The U.S. Food and Drug Administration (FDA) has issued a second Complete Response Letter (CRL) for the combination of rivoceranib plus camrelizumab as a frontline treatment for patients with unresectable hepatocellular carcinoma (HCC), marking another setback for a therapy that demonstrated significant survival benefits in clinical trials.
According to Korean news sources, the FDA delivered this decision on March 20, 2025, without specifying the deficiencies that led to the rejection. HLB Group, the owner of Elevar Therapeutics which developed rivoceranib, reported that the FDA has not disclosed the reasons for withholding approval in this latest regulatory action.
This marks the second rejection for the combination therapy. The initial CRL was issued on May 16, 2024, due to deficiencies related to the inspection of camrelizumab's manufacturing site, though no issues were noted regarding rivoceranib's manufacturing facilities. Antengene Corporation, the developer of camrelizumab, is expected to contact the FDA to address the concerns raised in this latest CRL.
Clinical Trial Results Showed Promising Efficacy
The regulatory submission was based on data from the phase 3 CARES-310 study, which was conducted across 95 sites in 13 countries. The final analysis, presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, demonstrated significant clinical benefits for the combination therapy compared to the tyrosine kinase inhibitor (TKI) sorafenib, which has been a standard treatment option.
After a median follow-up of 22.1 months for the combination arm and 14.9 months for the sorafenib arm, the study showed:
- Median overall survival (OS) of 23.8 months (95% CI, 20.6-27.2) with the combination versus 15.2 months (95% CI, 13.2-18.5) with sorafenib (HR, 0.64; 95% CI, 0.52-0.79; P < .0001)
- Progression-free survival (PFS) of 5.6 months with the combination compared to 3.7 months with sorafenib (HR, 0.54; 95% CI, 0.44-0.67; P < .0001)
- Objective response rate (ORR) of 26.8% for the combination versus 5.9% for sorafenib
- Median duration of response of 17.5 months for the combination versus 9.2 months for sorafenib
The 24-month OS rate was 49% for patients receiving the combination compared to 36.2% for those on sorafenib. At 36 months, the OS rates were 37.7% and 24.8%, respectively, maintaining the survival advantage for the combination therapy.
Safety Profile and Treatment Discontinuation
The safety profile of the combination therapy showed higher rates of treatment discontinuation due to treatment-related adverse events (TRAEs) compared to sorafenib. In the combination arm, 17.6% of patients discontinued camrelizumab, 16.9% discontinued rivoceranib, and 4.4% discontinued both drugs due to TRAEs. In comparison, only 4.8% of patients discontinued sorafenib due to TRAEs.
The most common TRAEs in the combination arm included hypertension (69.5%), increased aspartate aminotransferase (54.8%), proteinuria (49.6%), increased alanine aminotransferase (47.4%), and decreased platelet count (46.3%). Hypertension was the most common grade 3 or higher TRAE in the combination arm (38.2%), while palmar-plantar erythrodysesthesia syndrome was the most common in the sorafenib arm (15.6%).
Current Treatment Landscape for HCC
Hepatocellular carcinoma represents a significant unmet medical need globally. The current standard of care for frontline treatment of unresectable HCC is atezolizumab plus bevacizumab. Other frontline options include durvalumab plus tremelimumab-actl and single-agent TKIs such as sorafenib and lenvatinib.
Camrelizumab is an anti–PD-1 antibody, while rivoceranib is a VEGFR2-targeted TKI. The combination represents a dual approach targeting both immune checkpoint inhibition and angiogenesis, which has shown promise in clinical trials.
Regulatory Journey
The regulatory path for this combination has been challenging:
- July 2023: FDA accepted the initial new drug application (NDA) for camrelizumab/rivoceranib
- May 2024: FDA issued the first CRL citing manufacturing concerns
- October 2024: FDA accepted a resubmitted NDA
- March 2025: FDA issued a second CRL
This latest rejection comes amid a broader trend of manufacturing-related concerns affecting cancer drug approvals. Throughout 2024, the FDA delivered multiple CRLs to cancer drugs specifically due to manufacturing issues.
HLB and Antengene Corporation will need to work closely with the FDA to address the unspecified concerns before potentially resubmitting the application. The companies have not yet announced their next steps or timeline for addressing the issues raised in the latest CRL.
