FDA Issues Complete Response Letter to Rivoceranib/Camrelizumab in Hepatocellular Cancer

• The FDA has issued a complete response letter (CRL) for the combination of rivoceranib (apatinib) plus camrelizumab for the first-line treatment of unresectable hepatocellular carcinoma (uHCC).
• The combination was studied in the phase 3 CARES 310 trial (NCT03764293) and showed a meaningful improvement in overall survival (OS) and progression-free survival (PFS).
• An initial CRL was issued to the combination on May 16, 2024.

The FDA has issued a second CRL for the combination of rivoceranib, an oral tyrosine kinase inhibitor, and camrelizumab, a PD-1 inhibitor, for the treatment of patients with uHCC.¹

The first CRL was issued due to deficiencies which were related to the inspection of the manufacturing site for camrelizumab. However, there were no issues noted related to the manufacturing site for rivoceranib. In 2024, the FDA delivered multiple CRLs to cancer drugs due to manufacturing concerns.

HLB, the owner of Elevar Therapeutics, has stated that the FDA had not disclosed the reasons for the lack of approval this time around.

The combination previously was evaluated in the randomized, open-label, international phase 3 CARES 310 trial. According to data from the final analysis of the phase 3 CARES-310 trial presented during the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, the median OS was 23.8 months with the combination compared with 15.2 months (95% CI, 13.2-18.5) with sorafenib (Nexavar; HR, 0.64; 95% CI, 0.52-0.79; 1-sided P <.0001). This result marked the longest median OS observed for any treatment in a global phase 3 trial in patients with uHCC.² With camrelizumab and rivoceranib, the OS rate was 49.0% vs 36.2% with sorafenib at 24 months, and 37.7% vs 24.8% at 36 months.

The combination therapy showed consistent efficacy results across subgroups, including in patients with hepatitis C virus-based etiology and nonviral etiology.

Prior findings from the interim analysis showed that at a median follow-up of 14.5 months (IQR, 9.1-18.7), the median OS observed among those treated with the combination was 22.1 months (95% CI, 19.1-27.2) vs 15.2 months (95% CI, 13.0-18.5) among those treated with the monotherapy, conferring a reduction in the risk of death of 38% with the combination vs sorafenib (Nexavar; stratified HR, 0.62; 95% CI, 0.49-0.80; 1-sided log-rank P <.0001).^3,4

At 12 months, the OS rates across the arms were 76.5% (95% CI, 71.0%-81.1%) vs 60.8% (95% CI, 54.6%-66.4%), respectively, and at 18 months, the OS rates were 60.9% (95% CI, 54.2%-66.9) vs 45.2% (95% CI, 38.8%-51.4%), respectively.

At a median follow-up of 7.8 months (IQR, 4.1-10.6), the median PFS in the camrelizumab plus rivoceranib arm was 5.6 months (95% CI, 5.5-6.3) vs 3.7 months (95% CI, 2.8-3.7) in the sorafenib arm (stratified HR, 0.52; 95% CI, 0.41-0.65; 1-sided log-rank P < .0001). PFS rates at 6 months were 48.2% (95% CI, 41.9%-54.3%) vs 25.3% (95% CI, 19.8%-31.1%), respectively, and at 12 months, these rates were 29.8% (95% CI, 24.1%-35.8%) vs 12.4% (95% CI, 8.3%-17.3%), respectively.

The study combination also demonstrated a disease control rate of 78% (95% CI, 73%-83%) vs 54% (95% CI, 48%-60%) with sorafenib. The median duration of response with rivoceranib plus camrelizumab was 14.8 months (95% CI, 8.4-not reached) compared with 9.2 months (95% CI, 5.3-NR) with sorafenib. In the combination arm, patients had a median time to response of 1.9 months (IQR, 1.9-3.7) vs 3.7 months (IQR, 1.9-4.7) in the sorafenib arm.³ Moreover, the median duration of treatment was 6.9 months (IQR, 3.6-13.4) for camrelizumab, 6.5 months (IQR, 3.4-11.9) for rivoceranib, and 3.8 months (IQR, 1.9-7.4) for sorafenib.

Regarding safety, any-grade adverse events (AEs) were observed in 99% of patients who received rivoceranib plus camrelizumab and sorafenib.³ Grade 3 or higher AEs were observed in 88% of patients in the rivoceranib plus camrelizumab arm vs 68% of the sorafenib arm.

REFERENCES:

1. HLB, Antengene fail to gain U.S. FDA approval for liver cancer drug combo. News release. Chosun Biz. March 21, 2025. Accessed March 21, 2025. https://biz.chosun.com/en/en-science/2025/03/21/F463ABI2GJFXRA673MXKGE3H4I/

2. Elevar Therapeutics announces FDA acceptance of new drug application resubmission for rivoceranib in combination with camrelizumab as a first-line systemic treatment for unresectable hepatocellular carcinoma. News release. Elevar Therapeutics, Inc. October 21, 2024. Accessed March 20, 2025. https://tinyurl.com/mp9tkz63

3. Elevar Therapuetics announces FDA acceptance of filing of new drug application for rivoceranib in combination with camrelizumab as a first-line treatment for unresectable hepatocellular carcinoma. News release. Elevar Therapeutics. July 17, 2023. Accessed March 20, 2025. https://tinyurl.com/4uppvjf3

4. Qin S, Chan SL, Gu S, et al. Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study. Lancet. 2023;402(10408):1133-1146. doi:10.1016/S0140-6736(23)00961-3