FDA Approves Adjuvant Belzutifan Plus Pembrolizumab in ccRCC

The 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) at intermediate-high or high risk of recurrence following nephrectomy or following nephrectomy and resection of metastatic lesions.¹

The approval is supported by data from the phase 3 LITESPARK-022 trial (NCT05239728). Findings from LITESPARK-022 demonstrated that patients who received belzutifan plus pembrolizumab experienced a significant disease-free survival (DFS) benefit compared with those who received placebo plus pembrolizumab (HR, 0.72; 95% CI, 0.59-0.87; P = .0003). The median DFS was not reached in either arm. Overall survival (OS) data were not mature at the protocol pre-specified interim analysis.

The recommended belzutifan dose is 120 mg orally once daily in combination with pembrolizumab or pembrolizumab and berahyaluronidase-pmph alfa until disease recurrence or unacceptable toxicity, or for up to 54 weeks.

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

How was LITESPARK-022 designed?

LITESPARK-022 enrolled patients with histologically confirmed clear cell RCC with no prior exposure to systemic therapy, had undergone surgery within 12 weeks prior to random assignment, and had an ECOG performance status of 0 or 1.² One of the following was also required:

• Intermediate-high risk of recurrence (M0) that was defined by pT2, grade 4/sarcomatoid, N0 disease, or pT3, N0 disease of any grade
• High risk of recurrence (M0) defined by pT4, N0 disease of any grade, or any pT, any grade, N+ disease
• M1 with no evidence of disease (NED).

A total of 1841 patients were randomly assigned 1:1 to receive 400 mg of pembrolizumab every 6 weeks for approximately 1 year and not exceeding 9 cycles, plus 120 mg of daily belzutifan for no more than 54 weeks; or the same dose and schedule of pembrolizumab plus matched placebo.

Patients were stratified by risk (intermediate-high vs high vs M1 NED) and tumor grade (1-2 vs 3-4).

The primary end point was investigator-assessed DFS. Secondary end points included OS and safety.

What was the safety profile of the combination?

Safety data presented during the 2026 Genitourinary Cancers Symposium (ASCO GU) showed that the median duration of study therapy was 12.4 months (range, 0.03-20.1) in the combination arm (n = 915) vs 12.4 months (range, 0.3-18.9) in the monotherapy arm (n = 913).² Treatment-emergent AEs (TEAEs; 98.9%) that were grade 3 or greater, led to discontinuation of all study therapy, led to death, were classified as serious, or were serious and led to discontinuation of all study treatment occurred in 52.1%, 11.9%, 1.1%, 29.5%, and 6.4% of patients in the combination arm, respectively; the corresponding rates of TEAEs (94.5%) in the monotherapy arm were 30.2%, 9.0%, 1.2%, 19.9%, and 4.7%.

Treatment-related AEs (TRAEs) in the combination arm (96.6%) were grade 3 or greater, led to discontinuation of all study treatment, or led to death in 42.2%, 10.2%, and 0.3% of patients, respectively; these rates of TRAEs (80.7%) were 17.9%, 7.3%, and 0.3% in the monotherapy arm. Immune-mediated AEs or infusion reactions in the combination and monotherapy arms occurred in 35.4% (grade ≥3, 9.4%) and 38.7% (grade ≥3, 8.3%) of patients, respectively.

The following TEAEs occurred in the combination and monotherapy arms, respectively: anemia (84.0%; 11.4%), fatigue (36.4%; 26.3%), increased alanine aminotransferase levels (28.9%; 14.1%), increased aspartate aminotransferase levels (22.0%; 11.9%), diarrhea (20.9%; 16.2%), pruritus (20.3%; 23.5%), dizziness (19.3%; 8.2%), headache (16.9%; 10.8%), nausea (16.3%; 12.2%), arthralgia (15.1%; 16.9%), hypothyroidism (14.9%; 18.8%), asthenia (12.9%; 7.4%), rash (12.3%; 15.4%), increased blood creatinine levels (12.0%; 12.3%), dyspnea (10.7%; 4.4%), hyperthyroidism (7.7%; 11.4%), and cough (7.5%; 10.2%).

What were the additional efficacy data presented during ASCO GU?

In the intention-to-treat population, the landmark 12-, 24-, and 30-month DFS rates with the combination (n = 921) were 91.9%, 80.7%, and 75.8%, respectively; these rates were 85.2%, 73.7%, and 68.6% with pembrolizumab alone (n = 920). The 12-, 24-, and 30-month OS rates in the combination arm were 98.3%, 96.2%, and 95.6%, respectively; these rates were 98.6%, 95.7%, and 93.8% in the pembrolizumab monotherapy arm.

References

1. FDA approves belzutifan with pembrolizumab for adjuvant treatment of renal cell carcinoma. FDA. 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. J Clin Oncol. 2026;44(suppl 7):LBA418. doi:10.1200/JCO.2026.44.7_suppl.LBA418