FDA approves adjuvant belzutifan with pembrolizumab for ccRCC

The FDA has approved belzutifan (Welireg) in combination with pembrolizumab (Keytruda) or pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex) as adjuvant treatment for adult patients with renal cell carcinoma with a clear cell component (ccRCC) at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions.¹

“This is a major advancement,” said Toni K. Choueiri, MD, of Dana-Farber Cancer Institute, in correspondence with Urology Times®. “We waited 5 decades to finally have a systemic treatment [that can] decrease the chance of kidney cancer coming back and killing patients; with pembrolizumab, in 2021, we had that drug. Belzutifan is able to further decrease the chance of recurrence[, metastasis, or death] by close to 30%, so we're very ecstatic about this.”

Data on belzutifan plus pembrolizumab

The application was supported by data from the phase 3 LITESPARK-022 study (NCT05239728), which met its primary end point by showing that the addition of belzutifan to adjuvant pembrolizumab significantly improved disease-free survival (DFS) vs pembrolizumab alone (HR, 0.72; 95% CI, 0.59 to 0.87; P = .0003).

In total, the LITESPARK-022 trial enrolled 1841 patients. Participants were eligible for the study if they had histologically confirmed ccRCC with no prior systemic therapy, had undergone surgery 12 weeks or sooner prior to randomization, had an ECOG Performance Status of 0 or 1, and had either intermediate-high risk of recurrence, high risk of recurrence, or M1 no evidence of disease.

Those included in the study were randomly assigned 1:1 to either pembrolizumab 400 mg every 6 weeks for approximately 1 year (9 or fewer cycles) plus belzutifan 120 mg once daily for 54 weeks or less (n = 921), or to pembrolizumab 400 mg every 6 weeks for approximately 1 year (9 or fewer cycles) plus placebo once daily for 54 weeks or less (n = 920). The primary end point was DFS by investigator assessment, and OS and safety were key secondary end points.

A total of 636 (69.5%) patients completed treatment in the belzutifan arm, and 649 (71.1%) patients completed treatment in the placebo arm.

At the median follow-up of 28.4 months, the median DFS had not been reached in either arm. The estimated 24-month DFS rate was 80.7% (95% CI, 77.7 to 83.2) for the belzutifan plus pembrolizumab arm and was 73.7% (95% CI, 70.6 to 76.6) for the pembrolizumab monotherapy arm.

Overall survival data were not mature at the time of the interim analysis. At data report, the HR was 0.78 (95% CI, 0.51 to 1.19; P = .1220).

Regarding safety, grade 3 or higher adverse events (AEs) were reported in 52.1% of patients in the combination arm and 30.2% of patients in the pembrolizumab monotherapy arm. The most common treatment-emergent AEs were anemia (12.1% vs 0.5%), increased alanine aminotransferase (6.4% vs 2.0%) and hypoxia (4.6% vs 0%). The incidence of grade 5 treatment-emergent AEs was 1.1% in the combination arm vs 1.2% in the pembrolizumab monotherapy arm. The incidence of treatment-related AEs was also comparable between both study cohorts, with a rate of 0.3% in each.

FDA recommendations

According to the FDA, the recommended dose for belzutifan is 120 mg orally once daily until disease recurrence or unacceptable toxicity, or for up to 54 weeks. The recommended dose for pembrolizumab is 200 mg intravenously every 3 weeks or 400 mg every 6 weeks until disease recurrence, unacceptable toxicity, or for up to 12 months. The recommended dose for pembrolizumab and berahyaluronidase alfa-pmph is 395 mg/4,800 units subcutaneously every 3 weeks or 790 mg/9,600 units every 6 weeks until disease recurrence, unacceptable toxicity, or for up to 12 months.

The agency also noted, “The belzutifan prescribing information includes a boxed warning for embryo-fetal toxicity and warnings and precautions for anemia and hypoxia. The pembrolizumab prescribing information includes warnings and precautions for immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation, and embryo-fetal toxicity.”

REFERENCES

1. FDA approves belzutifan with pembrolizumab for adjuvant treatment of renal cell carcinoma. News release. US Food & Drug Administration. 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. Choueiri TK, Motzer RJ, Karam JA, et al. Adjuvant pembrolizumab plus belzutifan versus pembrolizumab for clear cell renal cell carcinoma (ccRCC): The randomized phase 3 LITESPARK-022 study. Presented at: 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium. February 26-28, 2026. San Francisco, California. Abstract LBA418. https://meetings.asco.org/meetings/2026-asco-genitourinary-cancers-symposium/334/16925?presentation=256660