A new drug application (NDA) seeking the approval of rivoceranib plus camrelizumab as a potential first-line treatment for patients with unresectable hepatocellular carcinoma (HCC) has been resubmitted to the FDA, restarting the agency’s formal review of this regimen for a third time.¹
The resubmission follows the receipt of 2 complete response letters (CRLs) previously issued by the FDA.²˒³ The initial CRL, issued on May 16, 2024, cited good manufacturing practice deficiencies at the Hengrui Pharma manufacturing facility responsible for producing camrelizumab, as well as incomplete bioresearch monitoring clinical inspections that were constrained by FDA travel restrictions.² Importantly, the FDA did not identify deficiencies related to the clinical efficacy or safety data supporting the combination, nor were concerns raised regarding the manufacturing site for rivoceranib. Despite a subsequent resubmission, the agency issued a second CRL for the combination in the frontline unresectable HCC setting for reasons that were not publicly disclosed.³
The present NDA is supported by findings from the phase 3 CARES-310 trial (NCT03764293), which evaluated rivoceranib plus camrelizumab compared with sorafenib (Nexavar), the former standard of care, in patients with unresectable HCC.1
What is the design of CARES-310?
Side bar: What You Need to Know About Rivoceranib/Camrelizumab’s Newest NDA for Frontline Unresectable HCC
- The FDA has accepted a third NDA resubmission for rivoceranib plus camrelizumab as a potential first-line treatment for unresectable hepatocellular carcinoma following 2 prior CRLs related to manufacturing and inspection issues.
- The application is supported by the phase 3 CARES-310 trial, which showedsignificant improvements in OS and PFS with rivoceranib plus camrelizumab compared with sorafenib.
- Prior FDA review did not identify concerns with the combination’s clinical efficacy or safety data, nor with the manufacturing site for rivoceranib.
The randomized, open-label, international, multicenter CARES-310 trial enrolled patients at least 18 years of age with histologically or cytologically confirmed unresectable or metastatic HCC who had not previously received systemic therapy.⁴ Additional eligibility criteria included an ECOG performance status of 0 or 1, Child-Pugh class A liver function, Barcelona Clinic Liver Cancer (BCLC) stage B or C disease not amenable to surgery or locoregional therapy, adequate organ function, and a life expectancy of at least 12 weeks.
Patients with known hepatocholangiocarcinoma, sarcomatoid HCC, mixed cell carcinoma, lamellar cell carcinoma, or other active malignancies aside from HCC were not eligible for enrollment.
A total of 543 patients were randomly assigned 1:1 to receive either camrelizumab at a dose of 200 mg intravenously every 2 weeks in combination with oral rivoceranib at 250 mg once daily, or oral sorafenib at 400 mg twice daily.
The study’s coprimary end points were overall survival (OS) and progression-free survival (PFS), assessed by a blinded independent review committee using RECIST 1.1 criteria. Secondary end points included overall response rate, disease control rate, duration of response, and overall safety and tolerability.
What efficacy and safety data from CARES-310 supported the most recent NDA submission for rivoceranib plus camrelizumab in HCC?
Final OS results published in Lancet Oncology and presented at the 2024 ASCO Annual Meeting demonstrated a statistically significant and clinically meaningful benefit with rivoceranib plus camrelizumab.⁵ At a median follow-up of 22.1 months, the median OS was 23.8 months (95% CI, 20.6-27.2) in the combination arm compared with 15.2 months (95% CI, 13.2-18.5) in the sorafenib arm (HR, 0.64; 95% CI, 0.52-0.79; P < .0001). The median PFS was also significantly prolonged with the combination at 5.6 months (95% CI, 5.5-7.4) vs 3.7 months (95% CI, 3.1-3.7) with sorafenib (HR, 0.54; 95% CI, 0.44-0.67; P < .0001).
Regarding safety, the most common grade 3 or higher treatment-related adverse effects (AEs) in the camrelizumab-containing arm included hypertension (38.2%), palmar-plantar erythrodysesthesia syndrome (12.1%), increased aspartate aminotransferase levels (17.3%), and increased alanine aminotransferase levels (14.0%). In the combination arm, TRAEs led to camrelizumab and rivoceranib discontinuation in 17.6% and 16.9% of patients, respectively. The discontinuation rate of both agents was 4.4%.
References
- Ji-hye K. HLB restarts FDA review with resubmitted liver cancer combo application. News release. Korea Biomedical Review. January 26, 2026. Accessed January 29, 2026. https://www.koreabiomed.com/news/articleView.html?idxno=30411
- Elevar Therapeutics reports plans for near-term resubmission of NDA for first-line treatment option for unresectable hepatocellular carcinoma following Type A FDA meeting. News release. Elevar Therapeutics. July 9, 2024. Accessed January 29, 2026. https://elevartherapeutics.com/2024/07/09/elevar-therapeutics-first-line-treatment-option/
- 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 29, 2026. https://biz.chosun.com/en/en-science/2025/03/21/F463ABI2GJFXRA673MXKGE3H4I/
- 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 29, 2026. https://clinicaltrials.gov/study/NCT03764293
- 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
