Rivoceranib Plus Camrelizumab Resubmitted to FDA in Frontline HCC

Elevar Therapeutics and Hengrui Pharma have resubmitted applications to the FDA seeking approval of rivoceranib plus camrelizumab as first-line treatment of unresectable or metastatic hepatocellular carcinoma (HCC), following the conclusion of manufacturing site inspections tied to the combination.¹

On October 9, Elevar, the US subsidiary of HLB, submitted a new drug application (NDA) for rivoceranib, and Hengrui submitted a biologics license application for camrelizumab. The resubmissions follow a complete response letter (CRL) the FDA issued in July for the NDA that Elevar submitted in January. The 2 companies then worked with the agency to resolve the issues raised in the letter.¹

In the final analysis of the phase 3 CARES-310 trial (NCT03764293), frontline camrelizumab plus rivoceranib produced a median overall survival (OS) of 23.8 months (95% CI, 20.6-27.2) vs 15.2 months (95% CI, 13.2-18.5) with sorafenib (HR, 0.64; 95% CI, 0.52-0.79; P < .0001) in patients with unresectable or metastatic HCC.³ According to HLB, the 23.8-month median OS is the longest reported to date in a phase 3 study of a first-line treatment for unresectable HCC, and the benefit was consistent across multiple patient subgroups.¹ Median progression-free survival was 5.6 months (95% CI, 5.5-7.4) with camrelizumab plus rivoceranib vs 3.7 months (95% CI, 3.1-3.7) with sorafenib (HR, 0.54; 95% CI, 0.44-0.67; P < .0001).³

The final CARES-310 analysis was published in The Lancet Oncology in December 2025.³ Although the combination is not yet approved in the United States, it has been incorporated as a first-line option in the 2025 Barcelona Clinic Liver Cancer strategy and in European Society for Medical Oncology guidelines.¹

“Unresectable HCC remains an area of significant unmet medical need, and Elevar has remained committed to bringing a new treatment option to patients and physicians,” said Dong-Gun Kim, CEO of Elevar Therapeutics. “With the manufacturing site inspection process now concluded, we will continue to work closely with the FDA throughout the review process, building on the clinical value demonstrated in CARES-310, with the goal of successfully completing the regulatory review.”

Safety of Camrelizumab Plus Rivoceranib

In CARES-310, the safety profile of camrelizumab plus rivoceranib was broadly consistent with the known profiles of each agent, though the combination carried a higher rate of grade 3 or 4 treatment-related adverse events than sorafenib in some categories. The most common grade 3 or 4 treatment-related adverse events were hypertension (38% with camrelizumab plus rivoceranib vs 15% with sorafenib), increased aspartate aminotransferase (17% vs 5%), increased alanine aminotransferase (14% vs 3%), and palmar-plantar erythrodysaesthesia syndrome (12% vs 16%).³ One treatment-related death occurred in each arm: multiple organ dysfunction syndrome in the combination arm and respiratory failure and circulatory collapse in the sorafenib arm.³

CARES-310 Study Design and Patient Population

CARES-310 was a randomized, open-label, international trial conducted at 95 sites across 13 countries and regions. Eligible patients were 18 years and older with unresectable or metastatic HCC, no prior systemic therapy, and an ECOG performance status of 0 or 1.³ A total of 543 patients were enrolled between June 28, 2019, and March 24, 2021, and randomly assigned 1:1 to camrelizumab 200 mg intravenously every 2 weeks plus rivoceranib 250 mg orally once daily (n = 272) or sorafenib 400 mg orally twice daily (n = 271). Of those enrolled, 84% were male, and 83% were Asian.³

Regulatory History of Rivoceranib Plus Camrelizumab

The NDA was originally submitted in 2023 and received its first CRL in May 2024, citing current good manufacturing practice (cGMP) deficiencies at the Jiangsu Hengrui Pharma facility in China that manufactures camrelizumab. A second CRL was issued in March 2025 after the company resubmitted.²

The third CRL, issued in July 2026, was again based on deficiencies identified during a cGMP inspection, this time of a manufacturing site listed on the rivoceranib NDA, rather than on clinical efficacy or safety data. Elevar noted at the time that the FDA had previously acknowledged substantial clinical data supporting the application and that clinical efficacy and safety were not cited as concerns in any of the 3 CRLs.²

REFERENCES

1. HLB resubmits FDA applications for first-line liver cancer treatment. News release. HLB. October 13, 2026. Accessed October 13, 2026. https://tinyurl.com/2k6ykcru

2. Elevar Therapeutics receives FDA complete response letter for combination of rivoceranib and camrelizumab as a first-line treatment for unresectable or metastatic hepatocellular carcinoma. News release. Elevar Therapeutics. July 10, 2026. Accessed October 13, 2026. https://tinyurl.com/msf5ps9f

3.Qin S, Chan SL, Gu S, 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;26(12):1598-1611. doi:10.1016/S1470-2045(25)00543-1