FDA Issues Second Camrelizumab/Rivoceranib CRL in Hepatocellular Carcinoma

The complete response letter for camrelizumab/rivoceranib for patients with advanced HCC did not specify what deficiencies regulators found.

The FDA has issued a second complete response letter (CRL) for camrelizumab plus rivoceranib as a frontline treatment for patients with unresectable or metastatic hepatocellular carcinoma (HCC), according to a news release.¹

According to Korean news sources, the FDA decision was issued March 20, and the CRL did not specify what deficiencies regulators found, according to HLB Group chairman, Jin Yang-gon. Additionally, Antengene Corporation, who developed camrelizumab, will contact the FDA to address concerns raised in the CRL.

Initially, the FDA accepted a new drug application (NDA) for the camrelizumab/rivoceranibas a treatment for patients with unresectable HCC in July 2023.² Then, the FDA sent its initial CRL for camrelizumab/rivoceranib in unresectable liver cancer in May 2024.³ Most recently, the FDA accepted a second NDA for camrelizumab/rivoceranib as a treatment for patients with unresectable HCC in October 2024.⁴

Data in this indication came from a presentation of the final analysis of the phase 3 CARES-310 study (NCT03764293), presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, evaluating treatment with camrelizumab/rivoceranib vs sorafenib (Nexavar) in patients with unresectable or metastatic HCC (uHCC).

Findings from the study reveal a median overall survival (OS) benefit with camrelizumab/rivoceranib vs the standard of care (SOC) tyrosine kinase inhibitor (TKI) inhibitor, sorafenib (Nexavar) at 23.8 months (95% CI, 20.6-27.2) vs 15.2 months (95% CI, 13.2-18.5), respectively (HR, 0.64; 95% CI, 0.52-0.79; P < .0001).⁵ Additionally, the median progression-free survival (PFS) was 5.6 months (95% CI, 5.5-7.4) with the combination therapy vs 3.7 months (95% CI, 3.1-3.7) with SOC (HR, 0.54; 95% CI, 0.44-0.67; P < .0001).

The open-label phase 3 trial randomly assigned 543 patients 1:1 with locally advanced or metastatic uHCC not having received previous systemic therapy to either 200 mg intravenous camrelizumab once every 2 weeks plus 250 mg oral rivoceranib once daily (n = 272) or 400 mg oral sorafenib twice daily (n = 271). The study began on June 10, 2019, and the protocol-specified final analysis was performed on June 14, 2023, after 351 (65%) deaths.

The coprimary end points of the study were OS and PFS assessed by a blinded independent review committee (BIRC).⁶ Secondary end points included objective response rate (ORR), disease control rate (DCR), and duration of response (DOR).

The ORR between the camrelizumab/rivoceranib and SOC arms was 26.8% (95% CI, 21.7%-32.5%) and 5.9% (95% CI, 3.4%-9.4%), respectively. Furthermore, the median DOR between respective arms were 17.5 months (95% CI, 9.3 – not reached [NR]) and 9.2 months (95% CI, 5.3-NR).

OS events occurred in 58.5% (n = 159) of the combination arm and 70.8% (n = 192) of the SOC arm. In respective arms, PFS events occurred in 73.2% (n = 199) and 77.1% (n = 209) of patients. The 24-month OS rate was 49.0% with rivoceranib plus camrelizumab vs 36.2% with sorafenib. It was 37.7% vs 24.8%, respectively, at 36 months.

OS benefit was similar across patient subgroups. PFS, ORR, and DOR benefits persisted through prolonged follow-up. Safety data was consistent with interim OS analysis, and no new safety signals were observed.

Findings from the final OS analysis presented at ASCO showed that 17.6% of patients discontinued camrelizumab and 16.9% discontinued rivoceranib due to treatment-related adverse effects (TRAEs). Furthermore, 4.8% of patients discontinued treatment with sorafenib due to a TRAE.

Common any-grade TRAEs in the combination and SOC arms included hypertension (69.5% vs 43.5%), aspartate aminotransferase increased (54.8% vs 37.5%), proteinuria (49.6% vs 27.1%), alanine aminotransferase increased (47.4% vs 30.1%), and platelet count decreased (46.3% vs 33.5%). The most common grade 3 or higher TRAE was hypertension in the camrelizumab/rivoceranib arm (38.2%) and palmar-plantar erythrodysesthesia syndrome in the sorafenib arm (15.6%).

References

1. Ji-Yoon H. HLB, Antengene fail to gain U.S. FDA approval for liver cancer drug combo. News release. Chosun Biz. March 21, 2025. Accessed March 21, 2025. https://tinyurl.com/3jcd2j5m
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, Inc. July 17, 2023. Accessed March 21, 2025. https://shorturl.at/oxBC8
3. Announcement on receipt of complete response letter regarding camrelizumab for injection. News release. Jiangsu Hengrui Pharmaceuticals Co., Ltd. May 17, 2024. Accessed March 21, 2025. https://tinyurl.com/3kdz97k9
4. Elevar Therapeutics announces FDA acceptance of new drug application resubmission for rivoceranib in combination with camrelizumab as a first-line systemic treatment for unresectable hepatocellular carcinoma. News release. Elevar Therapeutics. October 21, 2024. Accessed March 21, 2025. https://tinyurl.com/ytzrfuc9
5. 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). doi:10.1200/JCO.2024.42.16_suppl.4110
6. A study to evaluate SHR-1210 in combination with apatinib as first-line therapy in patients with advanced HCC. ClinicalTrials.gov. Updated February 6, 2024. Accessed March 21, 2025. https://tinyurl.com/453zf9s5