Tislelizumab vs Sorafenib as First-Line Treatment for Unresectable Hepatocellular Carcinoma

Abstract

ImportanceHepatocellular 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.ObjectiveTo investigate efficacy and safety of tislelizumab vs sorafenib tosylate for first-line treatment of unresectable HCC.Design, Setting, and ParticipantsThe 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.InterventionPatients were randomized 1:1 to receive tislelizumab, 200 mg intravenously every 3 weeks, or sorafenib tosylate, 400 mg orally twice daily.Main Outcomes and MeasuresThe primary end point was overall survival (OS); secondary end points included objective response rate, progression-free survival, duration of response, and safety.ResultsA 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 RelevanceIn 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 RegistrationClinicalTrials.gov Identifier: NCT03412773

Quantification of Treatment Effect of Tislelizumab vs Sorafenib for Hepatocellular Carcinoma

“…To the Editor Qin and colleagues conducted an important trial to compare tislelizumab with sorafenib. The study was designed within a noninferiority setting for overall survival (OS) by claiming tislelizumab would be noninferior to sorafenib if the upper bound of the 95.003% CI for the hazard ratio (HR) was less than 1.08.…”

“…The objective response rates were 14.3% and 5.4% for tislelizumab and sorafenib, respectively. The corresponding median durations of response were 36.1 and 11.0 months, respectively . There are several issues that may deserve our attention for conducting future clinical studies in a similar setting.…”

“…The Kaplan-Meier curves for OS presented in Figure 2A of the study by Qin and colleagues are tangled together until month 14. Therefore, the validity of using HRs to quantity the OS difference between 2 treatments may be questionable.…”

“…Using reconstructed OS data from Figure 2A of the study by Qin and colleagues, 4-year mean survival times for tislelizumab and sorafenib were 22.22 and 19.90 months, respectively. The difference was 2.32 months with a 95% CI of −0.29 to 4.92.…”

Quantification of Treatment Effect of Tislelizumab vs Sorafenib for Hepatocellular Carcinoma—Reply

“…In Reply I thank and have provided responses to Sun et al for their comments on our article that compared tislelizumab vs sorafenib in first-line treatment of unresectable hepatocellular carcinoma. The noninferiority margin of 1.08 is clearly clinically justifiable.…”