Dr Burgoyne on OS Data With Camrelizumab/Rivoceranib in Unresectable HCC

Adam M. Burgoyne, MD, PhD, associate clinical professor, medicine, the University of California San Diego, discusses updated efficacy and safety findings from the phase 3 CARES-310 trial (NCT03764293) investigating camrelizumab plus rivoceranib in patients with unresectable hepatocellular carcinoma (HCC), as well as considerations for future drug development and disease management in this patient population.

Final overall survival (OS) data from CARES-310, which were presented at the 

, confirmed the OS benefit that was previously reported with camrelizumab plus rivoceranib vs sorafenib (Nexavar) in this patient population, Burgoyne says. However, the safety profile of camrelizumab plus rivoceranib raises concerns, as the rates of adverse effects associated with the combination appeared to be higher than those observed with FDA-approved regimens for patients with HCC, Burgoyne emphasizes. Therefore, if camrelizumab plus rivoceranib were to gain FDA approval for this patient population in the future, the safety profile of this combination would need to be weighed against the safety profiles of standard regimens, Burgoyne notes.

 a new drug application (NDA) seeking the approval of the combination as a frontline regimen for patients with unresectable HCC. This NDA was supported by prior findings from CARES-310. However, in May 2024, the FDA issued a complete response letter to the NDA.

In recent years, several developments have been made to propel the field of advanced HCC management forward, according to Burgoyne. Expanding the number of effective treatment combinations and positive clinical trials in this disease setting provides more opportunities for patients to access critical cancer care, Burgoyne explains. However, as novel agents and regimens come down the pike, individualized treatment selection will become increasingly critical, Burgoyne says. Oncologists should discuss the safety profiles of these regimens with patients and consider characteristics such as ECOG performance status and liver function, Burgoyne emphasizes. Overall, patients’ individual needs should influence and help refine the broadening HCC treatment paradigm, Burgoyne concludes.

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Adam M. Burgoyne, MD, PhD, discusses updated findings from the CARES-310 trial and future considerations for unresectable HCC management.

Frontline treatment with rivoceranib plus camrelizumab maintained a clinically meaningful survival improvement compared with sorafenib (Nexavar) alone in patients with advanced, unresectable hepatocellular carcinoma (HCC), according to data from the final analysis of the phase 3 CARES-310 trial (NCT03764293) presented at the 

Findings showed that at a median follow-up of 22.1 months in the combination arm and 14.9 months in the sorafenib arm, the median overall survival (OS) was 23.8 months (95% CI, 20.6-27.2) in the combination arm (n = 272) vs 15.2 months (95% CI, 13.2-18.5) in the sorafenib arm (n = 271; HR, 0.64; 95% CI, 0.52-0.79; 1-sided 

 <.0001). Notably, at 24 months and 36 months, the respective OS rates were 49.0% and 37.7% for rivoceranib/camrelizumab vs 32.6% and 24.8% for sorafenib. These rates were similar between most subgroups, regardless of geographical race, region, and etiology.

Furthermore, the median progression-free survival (PFS) was 5.6 months (95% CI, 5.5-7.4) for the combination vs 3.7 months (95% CI, 3.1-3.7) for sorafenib alone (HR, 0.54; 95% CI, 0.44-0.67; 

"The extended follow-up further confirmed the favorable benefit-to-risk profile of camrelizumab plus rivoceranib, supporting it as a new first-line treatment option for unresectable HCC," Arndt Vogel, MD, stated in the poster presentation of data. Vogel serves as a professor of medicine at the University of Toronto and a clinician scientist in the University Health Network, at the Toronto Centre for Liver Disease, and is the Longo Family Chair in Liver Cancer Research in the Division of Gastroenterology and Hepatology at Toronto General Hospital/Princess Margaret Cancer Center in Canada.

the FDA accepted for review a new drug application (NDA)

 seeking the approval of rivoceranib in combination with camrelizumab as a first-line treatment option for patients with unresectable HCC, based on prior data from CARES-310.

 However, in May 2024, the regulatory agency issued a complete response letter (CRL) to the NDA, according to a news release from Jiangsu Hengrui Medicine in Korea. The CRL cited deficiencies related to the FDA’s inspection of the developer’s manufacturing site.

Prior data from CARES-310 demonstrated improvements in PFS and OS with the combination of rivoceranib and camrelizumab vs sorafenib. In the primary PFS analysis, with a data cut-off of May 10, 2021, and the interim OS analysis, with a data cut-off of February 8, 2022, the combination elicited a median PFS of 5.6 months vs 3.7 months for sorafenib (HR, 0.52; 95% CI, 0.41-0.65; 

 < .0001). The median OS was 22.1 months with the combination vs 15.2 months for sorafenib (HR, 0.62; 95% CI, 0.49-0.80; 

The international, randomized, open-label study enrolled patients with unresectable or metastatic HCC, classified as Barcelona Clinic Liver Cancer (BCLC) stage B (unsuitable for radical surgery or locoregional therapy) or C. No prior systemic therapy was allowed. Patients needed to have an ECOG performance status of 0 or 1, Child-Pugh A classification, and at least one measurable lesion per RECIST 1.1 criteria.

