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Jump to Key Points The FDA has approved belzutifan (WELIREG, Merck) in combination with lenvatinib (Lenvima, Eisai) for adults with advanced renal cell carcinoma with a clear cell component (ccRCC) who have received a PD-1 or a PD-L1 inhibitor.
This marks the third ccRCC approval for the hypoxia-inducible factor-2-alpha inhibitor belzutifan. Its previous approvals were for adjuvant ccRCC treatment with pembrolizumab and as monotherapy for advanced ccRCC after both a PD-1 or PD-L1 inhibitor and a VEGF TKI.
Lenvatinib is a multitarget VEGF receptor (VEGFR) TKI and carries previous indications for advanced RCC — first line in combination with pembrolizumab and second line with everolimus following one prior anti-angiogenic therapy.
The new indication is based on the LITESPARK-011 trial involving 747 patients after progression on or within 6 months of immunotherapy. Patients were randomly assigned evenly to either belzutifan with lenvatinib or cabozantinib monotherapy. Cabozantinib is also a multitarget VEGFR TKI that is indicated for advanced RCC.
- FDA approved belzutifan + lenvatinib for advanced ccRCC after PD-1/PD-L1 inhibitor.
- Third ccRCC indication for belzutifan; prior uses: adjuvant + monotherapy post PD-1/PD-L1+VEGF TKI.
- LITESPARK-011: 747 pts; PFS 14.6 vs 10.6 months vs cabozantinib.
- OS 33.7 vs 28.6 months; difference not statistically significant.
- Serious AEs 51.6%; deaths from AEs 5.4%; monitor anemia, hypoxia, HTN, cardiac dysfunction.
Median progression-free survival was 14.6 months vs 10.6 months with belzutifan/lenvatinib vs with cabozantinib alone. Median overall survival was 33.7 and 28.6 months, respectively, but the difference was not statistically significant.
Serious adverse events were observed in 51.6% vs 43.9% of patients in the combination arm vs the cabozantinib-alone arm. Adverse events led to death in 5.4% vs 3.2% of belzutifan/lenvatinib vs cabozantinib patients.
Belzutifan’s label includes a boxed warning for embryo-fetal toxicity and warnings and precautions for anemia and hypoxia.
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 or thyroid dysfunction, impaired wound healing, osteonecrosis of the jaw, and embryo-fetal toxicity.
For belzutifan and lenvatinib together, warnings and precautions also include cardiac dysfunction.
The combination is dosed at 20 mg of lenvatinib and 120 mg of belzutifan once daily until disease progression or unacceptable toxicity.
M. Alexander Otto is a physician assistant and award-winning journalist. He is also an MIT science journalism fellow. Email: aotto@medscape.net
