EMA Grants Orphan Medicinal Product Designation to Rivoceranib/Camrelizumab in First-Line Unresectable HCC

Chris Galloway, MD

The European Medicines Agency (EMA) has granted orphan medicinal product designation to the combination of rivoceranib and camrelizumab as a potential first-line treatment for patients with unresectable hepatocellular carcinoma (HCC).¹

“This significant designation by the EMA underscores the ongoing unmet need for new liver cancer therapies. Orphan designation further supports Elevar’s mission to bring a novel first-line systemic treatment option to patients in the European Union [EU] diagnosed with HCC, a leading cause of cancer death in the EU and worldwide,” Chris Galloway, MD, senior vice president of clinical and medical affairs at Elevar Therapeutics, stated in a news release.

Elevar Therapeutics previously sought FDA approval for rivoceranib plus camrelizumab for the frontline treatment of patients with unresectable HCC; however, in May 2024, the FDA issued a complete response letter citing deficiencies in good manufacturing practice at the Hengrui Pharma facility, which manufactures camrelizumab. The company plans to resubmit a new drug application to the FDA.²

The combination was evaluated in the phase 3 CARES-310 trial (NCT03764293), and updated findings from the study’s final overall survival (OS) analysis presented at the 2024 ASCO Annual Meeting showed that patients treated with rivoceranib plus camrelizumab (n = 272) achieved a median OS of 23.8 months (95% CI, 20.6-27.2) compared with 15.2 months (95% CI, 13.2-18.5) for those given sorafenib (Nexavar) monotherapy (n = 271; HR, 0.64; 95% CI, 0.52-0.79; 1-sided P < .0001).³

The combination elicited a median progression-free survival (PFS) of 5.6 months (95% CI, 5.5-7.4) compared with 3.7 months (95% CI, 3.1-3.7) for sorafenib (HR, 0.54; 95% CI, 0.44-0.67; 1-sided P < .0001).

The international, randomized, open-label study enrolled patients with unresectable or metastatic HCC who received no prior systemic therapy. Patients were required to have Barcelona Clinic Liver Cancer stage B or C disease and a Child-Pugh A score. At least 1 measurable lesion per RECIST 1.1 criteria and an EGOG performance status of 0 or 1 were also required.

Patients were randomly assigned 1:1 to receive 250 mg of oral rivoceranib once per day plus 200 mg of intravenous camrelizumab once every 2 weeks; or 400 mg of oral sorafenib twice per day. Treatment continued until loss of clinical benefit or intolerable toxicity.

PFS and OS served as the trial’s coprimary end points. Overall response rate (ORR) was a key secondary end point.

Patients in the rivoceranib plus camrelizumab arm experienced an ORR of 26.8% (95% CI, 21.7%-32.5%) vs 5.9% (95% CI, 3.4%-9.4%) for those in the sorafenib arm. The median duration of response was 17.5 months (95% CI, 9.3-not reached [NR]) for the experimental arm vs 9.2 months (95% CI, 5.3-NR) for the control arm.

No new safety signals were reported in the final OS analysis. Treatment-related adverse effects (TRAEs) led to discontinuation of camrelizumab in 17.6% of patients and discontinuation of rivoceranib in 16.9% of patients; 4.4% of patients discontinued both agents due to TRAEs. TRAEs led to the discontinuation of sorafenib in 4.8% of patients.

TRAEs reported in the rivoceranib plus camrelizumab arm 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%), diarrhea (30.9%; 2.2%), reactive cutaneous capillary endothelial proliferation (30.1%; 2.9%), decreased neutrophil count (27.6%; 5.9%), decreased white blood cell count (27.2%; 2.6%), increased gamma-glutamyl transferase (GGT; 23.9%; 9.6%), hypothyroidism (21.3%; 0%), and fatigue (20.6%; 2.9%).

In the sorafenib group, TRAEs included hypertension (any grade, 43.5%; grade ≥3, 14.9%), increased AST (37.5%; 5.2%), proteinuria (27.1%; 1.9%), increased ALT (30.1%; 3.0%), decreased platelet count (33.5%; 1.5%), increased blood bilirubin (27.9%; 1.5%), PPE syndrome (61.0%; 15.6%), diarrhea (39.4%; 5.2%), decreased neutrophil count (10.4%; 1.1%), decreased white blood cell count (14.1%; 1.5%), increased GGT (18.2%; 7.1%), hypothyroidism (6.3%; 0%), and fatigue (7.8%; 0.4%).

References

1. Elevar Therapeutics granted orphan medicinal product designation by the European Medicines Agency for first-line systemic therapy for unresectable hepatocellular carcinoma. News release. Elevar Therapeutics. August 1, 2024. Accessed August 1, 2024. https://elevartherapeutics.com/2024/08/01/elevar-therapeutics-granted-orphan-designation/
2. 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 August 1, 2024. https://elevartherapeutics.com/2024/07/09/elevar-therapeutics-first-line-treatment-option/
3. 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):4110. doi:10.1200/JCO.2024.42.16_suppl.4110