Tislelizumab vs Sorafenib as First-Line Treatment for Unresectable Hepatocellular Carcinoma: A Phase 3 Randomized Clinical Trial

Abstract

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.

Conflict of interest statement

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.

Figures

Figure 1.. Patient Flow Diagram

aDiscontinuation for the following reasons: COVID-19, death, met the criteria of treatment discontinuation, prohibited anticancer therapy during treatment, or withdrew from study treatment and continued survival follow-up. bThe intention-to-treat (ITT) analysis set included all randomized patients analyzed according to their randomized treatment arm. cThe safety analysis set included all patients who received at least 1 dose of study drug analyzed according to the study treatment received.

Figure 2.. Survival Analysis by Intention-to-Treat

Data cutoff was July 11, 2022. A, The prespecified boundary of noninferiority was the upper bound of the 95.003% CI of a stratified hazard ratio (HR) less than 1.08; prespecified boundary of superiority, 1-sided P < .0223 (approximate HR <0.8352). A total of 242 events (70.8%) occurred in the tislelizumab group (median overall survival [OS], 15.9 [95% CI, 13.2-19.7] months) and 255 (76.8%) in the sorafenib group (median OS, 14.1 [95% CI, 12.6-17.4] months). B, Data for patients who started to receive new anticancer therapy or were lost to follow-up were censored at the last valid tumor assessment date. A total of 276 events (80.7%) occurred in the tislelizumab group (median progression-free survival [PFS], 2.1 [95% CI, 2.1-3.5] months) and 224 (67.5%) in the sorafenib group (median PFS, 3.4 [95% CI, 2.2-4.1] months). aBased on a Cox proportional hazards regression model including treatment as a covariate, geographic region (Asia [including Japan] vs rest of world [Europe and the US]), macrovascular invasion (MVI) and/or extrahepatic spread (EHS; present vs absent), etiology (hepatitis C virus [HCV] vs other), and Eastern Cooperative Oncology Group (ECOG) performance status (0 vs 1) as stratification factors. bCalculated using 1-sided stratified log-rank test. cBased on a Cox proportional hazards regression model including treatment as a covariate, geographic region (Asia [including Japan] vs rest of world [Europe and the US]), MVI and/or EHS (present vs absent), etiology (HCV vs other), and ECOG PS (0 vs 1) as stratification factors.