FDA Sends CRL for Camrelizumab/Rivoceranib in Unresectable Liver Cancer

The FDA previously accepted a new drug application (NDA) for camrelizumab/rivoceranib as a treatment for patients with unresectable HCC in July 2023.

The FDA has issued a complete response letter for frontline camrelizumab plus rivoceranib as a treatment for those with unresectable or metastatic hepatocellular carcinoma (HCC), according to a news release from the developers, Jiangsu Hengrui Pharmaceuticals Co., Ltd.¹

The regulatory agency’s complete response letter highlighted deficiencies related to its inspection of the developer’s manufacturing site. The agency will assess how developers respond to these manufacturing issues. Additionally, the FDA was not able to fully evaluate the camrelizumab combination within the review period due to travel restrictions in some countries.

Developers plan to remain in close contact with the regulatory agency and resubmit their marketing application for the novel treatment combination as soon as possible.

The FDA previously accepted a new drug application (NDA) for camrelizumab/rivoceranib as a treatment for patients with unresectable HCC in July 2023.² Supporting data for the NDA in this indication came from the phase 3 CARES-310 study (NCT03764293), in which investigators evaluated treatment with camrelizumab/rivoceranib vs sorafenib (Nexavar).

According to data published in The Lancet, the median progression-free survival (PFS) was 5.6 months (95% CI, 5.5-6.3) with the camrelizumab combination and 3.7 months (95% CI, 2.8-3.7) with sorafenib (HR, 0.52; 95% CI, 0.41-0.65; P <.0001).³ Data also highlighted a median overall survival (OS) of 22.1 months (95% CI, 19.1-27.2) vs 15.2 months (95% CI, 13.0-18.5) in each respective arm (HR, 0.62; 95% CI, 0.49-0.80; P <.0001). In each respective arm, the 12-month OS rate was 76.5% (95% CI, 71.0%-81.1%) vs 60.8% (95% CI, 54.6%-66.4%), and the 18-month rate was 60.9% (95% CI, 54.2%-66.9%) vs 45.2% (95% CI, 38.8%-51.4%).

Grade 3 or higher treatment-related adverse effects (TRAEs) affected 81% of those who received camrelizumab plus rivoceranib and 52% of those in the sorafenib arm. Common high-grade toxicities included hypertension, increased alanine aminotransferase, and increased aspartate aminotransferase.

“…Camrelizumab plus rivoceranib was associated with a statistically significant and clinically meaningful improvement in [PFS] and [OS] compared with sorafenib and had a manageable safety profile,” the study authors wrote.³ “The overall favorable benefit-to-risk profile supports camrelizumab with rivoceranib as a new first-line treatment option for patients with unresectable hepatocellular carcinoma who have not previously received any systemic therapy.”

In the open-label, global phase 3 CARES-310 study, 543 patients were randomly assigned to receive camrelizumab at 200 mg intravenously plus rivoceranib at 250 mg orally once daily (n = 272) or sorafenib at 400 mg orally twice daily (n = 271).

The trial’s primary end points were PFS based on blinded independent review committee assessment per RECIST v1.1 criteria and OS across the intent-to-treat population. Secondary end points included objective response rate, duration of response, time to progression, pharmacokinetics, and safety.

Patients 18 years and older with histopathologically or cytologically confirmed Barcelona Clinic Liver Cancer stage B or C HCC not amenable to surgical or locoregional care were eligible for enrollment on the trial. Additional eligibility criteria included having 1 or more measurable lesions per RECIST v1.1 guidelines, Child-Pugh class A liver function, an ECOG performance status of 0 or 1, a minimum life expectancy of 12 weeks, and adequate organ function.

Those with hepatocholangiocarcinoma, sarcomatoid HCC, mixed cell carcinoma, or lamellar cell carcinoma were ineligible for enrollment on the trial. Patients were also unsuitable for enrollment if they had prior gastrointestinal bleeding, uncontrolled hypertension, central nervous system metastases, metastatic disease with main airway or blood vessel involvement, or active or prior autoimmune disease.

References

1. Announcement on receipt of complete response letter regarding camrelizumab for injection. News release. Jiangsu Hengrui Pharmaceuticals Co., Ltd. May 17, 2024. Accessed May 20, 2024. https://tinyurl.com/3kdz97k9
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 May 20, 2024. https://shorturl.at/oxBC8
3. Qin S, Chan Sl, Gu S, et al. Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study. Lancet. Published online July 24, 2023. doi:10.1016/S0140-6736(23)00961-3