FDA Receives Resubmitted NDA for Camrelizumab/Rivoceranib Combo in Unresectable HCC

• The FDA has received a resubmitted new drug application (NDA) seeking the approval of camrelizumab plus rivoceranib for the frontline treatment of patients with unresectable hepatocellular carcinoma (HCC).
• In May 2024, the FDA issued a complete response letter (CRL) for the original NDA.
• The NDA submission is supported by data from the phase 3 CARES-310 trial (NCT03764293).

An NDA seeking the approval of the combination of camrelizumab and rivoceranib for the frontline treatment of patients with unresectable HCC has been resubmitted to the FDA.¹

The FDA issued a complete response letter (CRL) in May 2024 for the original NDA in this indication, which was submitted in May 2023. The CRL highlighted good manufacturing practice deficiencies at the Hengrui Pharma facility where camrelizumab is produced and noted incomplete bioresearch monitoring (BIMO) clinical inspections due to FDA travel restrictions. No concerns were raised about the clinical data or the manufacturing site for rivoceranib.

During a Type A meeting in July of this year, the FDA confirmed that the responses to the Hengrui site observations were adequate, allowing for resubmission without delay, with BIMO inspections to follow 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,” said 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 a press release. “The resubmission is strengthened by the recent CARES-310 landmark analysis, which reported the longest median overall survival [OS] for any treatment in a global phase 3 trial in the unresectable HCC setting.”

“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 press release. “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.”

Data from the phase 3 CARES-310 study support this NDA submission. In the trial, patients with previously untreated, unresectable HCC were randomized in a 1:1 fashion to receive either camrelizumab with rivoceranib (n = 272) or sorafenib monotherapy (Nexavar; n = 271).²

At the 2024 American Society of Clinical Oncology Annual Meeting, a final OS analysis of CARES-310 was shared. Findings showed that at a median follow-up of 22.1 months, the median OS for the combination was 23.8 months (95% CI, 20.6-27.2). This compared with an OS of 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). The OS rates at 24 months in these arms were 49.0% and 36.2%, and the respective OS rates at 36 months were 37.7% and 24.8%. These rates were similar between most subgroups, regardless of geographical race, region, and etiology.

With the combination, the overall response rate was 26.8% (95% CI, 21.7%-32.5%) compared with 5.9% (95% CI, 3.4%-9.4%) with sorafenib monotherapy. In these arms, the median durations of response were 17.5 months (95% CI, 9.3-not reached [NR]) and 9.2 months (95% CI, 5.3-NR), respectively. Additionally, the median progression-free survival was 5.6 months (95% CI, 5.5-7.4) for the combination vs 3.7 months (95% CI, 3.1-3.7) for sorafenib alone (HR, 0.54; 95% CI, 0.44-0.67; P <.0001).

Updated safety data remained consistent with prior findings. No new safety signals were identified. The most common grade 3 or higher treatment-related adverse effects in the camrelizumab plus rivoceranib arm included 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%).

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 24, 2024. https://tinyurl.com/ypjtpws2

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