NDA Resubmission Planned for Rivoceranib/Camrelizumab in Unresectable HCC Following FDA CRL

A new drug application (NDA) seeking the approval of rivoceranib plus camrelizumab for the frontline treatment of patients with unresectable hepatocellular carcinoma (HCC) will be resubmitted to the FDA following a complete response letter (CRL) from the regulatory agency, according to an announcement from Elevar Therapeutics.¹

On May 16, 2024, the FDA issued a CRL for the initial NDA, which cited good manufacturing practice deficiencies at the Hengrui Pharma facility, which manufactures camrelizumab. Additionally, the letter noted incomplete bioresearch monitoring clinical inspections that were limited by FDA travel restrictions. Notably, the CRL did not identify any issues regarding clinical data for the combination or the manufacturing site for rivoceranib.

During a Type A meeting, the FDA informed Elevar Therapeutics that resubmission of the NDA can occur without delay, and inspections hindered by travel restrictions will be allowed to occur after resubmission.

“The most critical outcome from our discussion with the FDA is that resubmission of Elevar’s NDA can occur without further remediation at the Hengrui manufacturing site,” Saeho Chong, PhD, chief executive officer of Elevar Therapeutics, stated in a news release. “Elevar left the meeting very motivated and with a clear path forward for resubmission, so patients and providers can soon have access to this novel combination therapy for unresectable HCC where there continues to be a high unmet need. The resubmission will include the [phase 3] CARES-310 [trial (NCT03764293)] landmark analysis recently presented at [the 2024 ASCO Annual Meeting], demonstrating the longest median overall survival (OS) of 23.8 months for any treatment in a global phase 3 trial for patients with unresectable HCC.”

The initial NDA was supported by data from CARES-310, which demonstrated that treatment with rivoceranib plus camrelizumab led to a statistically significant and clinically meaningful improvement in OS and progression-free survival (PFS) vs sorafenib (Nexavar) monotherapy in the first-line treatment of patients with unresectable HCC.²

Findings showed that patients treated with camrelizumab plus rivoceranib (n = 272) experienced a median OS of 22.1 months (95% CI, 19.1-27.2) vs 15.2 months (95% CI, 13.0-18.5) for those treated with sorafenib (n = 271; HR, 0.62; 95% CI, 0.49-0.80; 1-sided P < .0001). The median PFS was 5.6 months (95% CI, 5.5-6.3) for camrelizumab plus rivoceranib compared with 3.7 months (95% CI, 2.8-3.7) for sorafenib (HR, 0.52; 95% CI, 0.41-0.65; 1-sided P < .0001). The confirmed objective response rate was 25.4% (95% CI, 20.3%-31.0%) for camrelizumab plus rivoceranib vs 5.9% (95% CI, 3.4%-9.4%) for sorafenib.

Findings from the trial’s final OS analysis presented at the 2024 ASCO Annual Meeting showed that at a median follow-up of 22.1 months for the camrelizumab plus rivoceranib group and 14.9 months for the sorafenib group, patients in the experimental arm achieved a median OS of 23.8 months (95% CI, 20.6-27.2) vs 15.2 months (95% CI, 13.2-18.5) for those in the control group (HR, 0.64; 95% CI, 0.52-0.79; 1-sided P < .0001). The 36-month OS rates were 37.7% and 24.8%, respectively.³

The median PFS was 5.6 months (95% CI, 5.5-7.4) for camrelizumab plus rivoceranib vs 3.7 months (95% CI, 3.1-3.7) for sorafenib (HR, 0.54; 95% CI, 0.44-0.67; 1-sided P < .0001). The median duration of response was 17.5 months (95% CI, 9.3-not reached [NR]) in the experimental arm vs 9.2 months (95% CI, 5.3-NR) in the control arm.

The international, randomized, open-label CARES-310 study enrolled patients with unresectable or metastatic HCC who were naive to systemic therapy. Patients were required to have Barcelona Clinic Liver Cancer stage B or C disease. Other inclusion criteria consisted of an ECOG performance status of 0 or 1; a Child-Pugh A score; and at least 1 measurable lesion per RECIST 1.1 criteria.

Patients were randomly assigned 1:1 to receive 200 mg of intravenous camrelizumab once every 2 weeks plus 250 mg of oral rivoceranib once per day; or 400 mg of oral sorafenib twice per day. Treatment continued until loss of clinical benefit or unacceptable toxicity.

Stratification factors included macrovascular invasion and/or extrahepatic spread (yes vs no), geographical region (Asia vs non-Asia), and baseline serum alpha-fetoprotein level (<400 ng/mL vs ≥400 ng/mL).

PFS and OS were the trial’s co-primary end points. ORR was a key secondary end point.

Regarding safety, findings from the final OS analysis were consistent with the interim OS analysis. Treatment-related adverse effects (TRAEs) led to treatment discontinuation of camrelizumab in 17.6% of patients and the discontinuation of rivoceranib in 16.9% of patients. Notably, 4.4% of patients discontinued both agents due to TRAEs. TRAEs led to the discontinuation of sorafenib in 4.8% of patients.

The most common any-grade TRAEs included hypertension (camrelizumab plus rivoceranib, 69.5%; sorafenib, 43.5%), increased aspartate aminotransferase (54.8%; 37.5%), proteinuria (49.6%; 27.1%), increased alanine aminotransferase (47.4%; 30.1%), decreased platelet count (46.3%; 33.5%), increased blood bilirubin (43.0%; 27.9%), palmar-plantar erythrodysesthesia syndrome (37.5%; 61.0%), diarrhea (30.9%; 39.4%), reactive cutaneous capillary endothelial proliferation (30.1%; 0%), decreased neutrophil count (27.6%; 10.4%), decreased white blood cell count (27.2%; 14.1%), increased gamma-glutamyl transferase (23.9%; 18.2%), hypothyroidism (21.3%; 6.3%), and fatigue (20.6%; 7.8%).

References

1. Elevar Therapeutics reports plans for near-term resubmission of NDA for first-line treatment option for unresectable hepatocellular carcinoma following Type A FDA meeting. News release. Elevar Therapeutics. July 9, 2024. Accessed July 9, 2024. https://elevartherapeutics.com/2024/07/09/elevar-therapeutics-first-line-treatment-option/
2. Elevar Therapeutics announces FDA acceptance for 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 July 9, 2024. https://elevartherapeutics.com/2023/07/17/elevar-therapeutics-announces-fda-acceptance-for-filing-of-new-drug-application-for-rivoceranib-in-combination-with-camrelizumab-as-a-first-line-treatment-for-unresectable-hepatocellular-carcinoma/
3. 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