Highlights
– Final analysis of the international phase 3 CARES-310 trial reports a median overall survival of 23.8 months with camrelizumab plus rivoceranib versus 15.2 months with sorafenib (HR 0.64).
– Progression-free survival also favored the combination (median 5.6 vs 3.7 months; HR 0.54).
– The regimen produced higher rates of grade 3 to 4 treatment-related adverse events, particularly hypertension and hepatic enzyme elevations, but investigators judged toxicity manageable with monitoring and supportive care.
Background and disease burden
Hepatocellular carcinoma remains a leading cause of cancer mortality worldwide. Many patients present with advanced or unresectable disease at diagnosis, for which systemic therapy is the mainstay. Sorafenib, a multikinase inhibitor, established a survival benefit more than a decade ago and was the backbone for subsequent trials. The therapeutic landscape evolved rapidly following approvals of immune checkpoint inhibitor combinations, most notably atezolizumab plus bevacizumab, which reshaped first-line care by combining PD-L1 blockade with VEGF inhibition. Nevertheless, access, contraindications to bevacizumab, regional differences in etiologies such as hepatitis B virus predominance, and variable tolerability create ongoing unmet needs and demand alternative first-line regimens.
The biological rationale for combining anti-PD-1 antibodies with VEGF pathway inhibitors is robust. VEGF inhibition can normalize abnormal tumor vasculature, reduce immunosuppressive myeloid elements, and facilitate T-cell infiltration, potentially augmenting checkpoint blockade efficacy. Rivoceranib (also known as apatinib) is a selective oral VEGFR2 inhibitor. Camrelizumab is a monoclonal anti-PD-1 antibody. Prior early-phase data signaled promising activity for VEGF receptor tyrosine kinase inhibitors combined with PD-1/PD-L1 blockade in HCC; CARES-310 is the first large, randomized phase 3 study to compare such a VEGFR2 selective inhibitor plus PD-1 antibody against sorafenib in the first-line setting.
Study design and methods
CARES-310 was a randomized, open-label, international phase 3 trial conducted at 95 sites across 13 countries and regions. Eligible patients were adults with unresectable or metastatic hepatocellular carcinoma, no prior systemic therapy for HCC, and ECOG performance status 0 or 1. Key baseline characteristics included a predominance of male gender and Asian race; 83% of participants were Asian, reflecting the high prevalence of HBV-related disease in parts of the study population.
Participants were randomized 1:1 to receive either camrelizumab 200 mg intravenously every 2 weeks plus rivoceranib 250 mg orally once daily, or sorafenib 400 mg orally twice daily. The co-primary endpoints were progression-free survival assessed by a blinded independent review committee using RECIST v1.1, and overall survival in the intention-to-treat population. Safety analyses included all patients who received at least one dose of study treatment. The trial was registered at ClinicalTrials.gov, identifier NCT03764293, and funded by Jiangsu Hengrui Pharmaceuticals and Elevar Therapeutics.
Key findings and efficacy results
Population and follow-up
Between June 2019 and March 2021, 543 patients were randomized: 272 to camrelizumab plus rivoceranib and 271 to sorafenib. Median follow-up at final analysis (June 14, 2023) was 22.1 months (IQR 11.9–30.3) in the combination arm and 14.9 months (IQR 7.2–28.3) in the sorafenib arm.
Overall survival
The primary overall survival outcome favored camrelizumab plus rivoceranib. Median overall survival was 23.8 months (95% CI 20.6–27.2) with the combination versus 15.2 months (95% CI 13.2–18.5) with sorafenib (hazard ratio 0.64; 95% CI 0.52–0.79; one-sided p<0.0001). This absolute difference of 8.6 months is clinically meaningful and was preserved despite the open-label design and differences in follow-up duration between arms.
Progression-free survival and response
Median progression-free survival assessed by blinded independent review was 5.6 months (95% CI 5.5–7.4) in the combination group versus 3.7 months (95% CI 3.1–3.7) with sorafenib (HR 0.54; 95% CI 0.44–0.67; one-sided p<0.0001). Objective response rates and duration of response favored the camrelizumab plus rivoceranib arm, consistent with improved disease control and survival outcomes reported.
Secondary endpoints and subgroup analyses
The full manuscript provides additional secondary endpoint data and subgroup analyses. While the overall survival benefit was consistent across many preplanned subgroups, it is important to note the predominance of Asian patients and HBV etiology in the cohort. The observed benefit needs to be interpreted in the context of baseline population characteristics and local standards of care.
Safety profile and tolerability
Treatment-related adverse events were more frequent and more severe in the camrelizumab plus rivoceranib arm compared with sorafenib. The most common grade 3 or 4 treatment-related adverse events in the combination arm were hypertension (38%), increased aspartate aminotransferase (17%), increased alanine aminotransferase (14%), and palmar-plantar erythrodysaesthesia syndrome (12%). By comparison, the sorafenib arm had grade 3 or 4 rates of hypertension in 15% of patients, elevated AST in 5%, elevated ALT in 3%, and palmar-plantar erythrodysaesthesia syndrome in 16%.
