Published data show promise of frontline belzutifan/cabozantinib for ccRCC

Data from the phase 2 LITESPARK-003 trial (NCT03634540) have been published in the Lancet Oncology, showing that the combination of belzutifan (Welireg) and cabozantinib (Cabometyx) elicited promising antitumor activity with manageable toxicity in patients with clear cell renal cell carcinoma (ccRCC) who had not previously received treatment.^1,2

The LITESPARK-003 trial remains ongoing.

Data from cohort 2 of the trial, which included patients previously treated with immunotherapy, were published in the Lancet Oncology in May 2023.³ The current publication includes patients from cohort 1, who were treatment naïve.

In total, 50 patients were enrolled and treated in cohort 1.

At a median follow-up of 24.3 months, the confirmed objective response rate (ORR) was 70% (35 of 50), which consisted of 8% of patients with a complete response (n = 4) and 62% of patients with a partial response (n = 31). Stable disease was achieved in 28% of patients (n = 14), and 2% of patients experienced progressive disease (n = 1). The median duration of response was 28.6 months (95% CI, 11.2-not reached).

Additionally, the disease control rate was 98% (49 of 50 patients), according to a post-hoc analysis of the data. 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. In total, 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.

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).

Further, 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).

AEs 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.

In total, cohort 1 in 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.⁴ Those enrolled in the study received 120 mg belzutifan orally once daily plus 60 mg cabozantinib orally once daily until unacceptable AEs, disease progression, or withdrawal. The median duration of treatment was 12.6 months (IQR, 9.2-25.3).

The primary end point was investigator-assessed ORR. Anti-tumor activity and safety were also assessed in all patients who received at least 1 dose of study treatment.

The LITESPARK-003 trial remains ongoing, with final completion anticipated in February 2027.⁴

“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.”

References

1. Choueiri TK, Merchan JR, Figlin R, et al. Belzutifan plus cabozantinib as first-line treatment for patients with advanced clear-cell renal cell carcinoma (LITESPARK-003): an open-label, single-arm, phase 2 study. Lancet Oncol. 2025;26(1):64-73. doi:10.1016/S1470-2045(24)00649-1

2. Phase 2 LITESPARK-003 results suggest continued study of novel first-line combo for advanced kidney cancer. News release. Dana-Farber Cancer Institute. January 17, 2025. https://www.dana-farber.org/newsroom/news-releases/2025/phase-2-litespark-003-results-suggest-continued-study-of-novel-first-line-combo-for-advanced-kidney-cancer

3. Choueiri TK, McDermott DF, Merchan J, et al. Belzutifan plus cabozantinib for patients with advanced clear cell renal cell carcinoma previously treated with immunotherapy: an open-label, single-arm, phase 2 study. Lancet Oncol. 2023;24(5):553-562. doi:10.1016/S1470-2045(23)00097-9

4. A trial of belzutifan (PT2977, MK-6482) in combination with cabozantinib in patients with clear cell renal cell carcinoma (ccRCC) (MK-6482-003). ClinicalTrials.gov. Last updated December 20, 2024. Accessed January 20, 2025. https://clinicaltrials.gov/study/NCT03634540