On September 24, the U.S. Food and Drug Administration (FDA) approved the HIF-2α inhibitor belzutifan (Welireg) in combination with the tyrosine kinase inhibitor lenvatinib (Lenvima) for adults with advanced renal cell carcinoma with a clear cell component (ccRCC) following treatment with a PD-1 or PD-L1 inhibitor.
LITESPARK-011
Efficacy was evaluated in LITESPARK-011 (ClinicalTrials.gov identifier NCT04586231), an open-label, randomized, active-controlled trial in 747 patients with advanced ccRCC. Eligible patients had locally advanced or metastatic ccRCC which progressed on or after receipt of a PD-1 or PD-L1 inhibitor, or within 6 months of completing adjuvant therapy with a PD-1 inhibitor. Patients were randomly assigned 1:1 to receive either belzutifan and lenvatinib or cabozantinib.
The major efficacy outcome measures were progression-free survival measured by blinded independent central review using Response Evaluation Criteria in Solid Tumors version 1.1 and overall survival; objective response rate was an additional efficacy outcome measure.
There was a statistically significant improvement in progression-free survival for the belzutifan and lenvatinib arm compared to the cabozantinib arm. Median progression-free survival was 14.6 months (95% confidence interval [CI] = 11.1–16.6 months) in the belzutifan and lenvatinib arm and 10.6 months (95% CI = 9.2–11.1 months) in the cabozantinib arm (hazard ratio [HR] = 0.74, 95% CI = 0.61–0.89, one-sided P = .00095). The final analysis of overall survival was not statistically significant. Median overall survival was 33.7 months (95% CI = 29.0–46.9 months) and 28.6 months (95% CI = 24.1–31.4 months) in the respective arms (HR = 0.85, 95% CI = 0.70–1.03). Objective response rate was 53% (95% CI = 47%–58%) and 40% (95% CI = 35%–45%) in the respective arms (one-sided P = .0002).
The belzutifan prescribing information includes a boxed warning for embryo-fetal toxicity, as well as warnings and precautions for anemia and hypoxia. For the belzutifan and lenvatinib combination, warnings and precautions also include cardiac dysfunction.
The lenvatinib prescribing information includes warnings and precautions for hypertension, cardiac dysfunction, arterial thromboembolic events, hepatotoxicity, renal failure or impairment, proteinuria, diarrhea, fistula formation and gastrointestinal perforation, QT interval prolongation, hypocalcemia, reversible posterior leukoencephalopathy syndrome, hemorrhagic events, impairment of thyroid stimulating hormone suppression/thyroid dysfunction, impaired wound healing, osteonecrosis of the jaw, and embryo-fetal toxicity.
Recommended Dosage
The recommended dosage is 20 mg of lenvatinib in combination with 120 mg of belzutifan once daily until disease progression or unacceptable toxicity.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.
