FDA Accepts NDA Resubmission for First-Line Rivoceranib/Camrelizumab Combo in Unresectable HCC

The FDA has accepted the new drug application (NDA) resubmission for the first-line use of the oral VEGF TKI rivoceranib in combination with the PD-1 inhibitor camrelizumab for patients with unresectable or metastatic hepatocellular carcinoma (HCC). The Prescription Drug User Fee Act target action date is March 20, 2025.¹

On September 23, 2024, the company refiled the NDA for review, seeking the approval of the combination for the frontline treatment of patients with unresectable HCC. This came after the regulatory agency filed a complete response letter (CRL) in May 2024 for the combination’s initial NDA submission in this indication. Although the CRL from the FDA did not state issues related to the manufacturing site for rivoceranib or clinical data with the combination, the letter cited manufacturing practice deficiencies at the Hengrui Pharma facility, which manufactures camrelizumab, as well as incomplete bioresearch monitoring clinical inspections due to FDA travel restrictions.^2,3

The initial NDA was submitted to the FDA in May 2023, followed by the FDA’s acceptance of the submission in July of the same year.^4,5

The newest NDA filing that was accepted for review by the FDA cited data from the phase 3 CARES-310 trial (NCT03764293), which were presented at the 2024 ASCO Annual Meeting.1 With additional follow-up of approximately 16 months, the median overall survival (OS) was 23.8 months (95% CI, 20.6-27.2) with the combination vs 15.2 months (95% CI, 13.2-18.5) with sorafenib (Nexavar) in patients with previously untreated, unresectable HCC (HR, 0.64; 95% CI, 0.52%-0.79%; 1-sided P < .0001), representing the longest median OS reported for any treatment in a global phase 3 trial in this population.

“We believe rivoceranib plus camrelizumab has the potential to change the clinical practice in the first-line setting for patients with advanced liver cancer. The results of the pivotal CARES-310 trial demonstrated significant improvements in OS, with a very manageable safety profile compared with currently approved unresectable HCC therapies. Elevar is committed to working with the FDA to bring this combination to market for patients and health care providers,” Chris Galloway, MD, senior vice president of clinical and medical affairs at Elevar Therapeutics, stated in a press release.¹

An Overview of the CARES-310 Clinical Trial

The international, randomized, open-label trial also reported similar efficacy results across patient subgroups. CARES-310 enrolled 543 previously untreated patients with unresectable or metastatic HCC and demonstrated significant progression-free survival (PFS) and OS benefits with the combination vs standard TKI therapy with sorafenib as first-line treatment. In both the primary PFS and interim OS analysis, significant improvements were observed with the combination vs sorafenib.

Additional results indicated that the 24-month OS rate with the combination was 49.0% vs 32.6% with sorafenib; these rates were 37.7% and 24.8% at 36 months, respectively.

Improvements in PFS, objective response rate, and duration of response with the combination were also sustained with extended follow-up. The safety profile was consistent with that from the interim OS analysis, with no new safety signals identified.

Additionally, the extended follow-up confirmed the favorable risk-benefit profile of rivoceranib plus camrelizumab as a first-line treatment option for unresectable HCC.

Understanding the Investigational Combination

Rivoceranib selectively inhibits VEGFR, a key pathway in tumor angiogenesis, and is currently under investigation as a monotherapy and in combination with chemotherapy and immunotherapy across various solid tumor types. The agent became the first TKI approved for gastric cancer in China in October 2014 and gained approval in China as a first-line treatment for unresectable HCC in combination with camrelizumab in January 2023.

Camrelizumab is a humanized monoclonal antibody which blocks the PD-(L)1 signaling pathway and is currently being evaluated in 50 clinical trials for a range of tumors, including liver, lung, gastric, and breast cancer. This agent is approved in China across 8 indications including HCC, classic Hodgkin lymphoma, esophageal squamous cell carcinoma, nasopharyngeal carcinoma, and non–small cell lung cancer.

References

1. 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 October 21, 2024. https://elevartherapeutics.com/2024/10/21/elevar-therapeutics-fda-acceptance-of-new-drug-resubmission-2/
2. 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 October 21, 2024. https://elevartherapeutics.com/2024/09/23/elevar-therapeutics-resubmits-new-drug-application/
3. 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 October 21, 2024. https://elevartherapeutics.com/2024/07/09/elevar-therapeutics-first-line-treatment-option/
4. Elevar Therapeutics submits new drug application to FDA for combination of rivoceranib and camrelizumab as first-line treatment option for unresectable hepatocellular carcinoma. News release. Elevar Therapeutics. May 17, 2023. Accessed October 21, 2024. https://www.biospace.com/article/releases/elevar-therapeutics-submits-new-drug-application-to-fda-for-combination-of-rivoceranib-and-camrelizumab-as-first-line-treatment-option-for-unresectable-hepatocellular-carcinoma/
5. 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 October 21, 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/