FDA Accepts Resubmitted Rivoceranib/Camrelizumab NDA for Unresectable HCC

The new drug application (NDA) for rivoceranib plus camrelizumab as a potential first-line treatment for patients with unresectable hepatocellular carcinoma (HCC) has been resubmitted to the FDA, according to a statement from the developer, HLB.¹ This regulatory milestone restarts the formal review process for the tyrosine kinase inhibitor (TKI) and PD-1 inhibitor combination after the agency initially issued a complete response letter (CRL) in May 2024 citing manufacturing-related concerns, then another CRL in March 2025.^2,3

Similar to the previous NDA submissions by the developer, supporting evidence for rivoceranib plus camrelizumab’s viability in this unresectable HCC population came from the international, randomized, open-label phase 3 CARES-310 study (NCT03764293), which compared the combination against the former standard-of-care, sorafenib (Nexavar).

Clinical Efficacy and Survival Findings

Final overall survival (OS) results demonstrated a statistically significant and clinically meaningful improvement for the experimental arm.⁴ With a median follow-up of 22.1 months (IQR, 11.9-30.3), patients receiving rivoceranib plus camrelizumab achieved a median OS of 23.8 months (95% CI, 20.6-27.2) compared with 15.2 months (95% CI, 13.2-18.5) in the sorafenib cohort (HR, 0.64; 95% CI, 0.52-0.79; P <.0001). The median progression-free survival (PFS) was also significantly extended at 5.6 months (95% CI, 5.5-7.4) with the combination vs 3.7 months (95% CI, 3.1-3.7) with sorafenib (HR, 0.54; 95% CI, 0.44-0.67; P <.0001).

Trial Breakdown

The CARES-310 trial randomly assigned 543 patients in a 1:1 ratio to receive either the combination therapy or sorafenib monotherapy. Eligibility criteria required patients to be 18 years or older with histologically or cytologically confirmed unresectable or metastatic HCC with no prior systemic therapy.⁵ They were also required to have an ECOG performance status of 0 or 1, Child-Pugh class A liver function, and Barcelona Clinic Liver Cancer (BCLC) stage B or C disease not amenable to surgery or local intervention, as well as adequate organ function and a life expectancy of at least 12 weeks.

Those with known hepatocholangiocarcinoma, sarcomatoid HCC, mixed cell carcinoma and lamellar cell carcinoma, or other active malignant tumor types apart from HCC were ineligible for enrollment on the trial. Patients were also unable to enroll if they had abdominal fistula or gastrointestinal perforation within 6 months before beginning treatment, known genetic or acquired hemorrhage or thrombotic tendency, or prior or current presence of central nervous system metastases.

Of the enrolled patients, 84% were male, and 83% were Asian.

The treatment regimen for the experimental arm consisted of 200 mg of camrelizumab administered intravenously every 2 weeks alongside 250 mg of oral rivoceranib administered once daily. Patients in the control group received 400 mg of oral sorafenib twice daily.

The primary endpoints of the study were OS and PFS as assessed by a blinded independent review committee using RECIST v1.1 criteria. Secondary endpoints included overall response rate, disease control rate, duration of response, and overall safety and tolerability.

Safety

Safety data indicated that the most common treatment-related adverse events (TRAEs) of Grade 3 or higher in the camrelizumab group included hypertension (38%), palmar-plantar erythrodysesthesia syndrome (12%), increased aspartate aminotransferase (17%), and increased alanine aminotransferase (14%). Treatment-related serious AEs occurred in 25% of the camrelizumab group and 7% of the sorafenib group. Notably, treatment-related deaths occurred in 1 patient in each group, which included multiple organ dysfunction syndrome in the camrelizumab group and respiratory failure and circulatory collapse in the sorafenib group.

References

1. Ji-hye K. HLB restarts FDA review with resubmitted liver cancer combo application. News release. Korea Biomedical Review. January 26, 2026. Accessed January 27, 2026. https://tinyurl.com/3fddj45t
2. Announcement on receipt of complete response letter regarding camrelizumab for injection. News release. Jiangsu Hengrui Pharmaceuticals Co., Ltd. May 17, 2024. Accessed January 27, 2026. https://tinyurl.com/3kdz97k9
3. Ji-Yoon H. HLB, Antengene fail to gain U.S. FDA approval for liver cancer drug combo. News release. Chosun Biz. March 21, 2025. Accessed January 27, 2026. https://tinyurl.com/3jcd2j5m
4. Qin S, Gu S, Chan SL, et al. 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
5. A study to evaluate SHR-1210 in combination with apatinib as first-line therapy in patients with advanced HCC. ClinicalTrials.gov. Updated February 6, 2024. Accessed January 27, 2026. https://tinyurl.com/ymndkrsp