CARES-310 is the first phase III study to report significant benefits in both progression-free survival (PFS) and overall survival (OS) with the combination of an anti-PD1/PD-L1 antibody and an orally administered, small-molecule tyrosine kinase inhibitor (TKI) over standard TKI for unresectable hepatocellular carcinoma in the first-line setting. The dual primary endpoints were met with camrelizumab plus rivoceranib, showing an improvement of 6.9 months in median OS and 1.9 months in median PFS, and a corresponding reduction in risk of death by 38% and of progression or death by 48% compared with the sorafenib group.
The survival benefits with the combination therapy were supported by a significantly higher response rate and more durable response, as well as a higher rate of disease control than that seen in the sorafenib group. The findings are published by Prof. Shukui Qin of the Cancer Centre of Jinling Hospital, Nanjing University of Chinese Medicine and Nanjing Medical University in Nanjing, China, and colleagues from the CARES-310 Study Group on 24 July 2023 in The Lancet.
The authors wrote in the background that the multitargeted TKIs sorafenib and lenvatinib were established as the standard first-line treatment for unresectable hepatocellular carcinoma based on the SHARP, SHARP-Asia-Pacific, and REFLECT studies, but they showed a modest improvement in median OS against placebo. Over the past 5 years, the PD1/PD-L1 inhibitors have emerged as new treatment options for advanced hepatocellular carcinoma, but with only a small subset of patients have a response to monotherapy, and no survival gain over sorafenib was observed in the first-line setting.
Few phase III studies have assessed a combination of immune checkpoint inhibitor (ICI) with anti-angiogenic agent as first-line treatment for unresectable hepatocellular carcinoma, including the global IMbrave150, COSMIC-312, and LEAP-002 studies and the ORIENT-32 from China with mixed results reported for combination therapies when compared with sorafenib or lenvatinib monotherapies, with significant improvement in OS reached only with an ICI in combination with anti-VEGF antibody, but not with multitargeted TKI. Dual ICI regimen of tremelimumab plus durvalumab also showed improved OS versus sorafenib in the phase III HIMALAYA study. However, with a median OS of less than 2 years for all systemic treatments in phase III studies in unresectable hepatocellular carcinoma, there remains an unmet medical need for additional effective first-line regimens.
In a phase I study in pretreated hepatocellular carcinoma and gastric or gastro-oesophageal junction cancer, camrelizumab plus rivoceranib showed encouraging antitumour activity and acceptable tolerability. In a subsequent phase II study in advanced hepatocellular carcinoma, camrelizumab plus rivoceranib as second-line treatment showed improved clinical efficacy compared with historical data of camrelizumab or rivoceranib monotherapy. Additionally, the combination as first-line treatment led to an objective response rate of 34.3%, a median PFS of 5.7 months, and an 18-month OS rate of 58.1%.
In CARES-310 study, the study investigators assessed the efficacy and safety of anti-PD1 antibody camrelizumab plus the VEGFR2-targeted TKI rivoceranib (also known as apatinib) versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma. The randomised, open-label, international phase III CARES-310 study was done at 95 study sites across 13 countries and regions worldwide. Patients with unresectable or metastatic hepatocellular carcinoma who had not previously received any systemic treatment were randomly assigned (1:1) to receive either camrelizumab 200 mg intravenously every 2 weeks plus rivoceranib 250 mg orally once daily or sorafenib 400 mg orally twice daily.
The primary endpoints were PFS, as assessed by the blinded independent review committee per RECIST v1.1, and OS in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of the study drugs. In the article published in The Lancet, the authors report the findings from the prespecified primary analysis for PFS and interim analysis for OS.
Between 28 June 2019 and 24 March 2021, 543 patients were randomly assigned, of whom 272 to the camrelizumab plus rivoceranib and 271 to sorafenib group. At the primary analysis for PFS (10 May 2021), median follow-up was 7.8 months. Median PFS was significantly improved with camrelizumab plus rivoceranib versus sorafenib, 5.6 months [95% confidence interval [CI] 5.5–6.3]) versus 3.7 months (95% CU 2.8–3.7) with hazard ratio (HR) 0.52 (95% CI 0.41–0.65; one-sided p < 0.0001). At the interim analysis for OS (8 February 2022), median follow-up was 14.5 months. Median OS was significantly extended with camrelizumab plus rivoceranib versus sorafenib, 22.1 months (95% CI 19.1–27.2] versus 15.2 months (95% 13.0–18.5) with HR 0.62 (95% CI 0.49–0.80; one-sided p < 0.0001).
The most common grade 3 or 4 treatment-related adverse events were hypertension (38% in the camrelizumab plus rivoceranib group versus 15% in the sorafenib group), palmar-plantar erythrodysaesthesia syndrome (12% versus 15%), increased aspartate aminotransferase (17% versus 5%), and increased alanine aminotransferase (13% versus 3%). Treatment-related serious adverse events were reported in 24% of patients in the camrelizumab plus rivoceranib group and 6% in the sorafenib group. Treatment-related death occurred in two patients: one patient in the camrelizumab plus rivoceranib group (multiple organ dysfunction syndrome) and one patient in the sorafenib group (respiratory failure and circulatory collapse).
The authors concluded that the overall favourable benefit-to-risk profile supports camrelizumab with rivoceranib as a new first-line treatment option for patients with unresectable hepatocellular carcinoma who have not previously received any systemic therapy.
In an accompanied comment, Dr. David J Pinato of the Department of Surgery and Cancer, Faculty of Medicine, Hammersmith Hospital, Imperial College London in London, UK and Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale in Novara, Italy and colleagues wrote that although patients recruited to CARES-310 represent the target population for systemic treatment by staging and liver function criteria, 83% of the accrued patients were Asian, leading to prevalence of viral-related chronic liver disease in study participants, mainly secondary to hepatitis B virus. In endemic regions such as Asia, hepatitis B virus carriers are often younger at hepatocellular carcinoma diagnosis with consequently lower comorbid burden and lower prevalence of cirrhosis compared to other causes of chronic liver disease. Furthermore, when these hepatitis B virus carriers are on highly effective antiviral treatments, they are often able to preserve liver function. These factors might partly explain the improved outcomes observed for this subgroup in several immunotherapy studies.
With non-alcoholic fatty liver disease set to become the leading risk factor for hepatocellular carcinoma, especially in countries outside of Asia, and the scarcity of specific pharmacological treatments to prevent non-alcoholic fatty liver disease progression, the rather uneven representation of the full spectrum of the disease should be drawn to attention when considering the wider generalisability of this study's results.
Although CARES-310 investigators have reached the important milestone of presenting the first positive phase III study of an ICI plus TKI combination in hepatocellular carcinoma, the comparison with sorafenib, an outdated standard of care, and the clinical availability of other combination regimens including atezolizumab–bevacizumab or durvalumab–tremelimumab emphasises the need to carefully appraise survival benefit considering treatment-emerging toxicity and quality-of-life data ahead of clinical adoption according to Dr. Pinato and commenters.
The study was funded by Jiangsu Hengrui Pharmaceuticals and Elevar Therapeutics.
References
- Qin S, Chan SL, Gu S, et al. for the CARES-310 Study Group. Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study. The Lancet; Published online 24 July 2023. DOI: https://doi.org/10.1016/S0140-6736(23)00961-3
- Pinato DJ, D’Alessio A, Celsa C, et al. The price and value of therapeutic synergy in liver cancer. The Lancet; Published online 24 July 2023. DOI: https://doi.org/10.1016/S0140-6736(23)01297-7