FDA Approves Belzutifan Plus Pembrolizumab as Adjuvant Therapy for Clear Cell Renal Cell Carcinoma

The FDA has approved the combination of belzutifan and pembrolizumab as an adjuvant therapy for high-risk clear cell renal cell carcinoma after surgery. The approval is based on the LITESPARK-022 trial, which showed the combination significantly improved disease-free survival, reducing the risk of recurrence or death by 28% (HR 0.72) compared to pembrolizumab alone. The therapy carries a boxed warning for embryo-fetal toxicity.

FDA approval for adjuvant therapy

• ▪The FDA granted this application priority review and evaluated it under Project Orbis, an international program with partners including Australia and Canada.
• ▪The therapy is indicated for adult patients at intermediate-high or high risk of recurrence after nephrectomy, or after nephrectomy and resection of metastatic lesions.
• ▪The FDA has approved belzutifan (Welireg) in combination with pembrolizumab (Keytruda) as an adjuvant therapy for clear cell renal cell carcinoma (ccRCC).

LITESPARK-022 trial design

• ▪In the LITESPARK-022 trial, patients were randomized 1:1 to receive either belzutifan plus pembrolizumab or a placebo plus pembrolizumab.
• ▪The approval was based on the phase 3 LITESPARK-022 trial, a multicenter, randomized, double-blind study that enrolled 1,841 patients.

Disease-free survival outcomes

• ▪The trial met its primary endpoint, showing the combination therapy significantly improved disease-free survival (DFS) compared to pembrolizumab alone.
• ▪The hazard ratio for disease-free survival was 0.72 (95% CI, 0.59-0.87; P = .0003), favoring the combination therapy.
• ▪Dr. Toni K. Choueiri of Dana-Farber Cancer Institute stated that belzutifan can decrease the chance of recurrence, metastasis, or death by close to 30%.
• ▪Overall survival data was immature at the time of analysis and had not reached statistical significance (HR, 0.78; P = .1220).
• ▪The estimated 24-month disease-free survival rate was 80.7% with the combination therapy versus 73.7% with pembrolizumab alone.

Treatment-related adverse events

• ▪The most common grade 3+ adverse events in the combination arm were anemia (12.1%), increased alanine aminotransferase (6.4%), and hypoxia (4.6%).
• ▪Grade 3 or higher adverse events were reported in 52.1% of patients in the combination arm, compared to 30.2% in the pembrolizumab monotherapy arm.

Recommended dosing schedules

• ▪The recommended dose for belzutifan is 120 mg orally once daily for up to 54 weeks.
• ▪The recommended dose for pembrolizumab is 200 mg intravenously every 3 weeks or 400 mg every 6 weeks for up to 12 months.

Boxed warnings for toxicity

• ▪Warnings for belzutifan also include anemia and hypoxia, while pembrolizumab warnings include immune-mediated adverse reactions.
• ▪Belzutifan's prescribing information includes a boxed warning for embryo-fetal toxicity.

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