The US Food and Drug Administration (FDA) has recently approved belzutifan (Welireg, Merck and Co., Inc.) in combination with lenvatinib (Lenvima, Eisai Inc.) for adults with advanced Renal Cell Carcinoma with a clear cell component (ccRCC) following a Programed Death receptor-1 (PD-1) or Programed Death-Ligand 1 (PD-L1) inhibitor.

Efficacy was evaluated in LITESPARK-011 (NCT04586231), an open-label, randomised, active-controlled trial in 747 patients with advanced ccRCC. Eligible patients had locally advanced or metastatic ccRCC which progressed on or after a PD-1 or PD-L1 inhibitor, or within 6 months of completing adjuvant therapy with a PD-1 inhibitor. Patients were randomised (1:1) to receive either belzutifan and lenvatinib or cabozantinib.

The major efficacy outcome measures were Progression-Free Survival (PFS) measured by blinded independent central review using RECIST v1.1 and Overall Survival (OS). Objective Response Rate (ORR) was an additional efficacy outcome measure.

There was a statistically significant improvement in PFS for the belzutifan and lenvatinib arm compared to the cabozantinib arm.

Median PFS was 14.6 months (95 percent CI: 11.1, 16.6) in the belzutifan and lenvatinib arm and 10.6 months (95 percent CI: 9.2, 11.1) in the cabozantinib arm (Hazard Ratio 0.74 [95 percent CI: 0.61, 0.89]; one-sided p-value 0.00095). The final analysis of OS was not statistically significant. Median OS was 33.7 months (95 percent CI: 29.0, 46.9) and 28.6 months (95 percent CI: 24.1, 31.4) in the respective arms (Hazard Ratio 0.85 [95 percent CI: 0.70, 1.03]). ORR was 53 percent (95 percent CI: 47, 58) and 40 percent (95 percent CI: 35, 45) in the respective arms (one-sided p-value 0.0002).

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

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.