FDA Passes Again on Approving Rivoceranib Plus Camrelizumab in HCC

The FDA has issued a complete response letter (CRL) to the new drug application (NDA) for rivoceranib plus camrelizumab as first-line treatment of unresectable or metastatic hepatocellular carcinoma (HCC), according to Elevar Therapeutics.¹

This marks the third CRL the agency has issued for this combination. The FDA's decision was based on deficiencies identified during a current good manufacturing practice (cGMP) inspection of a manufacturing site listed on the rivoceranib NDA, not on clinical efficacy or safety data.

In the final analysis of the trial, 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 (Nexavar; HR, 0.64; 95% CI, 0.52-0.79; P <.0001) in patients unresectable or metastatic HCC.² Median progression-free survival (PFS) 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).

"[We] are reviewing the contents of the letter and intend to work closely with the FDA to determine the appropriate path forward. While we are disappointed by this outcome, we remain committed to patients with hepatocellular carcinoma and to advancing the development of rivoceranib and camrelizumab," said Dong-Gun Kim, chief executive officer of Elevar.¹

Elevar noted that the FDA has 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 issued to date.¹

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%).² 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.²

CARES-310 Study Design and Patient Population

CARES-310 was a randomized, open-label, international phase 3 trial conducted at 95 sites across 13 countries and regions. Eligible patients were aged 18 years or older with unresectable or metastatic HCC, no prior systemic therapy, and an ECOG performance status of 0 or 1.2 A total of 543 patients were enrolled between June 28, 2019, and March 24, 2021, and randomized 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.2

The NDA was originally submitted in 2023 and received its first CRL in May 2024, citing cGMP deficiencies at the Hengrui Pharma facility that manufactures camrelizumab. A second CRL was issued in March 2025 after the company resubmitted. The current CRL is the third, again citing manufacturing deficiencies, this time related to the rivoceranib manufacturing site specifically.¹

References

1. 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 July 10, 2026. https://www.globenewswire.com/news-release/2026/07/10/3325659/0/en/

2. Qin S, Chan SL, Gu S, 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. 2024;404(10453):662-674. doi:10.1016/S0140-6736(24)01002-8