Data from the phase 2 LITESPARK-003 trial, published in The Lancet Oncology, reveals that the combination of belzutifan (Welireg) and cabozantinib (Cabometyx) elicits promising antitumor activity with manageable toxicity in patients with clear cell renal cell carcinoma (ccRCC) who had not previously received treatment. This open-label, single-arm trial provides a rationale for further randomized trials of belzutifan in combination with other tyrosine kinase inhibitor-based regimens. The study enrolled 50 patients with ccRCC who had not received prior systemic therapy for locally advanced or metastatic RCC. Patients received 120 mg of belzutifan orally once daily plus 60 mg of cabozantinib orally once daily until unacceptable adverse events, disease progression, or withdrawal. The primary endpoint was investigator-assessed objective response rate (ORR).
Efficacy and Outcomes
At a median follow-up of 24.3 months, the confirmed objective response rate (ORR) was 70% (35 of 50 patients), comprising 8% complete responses (n = 4) and 62% partial responses (n = 31). Stable disease was achieved in 28% of patients (n = 14), and 2% experienced progressive disease (n = 1). The median duration of response was 28.6 months (95% CI, 11.2-not reached).
A post-hoc analysis of the data indicated a disease control rate of 98% (49 of 50 patients). The estimated progression-free survival rates at 12 and 24 months were 69% (95% CI, 52.1%-81.0%) and 57% (38.5%-72.0%), respectively. Overall, 38% of patients (n = 19) experienced progression or death.
The median overall survival was not reached at the time of data cutoff. In total, 5 patients died (10%). The estimated overall survival rates at 12 and 24 months were 96% (95% CI, 84.2%-98.9%) and 86% (95% CI, 68.2%-94.0%), respectively.
Safety and Tolerability
Regarding safety, all-cause adverse events (AEs) occurred in 100% of patients (n = 50), and grade 3-5 AEs occurred in 60% of patients (n = 30). Grade 3 treatment-related AEs occurred in 44% of patients (n = 22), and grade 4 treatment-related AEs occurred in 2% of patients (n = 1). No grade 5 treatment-related AEs were reported. The most common grade 3-4 treatment-related AEs included hypertension (12%), anemia (10%), fatigue (8%), hypoxia (6%), and palmar-plantar erythrodysesthesia (6%). Serious treatment-related AEs were reported in 14% of patients (n = 7).
Adverse events led to belzutifan dose reduction in 28% of patients (n = 14) and dose interruptions in 48% of patients (n = 24). Cabozantinib dose reductions and interruptions due to AEs were reported in 74% of patients (n = 37).
Overall, 48% of patients (24 of 50) discontinued treatment, primarily due to the progression of disease (54%; 13 of 24 patients). At the time of data cutoff, 48% (24 of 50) of patients remained on treatment.
Study Design and Patient Population
The open-label, single-arm trial included 50 adult patients with ccRCC who were enrolled across 10 clinical trial sites in the US. The median age of patients was 64 years (IQR, 57-72). The majority of patients were male (80%) and White (96%).
To be eligible for enrollment, patients needed to have an ECOG performance score of 0 or 1, adequate organ function, and had received no prior systemic therapy for locally advanced or metastatic RCC. The median duration of treatment was 12.6 months (IQR, 9.2-25.3).
Implications and Future Directions
"To our knowledge, this is the first trial in a first-line setting to show that the VEGFR-targeting combination of an HIF-2α inhibitor and tyrosine kinase inhibitor has manageable toxicity," the authors wrote. "Our findings provide rationale for further randomised trials of belzutifan in combination with other tyrosine kinase inhibitor-based regimens."
