Novel Combination Boosts Survival in Unresectable Liver Cancer

The PD-1 inhibitor camrelizumab combined with the VEGFR2-targeted inhibitor rivoceranib (also known as apatinib) significantly improved survival compared with sorafenib (Nexavar) alone for the treatment of patients with unresectable hepatocellular carcinoma (HCC), a randomized phase III trial showed.

At a median follow-up of 7.8 months, the median progression-free survival was 5.6 months with the two investigational agents versus 3.7 months with sorafenib (HR 0.52, 95% CI 0.41-0.65, P<0.0001), reported Shukui Qin, MD, of the Nanjing University of Chinese Medicine and Nanjing Medical University in China, and colleagues.

An interim analysis of overall survival (OS) showed that at a median follow-up of 14.5 months, median OS was 22.1 months with camrelizumab-rivoceranib compared with 15.2 months with sorafenib (HR 0.62, 95% CI 0.49-0.80, P<0.0001), they noted in The Lancet.

The so-called CARES-310 study “is the first to report significant progression-free survival and overall survival benefits with the combination of an anti-PD-1 antibody and an orally administered, small-molecule, anti-angiogenic agent over sorafenib as first-line treatment for unresectable hepatocellular carcinoma,” Qin and colleagues wrote.

Moreover, the median OS in the combination group was the longest observed with any systemic treatment in phase III trials in unresectable HCC, they added, noting that the survival benefits were supported by a significantly higher response rate and more durable response.

The objective response rate in the camrelizumab-rivoceranib group was 25% compared with 6% in the sorafenib group (P<0.0001), while the median duration of response was 14.8 months versus 9.2 months, respectively, with a median time to response of 1.9 months and 3.7 months.

In a commentary accompanying the study, David J. Pinato, MD, PhD, of Hammersmith Hospital and Imperial College London, and colleagues, pointed out that the study authors “have reached the important milestone of presenting the first positive phase III study of an ICI-TKI [immune checkpoint inhibitor-tyrosine kinase inhibitor] combination in hepatocellular carcinoma.”

However, they cautioned that CARES-310 compared the combination “with an outdated standard of care” and that the availability of other regimens such as atezolizumab [Tecentriq]-bevacizumab [Avastin] or durvalumab [Imfinzi]- tremelimumab [Imjudo] “emphasizes the need to carefully appraise survival benefit in light of treatment-emerging toxicity and quality-of-life data ahead of clinical adoption.”

In this trial, grade ≥3 treatment-related adverse events (TRAEs) occurred in 81% of patients treated with camrelizumab-rivoceranib compared with 52% in the sorafenib group. Serious TRAEs were reported in 24% and 6%, respectively.

TRAEs led to discontinuation of any study medication in 24% of patients in the combination group and 4% in the sorafenib group, and dose reductions occurred in 47% and 32%, respectively.

Considering the growing number of treatment options in a “once therapeutically deprived oncological diagnosis,” Pinato and team suggested that CARES-310 “instigates important points of reflection for drug development in hepatocellular carcinoma,” such as questions around the acceptable trade-off between extended OS and toxicity.

CARES-310 was an open-label, international trial conducted at 95 study sites across 13 countries. Of the 543 included patients, median age was 58 years, 84% were men, and 83% were Asian.

From June 2019 to March 2021, patients with unresectable or metastatic HCC who had not previously received any systemic treatment were randomly assigned 1:1 to receive camrelizumab 200 mg intravenously every 2 weeks plus rivoceranib 250 mg orally once daily or sorafenib 400 mg orally twice daily.

According to Elevar Therapeutics, the FDA has accepted a new drug application for rivoceranib in combination with camrelizumab as a frontline treatment for patients with unresectable HCC and set a PDUFA date of May 16, 2024.