Dr Choueiri on the Phase 3 LITESPARK-022 Trial of Belzutifan Plus Pembrolizumab in ccRCC

“It's very refreshing to see the curves separate…as early as 3 months, and continue to separate after a year.”

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, discussed the phase 3 LITESPARK-022 trial (NCT05239728), which supported the June 2026 FDA approval of adjuvant belzutifan (Welireg) plus pembrolizumab (Keytruda) in patients with clear cell renal cell carcinoma (ccRCC).

LITESPARK-022 trial evaluated whether adding belzutifan to standard adjuvant pembrolizumab could further improve outcomes for patients with ccRCC at intermediate-high risk, high risk, or M1 with no evidence of disease following surgery, Choueiri began. Eligible patients were randomly assigned within 3 months of nephrectomy to receive either pembrolizumab plus placebo or pembrolizumab plus belzutifan, an oral hypoxia- HIF-2α inhibitor that is already approved as monotherapy for previously treated RCC, he continued. The study’s primary end point was investigator-assessed disease-free survival (DFS), with overall survival (OS) and safety evaluated as key secondary end points, he noted.

Approximately 1,800 patients were randomly assigned 1:1 between the 2 treatment arms, Choueiri said. More than 80% had intermediate-high-risk disease approximately two-thirds had grade 3 or 4 tumors, he explained.

The trial successfully met its primary end point, demonstrating a statistically significant improvement in DFS with the addition of belzutifan, Choueiri said. The HR of 0.72 (95% CI, 0.59-0.87; P = .0003) translated to a 28% reduction in the risk of recurrence or death after a median follow-up of approximately 28 months, he said. Notably, the DFS curves separated as early as 3 months after treatment initiation and continued to diverge throughout follow-up, he added. Importantly, this separation persisted beyond the 1-year treatment period, suggesting that the benefit of combination therapy extended after completion of adjuvant treatment, he noted.

Prespecified subgroup analyses showed consistent benefit across patient populations, with no unexpected differences based on tumor grade, age, sex, or performance status, Choueiri said. Although the first interim OS analysis remains immature, with only 87 deaths representing approximately 29% of the expected events, the HR of 0.78 favored the combination arm, he noted. Additional follow-up will be required to determine whether the DFS benefit ultimately translates into a statistically significant improvement in OS, he concluded.