Significant progression-free survival and overall survival benefits were demonstrated with rivoceranib plus camrelizumab for patients with unresectable hepatocellular carcinoma when used in the first-line setting.
In the phase 3 CARES 310 study (NCT03764293), the combination of rivoceranib, an oral tyrosine kinase inhibitor (TKI) and camrelizumab, a PD-1 inhibitor, produced a statistically significant and clinically meaningful benefit in progression-free survival (PFS) and overall survival (OS) vs sorafenib (Nexavar) for the first-line treatment of previously untreated patients with unresectable hepatocellular carcinoma (uHCC), according to data published in The Lancet.1
Patients with advanced disease and uHCC are in need of more treatment options, and since benefits of immunotherapy plus an anti-angiogenic TKI in uHCC are unclear, the phase 3 CARES 310 study planned to camrelizumab plus rivoceranib in this patient population.
“Patients with hepatocellular carcinoma have many treatment options. However, the majority of patients present with advanced disease or recur despite intervention such as surgery. Those patients who are not suitable for ablative or curative approaches with surgery transplant, local ablation with the microwave or radiofrequency ablation, and even treatments that are hepatic arterial driven, those patients are generally treated with systemic therapy if they've had progressive disease despite those therapies and are otherwise not candidates,” Laura Dawson, MD, FRCPC of Princess Margaret Cancer Centre, told Targeted OncologyTM.
At a median follow-up of 7.8 months (interquartile range [IQR], 4.1-10.6) for the primary PFS analysis, 272 patients were treated with the combination of rivoceranib plus camrelizumab and had a median PFS of 5.6 months (95% CI, 5.5-6.3) vs 3.7 months (95% CI, 2.8-3.7) for the 271 patients treated with sorafenib (HR, 0.52; 95% CI, 0.41-0.65; 1-sided P <.0001).2
For the interim OS analysis with a median follow-up of 14.5 months (IQR, 9.1-18.7), the median OS for patients given the combination was 22.1 months (95% CI, 19.1-27.2) compared with 15.2 months (95% CI, 13.0-18.5) for those treated with sorafenib (HR, 0.62; 95% CI, 0.49-0.80; 1-sided P <.0001). Additionally, the confirmed overall response rate (ORR) for camrelizumab plus rivoceranib was 25.4% (95% CI, 20.3-31.0) vs 5.9% (95% CI, 3.4-9.4) with sorafenib.3
Regarding safety, 99% of patients given rivoceranib and camrelizumab arm had at least 1 any-grade adverse event (AE), as well as 99% of patients given sorafenib, and grade 3 or higher AEs were seen in 88% and 68% of patients, respectively.2
“As evidenced in the CARES 310 study, camrelizumab plus rivoceranib demonstrates significant promise as a potentially improved therapy for advanced HCC,” said Saeho Chong, chief executive officer of Elevar Therapeutics, in a press release.1 “Elevar is pleased The Lancet, a prestigious peer-reviewed journal, recognized the significance of these results as we continue to work toward commercial development of this combined therapy.”
Previously on July 17, 2023, the FDA accepted a new drug application for rivoceranib plus camrelizumab for the first-line treatment for patients with uHCC. Findings from the phase 3 CARES 310 study supported this regulatory decision.3
In the randomized, open-label, international CARES 310 trial, patients aged 18 years and older with unresectable or metastatic HCC who had not previously received any systemic therapy were randomly assigned in a 1:1 ratio and treated with 200 mg of intravenous camrelizumab every 2 weeks plus 250 mg of oral rivoceranib 250 mg once per day, or 400 mg of oral sorafenib twice per day.4 Treatment was given in 28-day cycles, which continued until unacceptable toxicity, withdrawal of consent, disease progression confirmed by blinded independent review committee (BIRC) per RECIST v1.1 criteria, or investigator's decision.
The trial enrolled patients with a Barcelona Clinic Liver Cancer (BCLC) stage B or C disease which was not amenable to or had progressed after surgical or locoregional therapy, who had at least 1 measurable lesion per RECIST v1.1 criteria, Child-Pugh class A liver function, an ECOG performance status of 0 or 1, a life expectancy of at least 12 weeks, and adequate organ function.
The primary end points of the study were PFS per RECIST v1.1 criteria as assessed by BIRC and OS in the intent-to-treat population. Secondary end points evaluated were investigator-assessed PFS, ORR, disease control rate (DCR), duration of response (DOR), time to progression, pharmacokinetics, and safety.
Among those enrolled, the median age of patients was 58 years (range, 48-66) in the combination arm and 56 years (range, 47-64) in the sorafenib arm, respectively.2 In both arms, most were younger than 65 (70% for rivoceranib and camrelizumab and 77% for sorafenib), male (83% and 85%), from Asia (83% and 83%), and had an ECOG performance status of 1 (56% and 57%).
Findings from the study also showed that at 12 months, the OS rate was 76.5% (95% CI, 71.0%-81.1%) among those given rivoceranib with camrelizumab vs 60.8% (95% CI, 54.6%-66.4%) for patients given sorafenib arm. Then at 18 months, the OS rates were 60.9% (95% CI, 54.2%-66.9%) and 45.2% (95% CI, 38.8%-51.4%), respectively. In most predefined subgroups, OS was more favorable with the experimental combination.
At the updated analysis, the median PFS was 5.6 months (95% CI, 5.5-7.4) among patients treated with rivoceranib and camrelizumab vs 3.7 months (95% CI, 3.1-3.7) for those treated with sorafenib (HR, 0.54; 95% CI, 0.44-0.67). At 6 months, the PFS rate for the rivoceranib with camrelizumab group was 48.2% (95% CI, 41.9%-54.3%) vs 25.3% (95% CI, 19.8%-31.1%) for the sorafenib group, and at 12 months, PFS rates were 29.8% (95% CI, 24.1%-35.8%) and 12.4% (95% CI, 8.3%-17.3%), respectively.
Additional findings showed that the combination of rivoceranib and camrelizumab led to a DCR of 78% (95% CI, 73%-83%) vs 54% (95% CI, 48%-60%) for sorafenib, making for a difference of 24% (95% CI, 17%-32%). The median DOR with the combination was 14.8 months (95% CI, 8.4-not reached [NR]) vs 9.2 months (95% CI, 5.3-NR) with sorafenib, and in the experimental arm, patients had a median time to response of 1.9 months (IQR, 1.9-3.7) vs 3.7 months (IQR, 1.9-4.7) in the control arm. Further, the median duration of treatment was 6.9 months (IQR, 3.6-13.4) for camrelizumab, 6.5 months (IQR, 3.4-11.9) for rivoceranib, and 3.8 months (IQR, 1.9-7.4) for sorafenib.
Other safety data demonstrated that 97% of patients had any-grade treatment-related AEs (TRAEs) in the combination arm vs 93% of patients in the sorafenib arm. Rates of grade 3 or higher TRAEs in these arms were 81% and 52%, respectively. Grade 3 or 4 TRAEs most commonly consisted of hypertension (38% v 15%), palmar-plantar erythrodysesthesia syndrome (12% v 15%), increased aspartate aminotransferase (17% v 5%), and increased alanine aminotransferase (13% v 3%).
In the combination arm, 24% of patients had treatment-related serious AEs compared with 6% in the sorafenib arm. There was 1 treatment-related death reported in each arm, including multiple organ dysfunction syndrome in 1 patient treated with rivoceranib and camrelizumab and respiratory failure and circulatory collapse in 1 patient given sorafenib.