NDA Resubmitted for Camrelizumab Plus Rivoceranib in Unresectable HCC

A new drug application (NDA) seeking the approval of camrelizumab plus rivoceranib for the frontline treatment of patients with unresectable hepatocellular carcinoma (HCC) has been resubmitted to the FDA.¹

In May 2024, the FDA issued a complete response letter (CRL) for the initial NDA in this indication, which was submitted in May 2023. The CRL cited good manufacturing practice deficiencies at the Hengrui Pharma facility that manufactures camrelizumab, as well as incomplete Bioresearch Monitoring (BIMO) clinical inspections due to FDA travel restrictions. The FDA did not note any issues related to the manufacturing site or clinical data for rivoceranib.

During a Type A meeting in July 2024, the FDA stated that responses to observations at the Hengrui Pharma manufacturing facility were sufficient, meaning that NDA resubmission for the combination could be initiated and BIMO inspections could occur after resubmission.

“The combination of camrelizumab and rivoceranib shows distinct promise as a potential therapy for patients suffering from advanced HCC, with efficacy results generally consistent across all subgroups,” Ahmed Omar Kaseb, MD, a professor in the Department of Gastrointestinal Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, stated in a news release. “The resubmission is strengthened by the recent [phase 3] CARES-310 [trial (NCT03764293)] landmark analysis, which reported the longest median overall survival [OS] for any treatment in a global phase 3 trial in the unresectable HCC setting.”

In CARES-310, patients with previously untreated, unresectable HCC were randomly assigned 1:1 to receive either camrelizumab plus rivoceranib (n = 272) or sorafenib monotherapy (n = 271).² Prior analyses showed a median progression-free survival of 5.6 months (95% CI, 5.5-7.4) with the combination vs 3.7 months (95% CI, 3.1-3.7) with sorafenib (Nexavar; HR, 0.52; 95% CI, 0.41-0.65; 1-sided P < .0001).

In the final OS analysis of CARES-310, data from which were presented at the 2024 ASCO Annual Meeting, at a median follow-up of 22.1 months, investigators reported a median OS of 23.8 months (95% CI, 20.6-27.2) with the combination vs 15.2 months (95% CI, 13.2-18.5) with sorafenib at a median follow-up of 14.9 months (HR, 0.64; 95% CI, 0.52-0.79; 1-sided P < .0001). In the investigational and control arms, the respective 24-month OS rates were 49.0% and 36.2%, and the respective 36-month OS rates were 37.7% and 24.8%.

The overall response rate with the combination was 26.8% (95% CI, 21.7%-32.5%) vs 5.9% (95% CI, 3.4%-9.4%) with sorafenib. The median durations of response in these respective arms were 17.5 months (95% CI, 9.3-not reached [NR]) and 9.2 months (95% CI, 5.3-NR).

At the final OS analysis, the agent’s safety profile was comparable with that reported in the interim OS analysis, and investigators noted no new safety signals. The most common treatment-related adverse effects of grade 3 or higher in the camrelizumab plus rivoceranib arm were hypertension (38.2%), increased aspartate aminotransferase (17.3%), increased alanine aminotransferase (14.0%), palmar-plantar erythrodysesthesia (12.1%), decreased platelet counts (11.8%), increased gamma-glutamyltransferase (9.6%), increased blood bilirubin (8.8%), proteinuria (5.9%), decreased neutrophil counts (5.9%), reactive cutaneous capillary endothelial proliferation (2.9%), decreased white blood cell counts (2.6%), fatigue (2.6%), and diarrhea (2.2%).

“Elevar’s timely resubmission of the NDA for the combination of camrelizumab and rivoceranib marks a critical milestone in our mission to bring a novel combination therapy for unresectable HCC to patients and health care providers. HCC remains an area of significant unmet medical need,” Saeho Chong, PhD, chief executive officer of Elevar Therapeutics, added in the news release.¹ “This achievement would not have been realized without the extraordinary dedication of Elevar’s teams. We are eager to work with the FDA in the coming months as we focus on the commercialization of our combination therapy.”

References

1. Elevar Therapeutics resubmits new drug application to FDA for combination of camrelizumab plus rivoceranib as first-line treatment option for unresectable hepatocellular carcinoma boosted by CARES-310 leading overall survival analysis. News Release. Elevar Therapeutics. September 23, 2024. Accessed September 23, 2024. https://elevartherapeutics.com/2024/09/23/elevar-therapeutics-resubmits-new-drug-application/
2. Vogel A, Chan SL, Ren Z, et al. Camrelizumab plus rivoceranib vs sorafenib as first-line therapy for unresectable hepatocellular carcinoma (uHCC): 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