Second CRL for Rivoceranib/Camrelizumab for Unresectable HCC

The combination therapy received a second complete response letter on its resubmission as a frontline therapy for unresectable hepatocellular carcinoma. | Image Credit: © Tada Images - stock.adobe.com

Despite receiving an initial complete response letter (CRL) on May 16, 2024,¹ the resubmitted new drug application for rivoceranib (Elevar Therapeutics) plus camrelizumab (Antiengene Corporation) to treat unresectable hepatocellular carcinoma (HCC) received a second CRL, reported Korean news sources.²

The initial CRL was due to deficiencies related to the inspection of the manufacturing site for camrelizumab, although 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.³

HLB, the owner of Elevar Therapeutics, said the FDA had not disclosed the reasons for the lack of approval this time around.²

The current standard of care for frontline treatment of unresectable HCC is atezolizumab (Tecentriq; Genentech) plus bevacizumab (Avastin; Genentech).⁴ Other frontline options are durvalumab (Imfinzi; AstraZeneca) plus tremelimumab-actl (Imjudo; AstraZeneca) and the single-agent tyrosine kinase inhibitors (TKIs) sorafenib (Nexavar; Bayer) and lenvatinib (Lenvima; Eisai). Camrelizumab is an anti–PD-1 antibody, and rivoceranib is a VEGFR2-targeted TKI.

The submission for rivoceranib and camrelizumab was based on the phase 3 CARES-310 study (NCT03764293), which was conducted at 95 sites across 13 countries. The findings from the final analysis were presented at the 2024 American Society of Clinical Oncology Annual Meeting.^5,6 A total of 543 patients were assigned in a randomized fashion to receive camrelizumab plus rivoceranib (n = 272) or sorafenib (n = 271). After a median follow-up of 22.1 months for the combination and 14.9 months for sorafenib, the median overall survival (OS) was 23.8 months (95% CI, 20.6-27.2) and 15.2 months (95% CI, 13.2-18.5) for the single agent (HR, 0.64; 95% CI, 0.52-0.79; 1-sided P < .0001).

At 24 months, the OS rate was 49% for patients receiving camrelizumab plus rivoceranib compared with 36.2% for those receiving sorafenib, and the combination maintained the edge at 36 months of follow-up, when OS rates were 37.7% and 24.8%, respectively. In addition, progression-free survival was 5.6 months (95% CI, 5.5-7.4) for the combination therapy and 3.7 months (95% CI, 3.1-3.7) for sorafenib (HR, 0.54; 95% CI, 0.44-0.67; P < .0001).

The median overall response rate was significantly higher for the combination at 26.8% compared with 5.9% for the sorafenib cohort, and the median duration of response was 17.5 months for the combination vs 9.2 months.

The discontinuation rate due to treatment-related adverse events (TRAEs) was much higher for the combination arm. Overall, 17.6% of patients discontinued camrelizumab, 16.9% discontinued rivoceranib, and 4.4% discontinued both due to TRAEs. In comparison, only 4.8% of patients discontinued sorafenib due to TRAEs. The most common TRAEs were hypertension, increased aspartate aminotransferase, palmar-plantar erythrodysaesthesia syndrome, increased blood bilirubin, decreased platelet count, diarrhea, and increased gamma-glutamyl transferase.

References

1. Conroy R. FDA sends CRL for camrelizumab/rivoceranib in unresectable liver cancer. Cancer Network^®. May 20, 2024. Accessed March 11, 2025. https://www.cancernetwork.com/view/fda-sends-crl-for-camrelizumab-rivoceranib-in-unresectable-liver-cancer

2. Ji-yoon H. HLB, Antengene fail to gain US FDA approval for liver cancer drug combo. Chosun Biz. March 21, 2025. Accessed March 21, 2025. https://biz.chosun.com/en/en-science/2025/03/21/F463ABI2GJFXRA673MXKGE3H4I/

3. Joszt L. 5 key drug approvals and CRLs in 2024. AJMC^®. December 27, 2024. Accessed March 11, 2025. https://www.ajmc.com/view/5-key-drug-approvals-and-crls-in-2024

4. Scott R. Navigating first-line treatment options in advanced, unresectable HCC. OncLive^®. March 26, 2024. Accessed March 11, 2025. https://www.onclive.com/view/navigating-first-line-treatment-options-in-advanced-unresectable-hcc

5. Vogel A, Chan SL, GU S, et al. Camrelizumab plus rivoceranib vs sorafenib as first-line therapy for unresectable hepatocellular carcinoma: final overall survival analysis of the phase 3 CARES-310 study. J Clin Oncol. 2024;42(suppl 16):4110. doi:10.1200/JCO.2024.42.16_suppl.4110

6. McNulty R. Camrelizumab plus rivoceranib improves survival vs standard first-line care for HCC. AJMC. June 5, 2024. Accessed March 11, 2025. https://www.ajmc.com/view/camrelizumab-plus-rivoceranib-improves-survival-vs-standard-first-line-care-for-hcc