Patients with advanced renal cell carcinoma (RCC) who have received anti-PD-1 or anti-PD-L1-based immunotherapy have limited treatment options. Results of a phase 2 trial, recently published in the Lancet Oncology, indicate that combining the hypoxia-inducible factor (HIF)-2α inhibitor belzutifan with cabozantinib results in promising antitumor activity in this setting. As such, these findings support further investigation of belzutifan in combination with a VEGFR tyrosine-kinase inhibitor in future randomised trials.
Anti-PD-(L)1 agents have become a pivotal component of the first-line treatment of patients with advanced renal cell carcinoma (RCC). Cabozantinib has shown activity against various receptors involved in the angiogenesis pathway, including VEGFR, c-MET, and AXL, and is approved in the first (in combination with nivolumab) and second-line treatment of advanced RCC. Belzutifan is a first-in-class hypoxia-inducible factor (HIF)-2α inhibitor with promising antitumour activity as monotherapy in patients with heavily pre-treated clear cell RCC. In this setting, this agent came with an objective response rate of 25%. The study at hand assessed whether combining belzutifan with cabozantinib could yield greater clinical benefits for patients with ccRCC than either drug alone.
This single-arm phase 2 trial was conducted at ten hospitals and cancer centres in the USA. This study included two cohorts of patients with advanced ccRCC, with cohort 1 consisting of patients with treatment-naive disease. Cohort 2 included patients who had previously received immunotherapy and up to two systemic treatment regimens. During the study, patients received belzutifan 120 mg and cabozantinib 60 mg orally once daily until disease progression, unacceptable toxicity, or patient withdrawal. The primary endpoint of the study was confirmed objective response. Antitumour activity and safety were assessed in all patients who received at least one dose of study treatment. In the Lancet oncology, results of cohort 2 of this study were reported.
Between September 2018 and July 2020, a total of 52 patients were enrolled in cohort 2 and received at least one dose of study treatment. After a median follow-up of 24.6 months, sixteen patients (30.8%), had a confirmed objective response, including one (2%) patients with a complete response and fifteen (29%) with a partial response. The median time to response was 3.2 months. The most frequent grade 3/4 treatment-related adverse events were anaemia (eight patients, 15%), fatigue (six patients, 12%) and hypertension (fourteen patients, 27%). In total, fifteen patients (29%) had serious treatment-related adverse events, including, among others, acute kidney injury, anaemia, asthenia, and cardiac failure. Three patients (6%) died from adverse events as of data cut-off, of whom two died due to disease progression and one from respiratory failure (possibly treatment-related).
In conclusion, the study findings showed that the combination of belzutifan and cabozantinib exhibits promising antitumour activity in patients with pre-treated ccRCC. These findings support further investigation of belzutifan in combination with a VEGFR tyrosine-kinase inhibitor in future randomised trials.
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