In the phase III RATIONALE-301 trial reported in JAMA Oncology, Shukui Qin, MD, PhD, and colleagues found that tislelizumab was noninferior to sorafenib in terms of overall survival as first-line treatment for patients with unresectable hepatocellular carcinoma.
Shukui Qin, MD, PhD
Study Details
In the open-label international noninferiority trial, 674 patients (primarily Asian) were randomly assigned between December 2017 and October 2019 to receive tislelizumab at 200 mg every 3 weeks (n =342) or sorafenib at 400 mg twice daily (n = 332) until disease progression or unacceptable toxicity. Patients had to have Barcelona Clinic Liver Cancer stage B or C disease, disease progression following locoregional therapy (or lack of amenability to such treatment), and Child-Pugh class A disease. For the tislelizumab vs sorafenib groups, 63% vs 63% of patients were from Asia, excluding Japan; 11% vs 12% were from Japan; and 26% vs 25% were from elsewhere.
The primary endpoint was overall survival. Noninferiority was claimed if the upper limit of the 95.003% confidence interval for the hazard ratio was > 1.08. If noninferiority was met, superiority was tested with a criterion of P < .0223.
Key Findings
Minimum follow-up was 33 months. Median overall survival was 15.9 months (95% CI = 13.2–19.7 months) in the tislelizumab group vs 14.1 months (95% CI = 12.6–17.4 months) in the sorafenib group (hazard ratio [HR] = 0.85, 95.003% confidence interval [CI] = 0.71-1.02), thus meeting the noninferiority criterion. Superiority of tislelizumab vs sorafenib was not met (P = .04). Rates at 24 and 36 months were 39.0% vs 31.8% and 29.2% vs 20.3%, respectively.
Objective response on blinded independent review committee assessment was observed in 14.3% vs 5.4% of patients (difference = 8.28%, 95% CI = 3.85%–12.70%), with median response durations of 36.1 months (95% CI = 16.8 months to not evaluable) vs 11.0 months (95% CI = 6.2–14.7 months).
Median progression-free survival was 2.1 months (95% CI = 2.1–3.5 months) vs 3.4 months (95% CI = 2.2–4.1 months; HR = 1.11, 95% CI = 0.92–1.33). Rates at 6, 12, 18, and 24 months were 35.8% vs 28.8%, 19.0% vs 18.1%, 16.1% vs 9.5%, and 13.9% vs 6.1%, respectively.
Grade ≥ 3 treatment-related adverse events occurred in 22.2% of patients in the tislelizumab group vs 53.4% of the sorafenib group; serious treatment-related adverse events occurred in 11.8% vs 10.2%. Treatment-related adverse events led to discontinuation of treatment in 6.2% vs 10.2% of patients. Immune-mediated adverse events occurred in 18.3% (grade ≥ 3 in 8.3%) of patients in the tislelizumab group vs 0% of the sorafenib group. Treatment-related death occurred in three patients (0.9%) vs two patients (0.6%).
The investigators concluded, “In RATIONALE-301, tislelizumab demonstrated overall survival 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.”
Dr. Qin, of Nanjing Tianyinshang Hospital of China Pharmaceutical University, Nanjing, is the corresponding author for the JAMA Oncology article.
Disclosure: The study was supported by BeiGene, Ltd. For full disclosures of the study authors, visit jamanetwork.com.
