Belzutifan (Welireg), in combination with pembrolizumab (Keytruda) or pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex), has been approved by the U.S. Food and Drug Administration for the adjuvant treatment of adults with renal cell carcinoma with a clear cell component.
The approval applies to patients with clear cell renal cell carcinoma who are at intermediate-high or high risk of recurrence after nephrectomy, as well as patients who underwent nephrectomy followed by resection of metastatic lesions and have no evidence of disease.
This approval introduces a new adjuvant option for patients with higher-risk clear cell RCC, combining PD-1 immune checkpoint inhibition with belzutifan, an oral HIF-2α inhibitor.
LITESPARK-022 Trial Supporting the Approval
The FDA decision was based on results from LITESPARK-022, a multicenter, double-blind, randomized phase 3 trial that enrolled 1,841 patients with clear cell RCC who had undergone prior nephrectomy. Eligible patients were at intermediate-high or high risk of recurrence, or had resected metastatic disease with no evidence of disease.
Patients were randomized 1:1 to receive either belzutifan plus pembrolizumab or placebo plus pembrolizumab as adjuvant therapy. Treatment continued until disease recurrence, unacceptable toxicity, or for a maximum of 54 weeks of belzutifan and 12 months of pembrolizumab.The primary efficacy endpoint was investigator-assessed disease-free survival, defined as time to recurrence, metastasis, or death.
Key Efficacy Results
At a prespecified interim analysis, belzutifan plus pembrolizumab significantly improved disease-free survival compared with placebo plus pembrolizumab.
There were 186 DFS events in the belzutifan plus pembrolizumab group and 246 events in the placebo plus pembrolizumab group. The combination reduced the risk of recurrence, metastasis, or death by 28%, with a hazard ratio of 0.72 and a 95% confidence interval of 0.59 to 0.87. The result was statistically significant, with a p-value of 0.0003.
Median disease-free survival was not reached in either treatment arm at the time of analysis. Overall survival data were not mature at the protocol-specified interim analysis.
Safety Considerations
Belzutifan is an oral, first-in-class hypoxia-inducible factor-2 alpha inhibitor. It targets the HIF-2α pathway, which plays an important role in tumor adaptation to low oxygen levels, angiogenesis, and cancer cell survival, particularly in clear cell renal cell carcinoma.
The belzutifan prescribing information includes a boxed warning for embryo-fetal toxicity, as well as warnings and precautions for anemia and hypoxia. These are important considerations because belzutifan targets the hypoxia-inducible factor pathway and can affect oxygen-related physiology.
Pembrolizumab carries warnings and precautions for immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation, and embryo-fetal toxicity.
Clinicians should monitor patients for known toxicities of both agents, including anemia, hypoxia, and immune-related adverse events, particularly in the adjuvant setting where patients may have no radiographic evidence of active disease after surgery.
Belzutifan is an oral, first-in-class hypoxia-inducible factor-2 alpha inhibitor. It targets the HIF-2α pathway, which plays an important role in tumor adaptation to low oxygen levels, angiogenesis, and cancer cell survival, particularly in clear cell renal cell carcinoma.
Recommended Dosing
The recommended belzutifan dose is 120 mg orally once daily in combination with pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph. Belzutifan may be continued until disease recurrence, unacceptable toxicity, or for up to 54 weeks.
Pembrolizumab may be given intravenously at 200 mg every 3 weeks or 400 mg every 6 weeks in combination with belzutifan, until disease recurrence, unacceptable toxicity, or for up to 12 months.
For the subcutaneous formulation, pembrolizumab and berahyaluronidase alfa-pmph may be administered at 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks in combination with belzutifan.
Regulatory Context
The review was conducted under Project Orbis, an FDA Oncology Center of Excellence initiative designed to support concurrent submission and review of oncology drugs with international regulatory partners. For this application, the FDA collaborated with the Australian Therapeutic Goods Administration and Health Canada, where reviews are ongoing.The application also received priority review and used the FDA Assessment Aid, a voluntary submission intended to facilitate regulatory assessment.
Key Takeaway
The approval of belzutifan plus pembrolizumab expands the adjuvant treatment landscape for patients with clear cell renal cell carcinoma at higher risk of recurrence after surgery. In LITESPARK-022, the regimen significantly improved disease-free survival compared with pembrolizumab alone, while overall survival data remain immature.
This FDA decision supports a new combination approach in the curative-intent setting, adding HIF-2α inhibition to established PD-1 blockade for selected patients with high-risk clear cell RCC.