Today, the U.S. Food and Drug Administration (FDA) approved the hypoxia-inducible factor-2 alpha inhibitor belzutifan (Welireg) in combination with pembrolizumab (Keytruda) or pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex) for the adjuvant treatment of adults with renal cell carcinoma with a clear cell component (ccRCC) at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions.
LITESPARK-022
Efficacy was evaluated in LITESPARK-022 (Clinicaltrials.gov identifier NCT05239728), a multicenter, double-blind, randomized trial in 1,841 patients with prior nephrectomy for ccRCC who were at intermediate-high or high risk of recurrence, or who had resected metastases with no evidence of disease. Patients were randomly assigned 1:1 to receive belzutifan in combination with pembrolizumab as adjuvant therapy or placebo in combination with pembrolizumab until disease recurrence or unacceptable toxicity, or for up to 54 weeks of belzutifan or 12 months of pembrolizumab.
The major efficacy outcome measure was investigator-assessed disease-free survival, defined as time to recurrence, metastasis, or death. A statistically significant improvement in disease-free survival was demonstrated at a prespecified interim analysis with 186 events in the belzutifan with pembrolizumab arm and 246 events in the placebo with pembrolizumab arm (hazard ratio = 0.72, 95% CI = 0.59–0.87, P = .0003). Median disease-free survival was not reached in either arm. Overall survival data were not mature at the protocol prespecified interim analysis.
The belzutifan prescribing information includes a boxed warning for embryo-fetal toxicity and warnings and precautions for anemia and hypoxia. The pembrolizumab prescribing information includes warnings and precautions for immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation, and embryo-fetal toxicity.
Recommended Dosage
The recommended belzutifan dose is 120 mg orally once daily in combination with pembrolizumab or pembrolizumab and berahyaluronidase-pmph alfa until disease recurrence or unacceptable toxicity, or for up to 54 weeks.
The recommended pembrolizumab dose is 200 mg intravenously every 3 weeks or 400 mg every 6 weeks in combination with belzutifan at 120 mg orally once daily until disease recurrence, unacceptable toxicity, or for up to 12 months. The recommended pembrolizumab and berahyaluronidase alfa-pmph dose is 395 mg/4,800 units subcutaneously every 3 weeks or 790 mg/9,600 units every 6 weeks in combination with belzutifan at 120 mg orally once daily until disease recurrence, unacceptable toxicity, or for up to 12 months.
This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence which provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, the FDA collaborated with the Australian Therapeutic Goods Administration and Health Canada. The application reviews are ongoing at the other regulatory agencies.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.
This application was granted Priority Review.
