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.

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.