Patients with unresectable hepatocellular carcinoma who received rivoceranib/camrelizumab achieved a median progression-free survival of 5.6 months vs 3.7 months with sorafenib.
Patients with unresectable hepatocellular carcinoma (HCC) who received rivoceranib and camrelizumab achieved a statistically significant and clinically meaningful benefit in progression-free survival (PFS) and overall survival (OS) compared to those who received sorafenib (Nexavar), according to data from the phase 3 CARES 310 trial (NCT03764293) published in The Lancet.1,2
Findings showed that at a median follow-up of 7.8 months (interquartile range [IQR], 4.1-10.6) for the primary PFS analysis, patients treated with rivoceranib plus camrelizumab (n = 272) experienced a median PFS of 5.6 months (95% CI, 5.5-6.3) compared with 3.7 months (95% CI, 2.8-3.7) for those treated with sorafenib (n = 271; HR, 0.52; 95% CI, 0.41-0.65; 1-sided P < .0001).
At a median follow-up of 14.5 months (IQR, 9.1-18.7) for the interim OS analysis, the median OS was 22.1 months (95% CI, 19.1-27.2) for the combination arm vs 15.2 months (95% CI, 13.0-18.5) for the sorafenib arm (HR, 0.62; 95% CI, 0.49-0.80; 1-sided P < .0001). Notably, OS was not formally tested at the data cutoff for the primary PFS analysis because the threshold for OS events required for simultaneous testing was not reached.
“As evidenced in the CARES 310 study, camrelizumab plus rivoceranib demonstrates significant promise as a potentially improved therapy for advanced HCC,” Saeho Chong, chief executive officer of Elevar Therapeutics, stated in a news release.2 “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.”
On July 17, 2023, the FDA accepted for review a new drug application seeking the approval of rivoceranib plus camrelizumab as a first-line treatment option for patients with unresectable HCC, based on data from CARES 310.3
The small-molecule TKI rivoceranib is a highly potent VEGFR-2 inhibitor, and camrelizumab is a humanized, PD-1–targeted monoclonal antibody.2
CARES 310 was a randomized, open-label, international study that enrolled patients at least 18 years of age with unresectable or metastatic HCC who had not previously received any systemic therapy.1 Key inclusion criteria included Barcelona Clinic Liver Cancer (BCLC) stage B or C disease which was not amenable to or had progressed after surgical or locoregional therapy, 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.
Patients were excluded if they had hepatocholangiocarcinoma, sarcomatoid hepatocellular carcinoma, mixed cell carcinoma, and lamellar cell carcinoma; a history of gastrointestinal bleeding or a high risk of gastrointestinal bleeding; uncontrolled hypertension; central nervous system metastases; or metastatic disease involving the main airway or blood vessels.
Patients were randomly assigned in a 1:1 fashion to receive 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. Treatment was given in 28-day cycles and 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.
PFS per RECIST v1.1 criteria as assessed by BIRC and OS in the intent-to-treat population served as the trial’s co-primary end points. Secondary end points included investigator-assessed PFS, objective response rate (ORR), disease control rate (DCR), duration of response (DOR), time to progression, pharmacokinetics, and safety.
The median age of patients was 58 years (range, 48-66) and 56 years (range, 47-64) in the rivoceranib/camrelizumab and sorafenib arms, respectively. The majority of patients in both arms were under 65 years of age (70% for rivoceranib/camrelizumab and 77% for sorafenib), male (83% and 85%), from Asia (83% and 83%), had an ECOG performance status of 1 (56% and 57%), had an alpha-fetoprotein level of less than 400 ng/mL (65% and 63%), had BCLC stage C disease (86% and 85%), and had a class A Child-Pugh score (87% and 85%).
The majority of patients in both arms also had an albumin-bilirubin grade of 1 (56% for rivoceranib/camrelizumab and 61% for sorafenib), had macrovascular invasion and/or extrahepatic metastasis (74% and 74%), had hepatitis B (76% and 73%), received prior local therapy for HCC (59% and 55%), had a PD-L1 tumor proportion score of less than 1% (81% and 78%), and had a PD-L1 combined positive score of less than 1 (70% and 66%).
