sNDA Seeking Approval of Belzutifan Plus Pembrolizumab in ccRCC Earns Priority Review From FDA

The FDA has accepted for priority review supplemental new drug applications (sNDAs) seeking the approval of the HIF-2α inhibitor belzutifan (Welireg) in combination with pembrolizumab (Keytruda) or berahyaluronidase alfa-pmph (Keytruda Qlex) for the adjuvant treatment of adult patients with renal cell carcinoma (RCC) with a clear cell component at an increased risk of recurrence following nephrectomy.¹ The FDA has set a Prescription Drug User Fee Act target action date of June 19, 2026, for both sNDAs.

The sNDAs are supported by data from the phase 3 LITESPARK-022 trial (NCT05239728).² Findings from the first interim analysis of the study presented during the 2026 Genitourinary Cancers Symposium showed that patients who received pembrolizumab plus belzutifan (n = 921) achieved a median investigator-assessed disease-free survival (DFS) of not reached (NR; 95% CI, 36.9 months-NR) compared with NR (95% CI, NR-NR) with pembrolizumab alone (n = 920; HR, 0.72; 95% CI, 0.59-0.87; P = .0003). In the combination arm, the 12-, 24-, and 30-month DFS rates were 91.9%, 80.7%, and 75.8%, respectively; these respective rates were 85.2%, 73.7%, and 68.6% with pembrolizumab monotherapy.

“The primary end point of DFS was met,” Toni Choueiri, MD, the director of the Lank Center for Genitourinary Oncology and the medical director of International Strategic Initiatives at Dana-Farber Cancer Institute, as well as the Jerome and Nancy Kohlberg Professor of Medicine at Harvard Medical School, both in Boston, Massachusetts, said in an exclusive interview with OncLive® during the meeting. “This was the first study [in this patient population] to build on adjuvant pembrolizumab. We're pushing the envelope, [and] more patients are going to be around for the next generation of drugs. [We are] quite happy with these data, and I'm sure this is not the end. There will be more data coming out of LITESPARK-022.”

How was LITESPARK-022 designed?

LITESPARK-022 enrolled patients with histologically confirmed clear cell RCC with no prior exposure to systemic therapy who had undergone surgery within 12 weeks prior to random assignment and had an ECOG performance status of 0 or 1. Patients were also required to have 1 of the following: 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; or M1 with no evidence of disease.

Patients were randomly assigned 1:1 to receive pembrolizumab at 400 mg every 6 weeks for approximately 1 year for no more than 9 cycles in combination with daily belzutifan at 120 mg for no more than 54 weeks or pembrolizumab plus matched placebo.

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

What were the safety and additional efficacy data?

Further efficacy data revealed that the median OS was NR (95% CI, NR-NR) in both arms. These findings did not meet statistical significance (HR, 0.78; 95% CI, 0.51-1.19; P = .1220). The 12-, 24-, and 30-month OS rates in the combination arm were 98.3%, 96.2%, and 95.6%, respectively; these respective rates were 98.6%, 95.7%, and 93.8% in the monotherapy arm.

In terms of safety, patients in the combination arm experienced any-grade treatment-related adverse effects (TRAEs) at a rate of 96.6%. TRAEs leading to study treatment discontinuation (10.2%) or death (0.3%) were also reported. In the control arm, any-grade TRAEs, TRAEs leading to treatment discontinuation, and TRAEs leading to death occurred at respective rates of 80.7%, 7.3%, and 0.3%, respectively.

“LITESPARK-022 is a critical part of our comprehensive RCC clinical development program, and the phase 3 results presented at ASCO GU underscore the importance of [pembrolizumab] and [belzutifan] in helping to treat patients with certain types of RCC,” said M. Catherine Pietanza, MD, the vice president of global clinical development at Merck Research Laboratories, stated in a news release.¹ “These findings represent the first positive phase 3 data for [belzutifan] in earlier stages of disease, as well as the first positive phase 3 results for a HIF‑2α inhibitor and immunotherapy combination, reinforcing our commitment to exploring novel treatment approaches to improve upon established treatment paradigms for patients in need.”

References

1. Keytruda (pembrolizumab) plus Welireg (belzutifan) given as adjuvant therapy reduced the risk of disease recurrence or death by 28% compared to Keytruda monotherapy in certain patients with earlier-stage renal cell carcinoma (RCC). News release. Merck. February 28, 2026. Accessed March 3, 2026. https://www.merck.com/news/keytruda-pembrolizumab-plus-welireg-belzutifan-given-as-adjuvant-therapy-reduced-the-risk-of-disease-recurrence-or-death-by-28-compared-to-keytruda-monotherapy-in-certain-patients-with/
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