Expanded Use of Targeted Therapy Belzutifan for Kidney Cancer
Under new approval, the drug can be given with immunotherapy to help reduce risk of recurrence after surgery in patients with clear cell renal cell carcinoma.
The U.S. Food and Drug Administration (FDA) has approved belzutifan (Welireg) in combination with pembrolizumab (Keytruda) or pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex) for the adjuvant treatment of adult patients with renal cell carcinoma with a clear cell component (ccRCC) who are at intermediate-high or high risk of recurrence after surgery to remove all or part of the kidney (nephrectomy) or nephrectomy and resection of metastatic lesions.
Belzutifan is a small-molecule inhibitor of hypoxia-inducible factor 2α (HIF-2α), a transcription factor that allows cancer cell growth in low oxygen conditions. In normal oxygen conditions, a protein called von Hippel-Lindau (VHL) targets HIF-2α for degradation. In low oxygen conditions and in cancers with inactivated or mutated VHL, such as ccRCC, VHL fails to bind to HIF-2α, resulting in its accumulation, which in turn drives tumor growth and metastasis. Belzutifan interferes with this process.
Belzutifan was the first HIF-2α inhibitor approved by the FDA in 2021 for certain cancers, including RCC, associated with VHL disease, a rare genetic disorder caused by a mutation in the VHL gene. Belzutifan use was then extended to include some patients with advanced RCC without VHL disease. The new approval further expanded belzutifan use as an adjuvant treatment, making it the first HIF‑2α inhibitor approved for reducing recurrence risk after surgery.
Pembrolizumab is a form of immunotherapy called an immune checkpoint inhibitor and is administered intravenously. Pembrolizumab and berahyaluronidase alfa-pmph is a formulation that can be administered under the skin (subcutaneous) thanks to the action of berahyaluronidase, an enzyme that helps the drug disperse and absorb into the body.
The new approval of belzutifan in combination with either intravenous or subcutaneous pembrolizumab was based on results from LITESPARK-022, a multicenter, double-blind, randomized phase III clinical trial that involved 1,841 patients with ccRCC who were at intermediate-high or high risk of disease recurrence after nephrectomy or who had no evidence of disease after resection of metastases. Patients were randomly assigned (1:1) to receive pembrolizumab with either belzutifan or placebo as adjuvant therapy until disease recurrence or unacceptable toxicity or for up to 54 weeks of belzutifan treatment or 12 months of pembrolizumab treatment.
A prespecified interim analysis of disease-free survival (DFS), which measured how long patients remained disease-free, showed that patients in the belzutifan arm were 28% less likely to experience disease recurrence, metastasis, or death. Among patients treated with belzutifan, there were 186 instances of recurrence, metastasis, or death compared with 246 among those treated with placebo, a statistically significant difference.
At the time of the analysis, median DFS was not reached in either arm, and it was not possible to conclude whether belzutifan treatment would help patients live longer.
The prescribing information for belzutifan includes a boxed warning for toxicity to the developing embryo or fetus in pregnant patients.
The recommended dose of belzutifan is 120 mg taken orally once a day in combination with pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph until disease recurrence or unacceptable toxicity, or for up to 54 weeks. The recommended dose of intravenous pembrolizumab is 200 mg every three weeks or 400 mg every six weeks in combination with belzutifan. The recommended dose of subcutaneous pembrolizumab is 395 mg pembrolizumab and 4,800 units berahyaluronidase alfa-pmph every three weeks or 790 mg/9,600 units every six weeks in combination with belzutifan. Both pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph are administered until disease recurrence, unacceptable toxicity, or for up to 12 months.
RCC is the most common type of kidney cancer in adults and originates in the lining of the kidney’s tubules, tiny ducts that process blood filtrate and reabsorb water, nutrients, and electrolytes back into the bloodstream. ccRCC is the most common subtype of RCC. The “clear cell” denomination derives from the microscopic appearance of the cancer cells as transparent or pale. According to federal statistics, it was estimated that 80,450 individuals would be diagnosed with cancer of the kidney and the renal pelvis (the funnel-shaped structure that collects urine and drains it to the ureters) and 15,160 patients would die of the disease in the United States in 2026.
The FDA rendered its decision on June 12, 2026. Check this resource for updated information on all therapeutics regulated by the FDA.