Treatment-related serious adverse events occurred in 25% of patients receiving the combination and 7% of those receiving sorafenib. There were treatment-related deaths in each arm (one patient each). Investigators reported that adverse events were manageable with dose modifications, interruptions, and standard supportive measures. Nonetheless, the higher incidence of hypertension and hepatic enzyme elevations with rivoceranib plus camrelizumab requires careful monitoring, particularly in patients with compromised liver function or cardiovascular comorbidities.
Clinical interpretation and position in the treatment landscape
CARES-310 demonstrates a robust overall survival advantage for camrelizumab plus rivoceranib over sorafenib in first-line unresectable HCC. The magnitude of benefit is clinically meaningful and adds an additional regimen to the expanding first-line therapeutic armamentarium for advanced HCC.
Comparative context
Atezolizumab plus bevacizumab set a high bar for first-line therapy by showing substantial survival benefit versus sorafenib in IMbrave150. Immune checkpoint inhibitor combinations with anti-VEGF strategies are biologically plausible and clinically validated. CARES-310 reinforces the concept that pairing PD-1/PD-L1 blockade with VEGF pathway inhibition can yield superior outcomes to multikinase inhibitor monotherapy. However, cross-trial comparisons should be made cautiously because of differences in trial design, patient populations, geographic distribution, underlying liver disease etiologies, and subsequent therapies.
Patient selection and real-world considerations
Key practical considerations include the toxicity profile, monitoring requirements, and patient comorbidities. The high incidence of grade 3 to 4 hypertension and hepatic enzyme abnormalities suggests the importance of baseline cardiovascular risk assessment, proactive blood pressure control, and frequent hepatic monitoring during therapy. Where bevacizumab or systemic anticoagulation is contraindicated, or where bevacizumab access is limited, a PD-1 antibody plus an oral VEGFR2 inhibitor may provide a viable alternative.
Expert commentary and limitations
Strengths
CARES-310 is a large, international randomized phase 3 study with blinded independent central review for progression assessment and a prespecified overall survival endpoint. The survival benefit is consistent across the primary endpoints and was maintained at final analysis with extended follow-up.
Limitations
The trial was open-label and used sorafenib as the comparator. Since the time of study initiation and completion, atezolizumab plus bevacizumab and other immune-based combinations have become standard in many regions, so direct comparisons against these newer standards are lacking. The population was predominantly Asian with a high prevalence of HBV-related disease, which may limit generalizability to regions where HCV and nonalcoholic fatty liver disease are more common etiologies. Additionally, the median follow-up was longer in the combination arm than in the sorafenib arm, which requires careful interpretation, although intention-to-treat survival analyses reduce bias risk. Data on post-progression therapies and biomarker correlates were not emphasized in the headline results and are areas for deeper evaluation.
Biological plausibility and translational insights
The observed benefit aligns with preclinical and translational evidence supporting synergy between VEGF pathway inhibition and PD-1 blockade. VEGFR2 inhibition can modulate tumor vasculature and the immune microenvironment to potentiate antitumor immunity. Future correlative studies assessing immune infiltration changes, PD-L1 expression, and biomarkers of angiogenesis may clarify which patients derive the greatest benefit and help refine selection.
Conclusion and practice implications
The final results of CARES-310 establish camrelizumab plus rivoceranib as an effective first-line option for unresectable hepatocellular carcinoma, producing a substantial median overall survival improvement versus sorafenib. The regimen has a distinct toxicity profile with higher rates of high-grade hypertension and hepatic enzyme elevations, necessitating careful patient selection and monitoring. In clinical contexts where atezolizumab plus bevacizumab or other immune-based standards are not accessible or are contraindicated, camrelizumab plus rivoceranib provides a validated alternative.
Unanswered questions and future directions
Head-to-head comparisons with current standard immunotherapy combinations, longer-term safety monitoring, and real-world effectiveness studies will be important to define the optimal place of this regimen in practice. Biomarker-driven strategies to predict benefit and mitigate toxicity remain an unmet need. Finally, efforts to assess efficacy across diverse etiologies and ethnic groups will help broaden applicability.
Funding and clinicaltrials.gov
CARES-310 was funded by Jiangsu Hengrui Pharmaceuticals and Elevar Therapeutics. The study is registered at ClinicalTrials.gov under identifier NCT03764293.
References
1. Qin S, Gu S, Chan SL, et al; CARES-310 Study Group. Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): final analysis of a randomised, open-label, international, phase 3 study. Lancet Oncol. 2025 Dec;26(12):1598-1611. doi: 10.1016/S1470-2045(25)00543-1.
2. Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382:1894-1905. doi: 10.1056/NEJMoa1915745.
3. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378-390. doi: 10.1056/NEJMoa0708857.
Author note
This article is intended for clinicians and healthcare professionals seeking an evidence-based summary and clinical interpretation of the CARES-310 final analysis. It highlights efficacy, safety, and practical considerations for implementing camrelizumab plus rivoceranib in practice while acknowledging the need for comparative and biomarker research.
