Belzutifan Plus Cabozantinib Boosts Antitumor Activity in Treatment-Naïve Advanced ccRCC

The phase 2 LITESPARK-003 study has shown that the first-in-class hypoxia-inducible factor 2α (HIF-2α) inhibitor belzutifan combined with cabozantinib for treatment-naive patients with advanced clear-cell renal cell carcinoma (acRCC) can provide promising antitumor activity.

The open-label, single-arm study comprised two cohorts, and investigators analyzed the combination in both treatment-naive patients (cohort 1) and patients previously treated with immunotherapy (cohort 2).

A total of 50 eligible patients were enrolled and assigned to cohort 1. Each patient had an Eastern Cooperative Oncology Group performance status of 0 or 1 and had not received any systemic therapy for locally advanced or metastatic RCC.

Patients were administered oral belzutifan, 120 mg once daily, in addition to oral cabozantinib, 60 mg once daily, until disease progression, unacceptable adverse events, or patient withdrawal occurred. The primary endpoint was investigator-assessed confirmed objective response (OR). Antitumor activity and safety were assessed in all patients who received at least one treatment dose.

As of the data cutoff in May 2023, the median follow-up was 24.3 months (interquartile range, 13.9–32.0). A confirmed OR was seen in 35 of 50 patients (70%; 95% CI, 55-82); four patients (8%) experienced a complete response, and 31 (62%) had a partial response.

The most common grade 3-4 treatment-related adverse events (TRAEs) included hypertension (12%), anemia (10%), and fatigue (8%). Serious TRAEs occurred in 14% of patients, and no treatment-related deaths occurred.

The study is ongoing and is estimated to be completed in 2027.