A phase 3 randomized clinical trial published on October 5, 2023 in JAMA Oncology evaluated the efficacy and safety of tislelizumab versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma (HCC). The global, multiregional RATIONALE-301 study was conducted at 117 sites across China, Europe, Japan, Taiwan, the UK, and the US. The trial was funded by BeiGene, Ltd.
The purpose of this open-label study was to investigate whether tislelizumab, an anti-PD-1 monoclonal antibody, could provide comparable or superior overall survival (OS) compared to the standard-of-care tyrosine kinase inhibitor sorafenib in patients with previously untreated advanced HCC. Secondary objectives included assessing objective response rate (ORR), progression-free survival (PFS), duration of response (DOR), and safety.
A total of 674 adult patients were randomized 1:1 to receive either tislelizumab 200 mg intravenously every 3 weeks or sorafenib 400 mg orally twice daily. Key inclusion criteria were histologically confirmed HCC, Barcelona Clinic Liver Cancer stage B or C disease not amenable to curative treatment, Child-Pugh class A liver function, and at least one measurable lesion. Patients were required to be systemic therapy-naïve and have an ECOG performance status of 0 or 1.
The study population was predominantly male (84.6%) with a median age of 61 years. Most patients had Barcelona Clinic Liver Cancer stage C disease (79.5% in the tislelizumab arm, 75.9% in the sorafenib arm). A higher proportion of patients in the tislelizumab group had extrahepatic spread (64.0% vs 59.6%) and alpha-fetoprotein levels ≥400 ng/mL (39.5% vs 34.9%) compared to the sorafenib group, indicating potentially more advanced disease at baseline in the experimental arm.
The primary endpoint of OS noninferiority was met, with tislelizumab demonstrating a median OS of 15.9 months compared to 14.1 months with sorafenib (hazard ratio 0.85, 95.003% CI 0.71-1.02). The prespecified noninferiority margin of an upper 95.003% CI limit less than 1.08 was achieved. However, the study did not meet the threshold for OS superiority of tislelizumab over sorafenib.
Confirmed ORR by blinded independent review was higher with tislelizumab (14.3% vs 5.4%), and responses were more durable (median DOR 36.1 vs 11.0 months). The median time to response was also shorter with tislelizumab (2.2 vs 4.0 months). However, median PFS favored sorafenib (3.4 vs 2.1 months), as did disease control rate (50.3% vs 44.2%). Interestingly, PFS rates at later time points (18 and 24 months) were higher in the tislelizumab arm, suggesting potential long-term benefit in a subset of patients.
The safety profile favored tislelizumab, with lower rates of grade ≥3 treatment-related adverse events (22.2% vs 53.4%) and treatment discontinuations due to adverse events (6.2% vs 10.2%) compared to sorafenib. The most common treatment-related adverse events with tislelizumab were increased aspartate aminotransferase (23.1%), increased alanine aminotransferase (16.6%), and increased blood bilirubin (12.4%). Immune-mediated adverse events occurred in 18.3% of tislelizumab-treated patients, with 8.3% being grade ≥3.
Some limitations of the study include its open-label design, which may have introduced bias for PFS and ORR assessments, though this was mitigated by using blinded independent review. The emergence of improved later-line therapies during the study period, to which patients could cross over after progression, may have confounded the OS analysis. Additionally, the sample size was somewhat imbalanced across geographic regions, with 63.1% of patients recruited from Asia (excluding Japan). However, this distribution is reflective of the global epidemiology of HCC.
The authors concluded that tislelizumab demonstrated comparable overall survival to sorafenib, with higher and more durable objective responses, while median PFS favored sorafenib. The favorable safety profile of tislelizumab compared to sorafenib, with no new safety signals identified, suggests it may represent a potential new first-line treatment option for patients with unresectable HCC.
These results have potential clinical implications for the management of advanced HCC. While the combination of atezolizumab plus bevacizumab has become the standard first-line therapy based on the IMbrave150 trial, there remains a need for alternative options, particularly for patients with contraindications to anti-VEGF therapy or tyrosine kinase inhibitors. The RATIONALE-301 data suggest that single-agent PD-1 inhibition with tislelizumab could provide a valuable treatment choice for such patients.
The observed efficacy and safety profile of tislelizumab appears comparable to that seen with nivolumab in the CheckMate 459 trial, which led to off-label use recommendations for nivolumab monotherapy in certain clinical scenarios. The RATIONALE-301 results may similarly support consideration of tislelizumab as a first-line option, especially given its more favorable toxicity profile compared to sorafenib.
It is worth noting that while tislelizumab did not demonstrate superiority over sorafenib, the numerically longer median OS, higher ORR, and more durable responses suggest it may offer advantages for some patients. The delayed separation of OS and PFS curves, with higher rates at later time points, indicates there may be a subset of patients who derive substantial long-term benefit from tislelizumab. Further biomarker analyses may help identify predictors of response to guide patient selection.
The safety findings are particularly noteworthy, as tolerability is a key consideration in the palliative treatment setting of advanced HCC. The lower rates of grade ≥3 adverse events and treatment discontinuations with tislelizumab compared to sorafenib could translate to improved quality of life for patients. This favorable toxicity profile may also allow for longer duration of treatment, potentially contributing to improved outcomes.
In the evolving landscape of HCC treatment, these results add to the growing body of evidence supporting the role of immune checkpoint inhibition. While combination approaches like atezolizumab plus bevacizumab have shown superiority to sorafenib, the RATIONALE-301 data suggest single-agent PD-1 blockade remains a viable strategy. This may be particularly relevant for patients who cannot tolerate or have contraindications to combination therapy.
As the field continues to advance, future research may explore biomarker-guided treatment selection, novel combination approaches, and sequencing strategies to optimize outcomes for patients with HCC. The results of RATIONALE-301 provide valuable insights to inform clinical decision-making and future trial designs in this challenging disease.
References
Qin S, Kudo M, Meyer T, et al. Tislelizumab vs Sorafenib as First-Line Treatment for Unresectable Hepatocellular Carcinoma: A Phase 3 Randomized Clinical Trial. JAMA Oncol. 2023;9(12):1651-1659. doi:10.1001/jamaoncol.2023.4003
