HEPATORCH Trial Key Points
The HEPATORCH trial demonstrated that toripalimab plus bevacizumab significantly improved both progression-free survival and overall survival compared to sorafenib in previously untreated advanced hepatocellular carcinoma, establishing this combination as a superior first-line treatment option. 1
Study Design and Population
- Randomized, open-label, phase 3 trial conducted across 57 hospitals in mainland China, Taiwan, and Singapore between November 2020 and January 2022 1
- 326 patients were randomized 1:1 to receive either toripalimab 240 mg IV every 3 weeks plus bevacizumab 15 mg/kg IV every 3 weeks (n=162) or sorafenib 400 mg oral twice daily (n=164) 1
- Eligible patients were aged 18-75 years with unresectable or metastatic hepatocellular carcinoma who had not received prior systemic treatment 1
- Median age was 58 years in the combination group and 56 years in the sorafenib group, with 87% male patients 1
Primary Efficacy Outcomes
Progression-Free Survival
- Median PFS: 5.8 months with toripalimab plus bevacizumab versus 4.0 months with sorafenib 1
- Hazard ratio: 0.69 (95% CI 0.53-0.91; p=0.0086), representing a 31% reduction in risk of progression or death 1
- Median follow-up at primary PFS analysis was 9.4 months 1
Overall Survival
- Median OS: 20.0 months with toripalimab plus bevacizumab versus 14.5 months with sorafenib 1
- Hazard ratio: 0.76 (95% CI 0.58-0.99; p=0.039), representing a 24% reduction in risk of death 1
- Median follow-up at final OS analysis was 16.4 months 1
Safety Profile
Grade 3-4 Adverse Events
- Overall incidence of grade 3 or higher adverse events was similar: 63% in the combination group versus 61% in the sorafenib group 1
- Most common grade 3-4 events in the toripalimab plus bevacizumab group included:
Treatment Discontinuation and Fatal Events
- Treatment discontinuation due to adverse events occurred in 13% of the combination group versus 12% of the sorafenib group 1
- Fatal adverse events were rare and similar between groups: 1% in both arms 1
- Most common serious adverse events (≥2% incidence) included upper gastrointestinal hemorrhage (7% vs 1%), abnormal hepatic function (5% vs 3%), ascites (4% vs 2%), and gastrointestinal hemorrhage (2% vs 2%) 1
Clinical Context and Significance
This trial provides Level 1 evidence that immunotherapy-based combination therapy outperforms sorafenib monotherapy, which had been the standard of care since the SHARP trial demonstrated sorafenib's survival benefit (10.7 vs 7.9 months) in 2008 2, 3, 4. The HEPATORCH results align with other recent trials showing superiority of PD-1/PD-L1 inhibitors combined with antiangiogenic agents over sorafenib, such as the IMbrave150 trial with atezolizumab plus bevacizumab 2.
Important Caveats
- The trial was conducted primarily in Asian populations, which historically show different sorafenib outcomes than Western populations (median OS 6.2 months in Asian trials versus 10.7 months in SHARP) 2
- All patients had Child-Pugh A liver function, as this is standard for systemic therapy trials in HCC 2, 3
- The increased risk of bleeding complications (particularly upper GI hemorrhage at 6% grade 3-4) requires careful patient selection and monitoring, especially given the antiangiogenic mechanism of bevacizumab 1
Regulatory Status
The toripalimab plus bevacizumab regimen has been approved by China's National Medical Products Administration based on these results 1. This adds to the growing list of immunotherapy-based first-line options for advanced HCC, though availability varies by region due to approval status, insurance coverage, and cost considerations 1.