Participants were randomly assigned 1:1 to receive either 200 mg of intravenous (IV) camrelizumab once every 2 weeks plus 250 mg of rivoceranib per day; or sorafenib at 400 mg twice daily. Treatment continued until the loss of clinical benefit or intolerable toxicity. By June 14, 2023, 351 deaths (65% of patients) had occurred, prompting the protocol-specified final analysis.

Key stratification factors included the presence of macrovascular invasion (MVI) or extrahepatic spread (EHS; yes vs no); geographic region (Asia vs non-Asia); and baseline serum alpha-fetoprotein levels (<400 vs ≥400 ng/mL). The primary end points of the investigation were PFS and OS, with objective response rate (ORR) serving as a key secondary end point.

Following study completion, 43.8% of patients in the combination group and 56.9% of patients in the monotherapy group received subsequent systemic anticancer therapy.

The median ages of patients enrolled were 58 years (range, 48-66) in the camrelizumab plus rivoceranib group and 56 years (range, 47-64) in the sorafenib group; 83.5% and 84.9% were male, respectively; 82.7% of patients in both groups were from Asia; and 86.0% and 85.2% were classified as BCLC stage C. Notably, 86.8% and 84.9% of patients had a Child-Pugh A score; 55.9% and 57.2% had an ECOG performance status of 1; and 35.3% and 36.9% of patients had alpha-fetoprotein levels at least 400 ng/mL.

The presence of MVI and/or EHS was noted in 73.5% of patients (in the camrelizumab plus rivoceranib group) and 73.8% (in the sorafenib group); the underlying etiology of HCC included hepatitis B virus (HBV) in 76.5% and 72.7%, hepatitis C virus (HCV) in 8.1% and 10.7%, and non-viral causes in 15.4% and 16.6% of patients, respectively; and previous local therapy was reported in 59.2% and 55.0% of patients.

Additional data showed the ORR for camrelizumab plus rivoceranib was 26.8% (95% CI, 21.7%-32.5%) compared with 5.9% (95% CI, 3.4%-9.4%) for sorafenib. The median duration of response was 17.5 months (95% CI, 9.3–not reached [NR]) for the camrelizumab plus rivoceranib group vs 9.2 months (95% CI, 5.3-NR) for the sorafenib group.

Updated safety data remained consistent with prior findings, with no new safety signals identified. Treatment-related adverse effects (TRAEs) led to the discontinuation of camrelizumab in 17.6% of patients and rivoceranib in 16.9% of patients in the combination group. The discontinuation rate for both agents was 4.4%. For the sorafenib group, the discontinuation rate due to TRAEs was 4.8%.

TRAEs in the camrelizumab plus rivoceranib group included hypertension (any-grade, 69.5%; grade ≥3, 38.2%), increased aspartate aminotransferase (AST; 54.8%; 17.3%), proteinuria (49.6%; 5.9%), increased alanine aminotransferase (ALT; 47.4%; 14.0%), decreased platelet count (46.3%; 11.8%), increased blood bilirubin (43.0%; 8.8%), palmar-plantar erythrodysesthesia (PPE) syndrome (37.5%; 12.1%), and diarrhea (30.9%; 2.2%). Other notable TRAEs included decreased neutrophil count (27.6%; 5.9%), decreased white blood cell count (27.2%; 2.6%), and increased gamma-glutamyl transferase (23.9%; 9.6%).

In the sorafenib group, common TRAEs included hypertension (any-grade, 43.5%; grade ≥3, 14.9%), increased AST (37.5%; 5.2%), PPE syndrome (61.0%; 15.6%), increased blood bilirubin (27.9%; 1.5%), decreased platelet count (33.5%; 1.5%), diarrhea (39.4%; 5.2%), and increased gamma-glutamyl transferase (18.2%; 7.1%). Other notable TRAEs included decreased neutrophil count (10.4%; 1.1%), decreased white blood cell count (14.1%; 1.5%), and fatigue (7.8%; 0.4%).

Vogel A Chan SL, GU S, et al. Camrelizumab plus rivoceranib vs sorafenib as first-line therapy for unresectable hepatocellular carcinoma: final overall survival analysis of the phase 3 CARES-310 study. 

. 2024;42(suppl 16):4110. doi:10.1200/JCO.2024.42.16_suppl.4110

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 June 2, 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/

Announcement on receipt of complete response letter regarding camrelizumab for injection. News release. Jiangsu Hengrui Pharmaceuticals Co., Ltd. May 17, 2024. Accessed June 2, 2024. https://static.sse.com.cn/disclosure/listedinfo/announcement/c/new/2024-05-18/600276_20240518_01L3.pdf

Articles

Frontline treatment with rivoceranib plus camrelizumab significantly improved overall survival (OS) and progression-free survival (PFS) compared to sorafenib in patients with advanced, unresectable hepatocellular carcinoma (HCC). The phase 3 CARES-310 trial demonstrated a median OS of 23.8 months for the combination therapy versus 15.2 months for sorafenib. The combination also showed a higher objective response rate (ORR) and a favorable safety profile. Despite these positive results, the FDA issued a complete response letter due to manufacturing site deficiencies.

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