Belzutifan Plus Pembro Approved for Adjuvant RCC

 The FDA has approved belzutifan (Welireg, Merck) in combination with pembrolizumab (Keytruda, Merck) or the subcutaneous formulation of pembrolizumab (Keytruda Qlex, Merck) for the adjuvant treatment of adults with clear cell renal cell carcinoma.

Specifically, patients must be at intermediate-high or high risk for recurrence after nephrectomy or nephrectomy with resection of metastatic lesions in order to receive the combination.

Belzutifan is a first-in-class oral hypoxia-inducible factor-2 alpha inhibitor that disrupts pathways used by certain tumors to adapt to low-oxygen conditions, including those that promote abnormal blood vessel formation and tumor survival. Belzutifan carries previous approvals for von Hippel-Lindau disease, pediatric pheochromocytoma/paraganglioma, and advanced clear cell renal cell carcinoma after failure of immune checkpoint and VEGF TKI. 

The new adjuvant indication with pembrolizumab is based on Merck’s LITESPARK-022 trial in 1841 patients with no evidence of disease after surgery. Patients were randomly assigned equally to pembrolizumab and belzutifan or pembrolizumab and placebo for up to 54 weeks of belzutifan and 12 months of pembrolizumab.

Estimated 24-month disease-free survival was 80.7% in the pembrolizumab/belzutifan arm vs 73.7% in the pembrolizumab/placebo group (hazard ratio, 0.72, P = .0003). Median disease-free survival was not reached at the interim analysis, and overall survival data were not mature.

Grade 3 or higher treatment-emergent adverse events occurred in 52.1% of patients in the belzutifan/pembrolizumab group vs 30.2% in the control arm. The most common were anemia (12.1% vs 0.5%), increased alanine aminotransferase (6.4% vs 2.0%), and hypoxia (4.6% vs 0%). 

Treatment-emergent deaths occurred in just over 1% of both groups. 

Belzutifan carries warnings for embryo-fetal toxicity, anemia, and hypoxia. 

Pembrolizumab labeling includes warnings and precautions for immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation, and embryo-fetal toxicity. 

The recommended belzutifan dose is 120 mg orally once daily in combination with pembrolizumab until disease recurrence or unacceptable toxicity, or for up to 54 weeks. Pembrolizumab is administered every 3 or 6 weeks, depending on dose, for up to a year.

https://www.medscape.com/viewarticle/belzutifan-plus-pembro-approved-adjuvant-rcc-2026a1000jxb