FDA Approves Belzutifan Plus Pembrolizumab for Adjuvant Treatment of High-Risk Clear Cell RCC

The FDA has approved belzutifan (Welireg; Merck) in combination with pembrolizumab (Keytruda; Merck) or pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex; Merck) for the adjuvant treatment of adults with renal cell carcinoma (RCC) containing a clear cell component who are at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions.¹

The approval was announced on June 12, 2026 and is supported by findings presented in the phase 3 LITESPARK-022 trial (NCT05239728), which demonstrated a statistically significant improvement in disease-free survival (DFS) when belzutifan was combined with pembrolizumab in the adjuvant setting.¹

The most common histologic subtype of kidney cancer is clear cell RCC and it remains associated with a substantial risk of recurrence which follows surgery, specifically among patients with high-risk disease. While immune checkpoint inhibition has improved outcomes in the adjuvant setting, recurrence continues to occur in a significant proportion of patients, creating a need for additional therapeutic strategies.²

Belzutifan is a first-in-class hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor which blocks a key transcription factor that is involved in tumor growth, angiogenesis, and cellular adaptation to hypoxia.³ The agent has previously demonstrated activity in advanced RCC and von Hippel-Lindau disease-associated tumors, supporting its evaluation in earlier-stage disease settings.³

The randomized, double-blind LITESPARK-022 trial enrolled 1841 patients who had undergone prior nephrectomy for clear cell RCC and were classified as having intermediate–high-risk disease, high-risk disease, or resected metastatic disease with no evidence of disease. The patients were randomly assigned to receive belzutifan plus pembrolizumab or placebo plus pembrolizumab as adjuvant therapy. Treatment progressed until disease recurrence, unacceptable toxicity, or completion of therapy, with belzutifan administered for up to 54 weeks and pembrolizumab administered for up to 12 months.¹

At a preplanned interim analysis, the data reported 186 DFS events in the belzutifan-pembrolizumab arm when compared with 246 events in the placebo-pembrolizumab arm. The combination reduced the risk of recurrence, metastasis, or death by 28% (HR, 0.72 [95% CI, 0.59-0.87]; P = .0003). Median DFS had not yet been reached in either treatment arm at the time of analysis. Overall survival data remain immature.¹

This approval provides expansion to the role of belzutifan into the curative-intent setting and represents another advance in the evolving management of localized RCC. For pharmacists, the approval highlights the growing importance of multidisciplinary monitoring as patients receive both immunotherapy and targeted therapy in the adjuvant setting. Moving forward, health care professionals should remain vigilant for adverse effects in association with belzutifan, including anemia and hypoxia, as well as immune-mediated toxicities associated with pembrolizumab.¹

The prescribing information for belzutifan includes a boxed warning for embryo-fetal toxicity and warnings regarding anemia and hypoxia. Pembrolizumab labeling includes warnings for immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation, and embryo-fetal toxicity.¹

The FDA review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence that enables concurrent review of oncology products among international regulatory partners, including the Australian Therapeutic Goods Administration and Health Canada.¹

REFERENCES

1. FDA. FDA approves belzutifan with pembrolizumab for adjuvant treatment of renal cell carcinoma. June 12, 2026. Accessed June 12, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-pembrolizumab-adjuvant-treatment-renal-cell-carcinoma

2. National Cancer Institute. Renal cell cancer treatment (PDQ®)–health professional version. Updated 2025. Accessed June 12, 2026. https://www.cancer.gov/types/kidney/hp/kidney-treatment-pdq

3. Choueiri, T.K., Kaelin, W.G. Targeting the HIF2–VEGF axis in renal cell carcinoma. Nat Med26, 1519–1530 (2020). https://doi.org/10.1038/s41591-020-1093-z