The data cutoff for the primary PFS analysis was May 10, 2021, and the cutoff for the interim OS analysis was February 8, 2022. As of the OS cutoff, 33% of patients in the experimental arm and 48% of patients in the control arm received subsequent systemic anticancer therapy, including targeted therapy (30% for rivoceranib/camrelizumab and 40% for sorafenib) and immunotherapy (15% and 33%).
Additional data showed the 12-month OS rate was 76.5% (95% CI, 71.0%-81.1%) for the rivoceranib/camrelizumab group and 60.8% (95% CI, 54.6%-66.4%) for the sorafenib arm. The 18-month OS rates were 60.9% (95% CI, 54.2%-66.9%) and 45.2% (95% CI, 38.8%-51.4%), respectively. Rivoceranib/camrelizumab produced an OS benefit in most predefined subgroups.
At the OS data cutoff, the median PFS was 5.6 months (95% CI, 5.5-7.4) for the rivoceranib/camrelizumab arm vs 3.7 months (95% CI, 3.1-3.7) for the sorafenib group (HR, 0.54; 95% CI, 0.44-0.67). The 6-month PFS rate was 48.2% (95% CI, 41.9%-54.3%) for the rivoceranib/camrelizumab group vs 25.3% (95% CI, 19.8%-31.1%) for the sorafenib group. The 12-month PFS rates were 29.8% (95% CI, 24.1%-35.8%) and 12.4% (95% CI, 8.3%-17.3%), respectively.
Since data for both PFS and OS were statistically significant, ORR as assessed by BIRC per RECIST v1.1 criteria was formally tested. The confirmed ORR was 25% (95% CI, 20%-31%) in the rivoceranib/camrelizumab arm vs 6% (95% CI, 3%-9%) in the sorafenib arm, translating to a 19% difference (95% CI, 14%-25%; 1-sided P < .0001). Rivoceranib/camrelizumab elicited a DCR of 78% (95% CI, 73%-83%) compared with 54% (95% CI, 48%-60%) for sorafenib, resulting in a difference of 24% (95% CI, 17%-32%).
The median DOR was 14.8 months (95% CI, 8.4-not reached [NR]) in patients treated with the combination vs 9.2 months (95% CI, 5.3-NR) in those given sorafenib. Patients in the experimental arm experienced a median time to response of 1.9 months (IQR, 1.9-3.7) compared with 3.7 months (IQR, 1.9-4.7) for those in the control arm.
Among patients with a target lesion diameter value after baseline, reduction of any magnitude in the sum of diameter in the target lesion was observed in 73% of patients (n = 182/250) in the rivoceranib/camrelizumab group vs 36% of patients (n = 84/236) in the sorafenib group. Additionally, 35% of these patients in the experimental arm achieved a reduction of 30% or more in the sum of diameter in the target lesion vs 9% of patients in the control group.
At the February 8, 2022, data cutoff, the median time to deterioration in global health status for the rivoceranib/camrelizumab arm was 11.2 months (95% CI, 7.6-NR) compared with NR (95% CI, 7.4-NR) for the sorafenib group (HR, 1.02; 95% CI, 0.77-1.36). Notably, a trend in favor of rivoceranib/camrelizumab was observed in all functioning and most symptom domains.
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. Regarding safety, 99% of treated patients in the rivoceranib/camrelizumab arm (n = 272) experienced at least 1 any-grade adverse effect (AE) compared with 99% of treated patients in the sorafenib group (n = 269). The rates of grade 3 or higher AEs were 88% and 68%, respectively.
Any-grade treatment-related AEs (TRAEs) were reported in 97% of patients in the combination arm vs 93% of patients in the sorafenib arm, and the rates of grade 3 or higher TRAEs were 81% and 52%, respectively. The most common grade 3 or 4 TRAEs included hypertension, palmar-plantar erythrodysesthesia syndrome, increased aspartate aminotransferase, and increased alanine aminotransferase.
Twenty-four percent of patients in the combination arm discontinued at least 1 study drug due to TRAEs, and 4% of patients discontinued sorafenib due to TRAEs. In the combination arm, 4% of patients discontinued both agents due to TRAEs. Additionally, 47% of patients in the rivoceranib/camrelizumab arm required dose reductions due to TRAEs compared with 32% in the sorafenib arm.
One treatment-related death occurred in each arm, consisting of multiple organ dysfunction syndrome in 1 patient in the rivoceranib/camrelizumab group and respiratory failure and circulatory collapse in 1 patient in the sorafenib arm.