Elevar Therapeutics is set to resubmit its New Drug Application (NDA) to the FDA for the combination of rivoceranib and camrelizumab as a first-line treatment for patients with unresectable hepatocellular carcinoma (HCC). This decision follows a Complete Response Letter (CRL) issued by the FDA on May 16, 2024.
The CRL cited good manufacturing practice (GMP) deficiencies at the Hengrui Pharma facility, which manufactures camrelizumab, and noted incomplete bioresearch monitoring clinical inspections due to FDA travel restrictions. Importantly, the FDA did not raise concerns regarding the clinical data for the combination therapy or the manufacturing site for rivoceranib.
Path Forward Clarified
During a Type A meeting with the FDA, Elevar Therapeutics received confirmation that the NDA could be resubmitted without further remediation at the Hengrui manufacturing site. Travel-restricted inspections will be permitted after the resubmission, paving the way for potential approval.
Saeho Chong, PhD, CEO of Elevar Therapeutics, stated, "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." He added that the company is motivated to resubmit the application, aiming to provide patients and providers access to this novel combination therapy for unresectable HCC, where a significant unmet need persists.
CARES-310 Trial Data
The resubmission will incorporate the landmark analysis from the phase 3 CARES-310 trial (NCT03764293), recently presented at the 2024 ASCO Annual Meeting. This analysis demonstrated a median overall survival (OS) of 23.8 months, the longest reported in a global phase 3 trial for patients with unresectable HCC.
The initial NDA was based on data from the CARES-310 trial, which showed that rivoceranib plus camrelizumab significantly improved OS and progression-free survival (PFS) compared to sorafenib monotherapy in the first-line treatment of unresectable HCC. Patients treated with the combination (n = 272) had a median OS of 22.1 months (95% CI, 19.1-27.2) compared to 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 the combination versus 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 (ORR) was 25.4% (95% CI, 20.3%-31.0%) for the combination and 5.9% (95% CI, 3.4%-9.4%) for sorafenib.
Updated OS Analysis
The final OS analysis, presented at the 2024 ASCO Annual Meeting, showed that at a median follow-up of 22.1 months for the combination arm and 14.9 months for the sorafenib arm, the combination achieved a median OS of 23.8 months (95% CI, 20.6-27.2) compared to 15.2 months (95% CI, 13.2-18.5) for sorafenib (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.
The median PFS was 5.6 months (95% CI, 5.5-7.4) for the combination versus 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-NR) in the combination arm versus 9.2 months (95% CI, 5.3-NR) in the sorafenib arm.
Trial Design and Patient Population
The CARES-310 study was an international, randomized, open-label trial that enrolled patients with unresectable or metastatic HCC who had not received prior systemic therapy. Patients were required to have Barcelona Clinic Liver Cancer stage B or C disease, an ECOG performance status of 0 or 1, a Child-Pugh A score, and at least one measurable lesion per RECIST 1.1 criteria.
Patients were randomized 1:1 to receive 200 mg of intravenous camrelizumab every two weeks plus 250 mg of oral rivoceranib once daily, or 400 mg of oral sorafenib twice daily. Treatment continued until loss of clinical benefit or unacceptable toxicity.
Safety Profile
Regarding safety, the final OS analysis findings were consistent with the interim OS analysis. Treatment-related adverse events (TRAEs) led to the discontinuation of camrelizumab in 17.6% of patients and rivoceranib in 16.9% of patients. Both agents were discontinued due to TRAEs in 4.4% of patients, while sorafenib was discontinued due to TRAEs in 4.8% of patients.
The most common any-grade TRAEs included hypertension (69.5% with the combination vs. 43.5% with sorafenib), increased aspartate aminotransferase (54.8% vs. 37.5%), proteinuria (49.6% vs. 27.1%), and increased alanine aminotransferase (47.4% vs. 30.1%).
