic Agents) SB - IM MH - Adult MH - Male MH - Humans MH - Middle Aged MH - Sorafenib/adverse effects MH - *Carcinoma, Hepatocellular/pathology MH - *Liver Neoplasms/pathology MH - *Antineoplastic Agents/adverse effects MH - Treatment Outcome PMC - PMC10557031 COIS- Conflict of Interest Disclosures: Dr Kudo reported receiving speaker fees from AstraZeneca, Bayer AG, Chugai Pharmaceutical Co, Ltd, Eisai Co, Ltd, Eli Lilly and Company, and Takeda Pharmaceutical Company Limited; consulting for F. Hoffmann-La Roche AG; and receiving research grants from AbbVie Inc, EA Pharma, Co, Ltd, Eisai Co, Ltd, Gilead Sciences, Inc, Otsuka Pharmaceutical Co, Ltd, Sumitomo Dainippon Pharma, Taiho Pharmaceutical Co, Ltd, Takeda Pharmaceutical Company Limited, and GE HealthCare outside the submitted work. Dr Meyer reported serving as a member the steering committee for BeiGene, Inc during the conduct of the study and consulting for Adaptimmune Therapeutics LC, AstraZeneca, BeiGene, Inc, Bristol Myers Squibb, Eisai Co, Ltd, Ipsen, MSD, and F. Hoffmann-La Roche AG and receiving grant funding from MSD outside the submitted work. Dr Satoh reported receiving grant funding from Bristol Myers Squibb, Chugai Pharmaceutical Co, Ltd, HUTCHMED, Ono Pharmaceutical Co, Ltd, Yakult Honsha Co, Ltd, Eli Lilly and Company, and BeiGene, Inc during the conduct of the study and receiving personal fees from Chugai Pharmaceutical Co, Ltd, Daiichi Sankyo Inc, Ono Pharmaceutical Co, Ltd, Bristol Myers Squibb, and Eli Lilly and Company outside the submitted work. Dr Marino reported receiving advisory board fees from F. Hoffmann-La Roche AG, MSD, and Merck & Co, Inc, and receiving travel expenses from Pierre Fabre and Amgen Inc outside the submitted work. Dr Assenat reported receiving advisory board fees from AstraZeneca, Ipsen, F. Hoffmann-La Roche AG, and Servier Laboratories. Dr Abdrashitov reported having stock ownership in AstraZeneca, BeiGene, Inc, Mirati Therapeutics, Inc, Syndax Pharmaceuticals Inc, and Takeda Pharmaceutical Company Limited. Dr Finn reported receiving serving on advisory boards for AstraZeneca, Bayer AG, Bristol Myers Squibb, CStone Pharmaceuticals, Eisai Co, Ltd, Eli Lilly and Company, Exelixis, Inc, Jiangsu Hengrui Pharmaceuticals Co, Ltd, Merck & Co, Inc, Pfizer Inc, and Roche-Genentech; receiving grant funding from Adaptimmune Therapeutics LC, Bayer AG, Bristol Myers Squibb, Eli Lilly and Company, Eisai Co, Ltd, Merck & Co, Inc, Pfizer Inc, and Roche-Genentech; and being a principal investigator for Bristol Myers Squibb, Eisai Co, Ltd, Merck & Co, Inc, Pfizer, and Roche-Genentech outside the submitted work. Dr Vogel reported receiving speaker fees from and serving on advisory boards for Amgen Inc, AstraZeneca, BeiGene, Inc, Bristol Myers Squibb, Boehringer Mannheim, BTG Limited, Daiichi Sankyo Inc, Eisai Co, Ltd, Incyte Corporation, Ipsen, MSD, Pierre Fabre, F. Hoffmann-La Roche AG, Servier Laboratories, Sirtex SIR-Spheres Pty Ltd, Taiho Pharmaceutical Co, Ltd, and Terumo Corporation and receiving speaking fees from GSK, AAA Imaging Solutions, and Jiangsu Hengrui Pharmaceuticals Co, Ltd, outside the submitted work. Dr Zhu reported having advisory roles and consulting for Eisai Co, Ltd, Roche-Genentech, Eli Lilly and Company, Sanofi SA, and Merck & Co, Inc. Dr Zhu reported consulting for Bayer AG, Eisai Co, Ltd, Eli Lilly and Company, Exelixis, Inc, Merck & Co, Inc, F. Hoffmann-La Roche AG, and Sanofi SA and being an employee of I-MAB Biopharma. No other disclosures were reported. EDAT- 2023/10/05 12:43 MHDA- 2023/12/22 06:42 PMCR- 2023/10/05 CRDT- 2023/10/05 11:34 PHST- 2023/12/22 06:42 [medline] PHST- 2023/10/05 12:43 [pubmed] PHST- 2023/10/05 11:34 [entrez] PHST- 2023/10/05 00:00 [pmc-release] AID - 2810119 [pii] AID - coi230052 [pii] AID - 10.1001/jamaoncol.2023.4003 [doi] PST - ppublish SO - JAMA Oncol. 2023 Dec 1;9(12):1651-1659. doi: 10.1001/jamaoncol.2023.4003.