Dr Choueiri on Safety Data From the Phase 3 LITESPARK-022 Trial in ccRCC

“The AEs in general were manageable because we have learned from using belzutifan in later-stage [disease and know] how to manage anemia.”

Toni K. 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 safety data from 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).

Safety findings from LITESPARK-022 trial demonstrated that the combination of belzutifan and pembrolizumab was associated with a higher incidence of adverse effects (AEs) than pembrolizumab alone, an expected outcome when comparing a two-drug regimen with single-agent therapy, Choueiri began. Although treatment-related toxicities and discontinuations occurred more frequently in the combination arm, the differences were modest and the overall safety profile was considered manageable, he noted.

Treatment-related AEs leading to discontinuation of all study therapy occurred in 10.2% of patients receiving belzutifan plus pembrolizumab compared with 7.3% of those treated with pembrolizumab alone, Choueiri said. Although this represents a numerical increase with combination therapy, the difference was not considered substantial, he added. Rather than focusing on statistical comparisons, investigators emphasized the overall magnitude of the difference, noting that the discontinuation rates remained relatively low for both treatment groups, he said.

The AEs observed with the combination were consistent with the known safety profile of belzutifan, and no unexpected toxicities emerged during the study, Choueiri said. The most common any-grade AEs included anemia, fatigue, and hypoxia, all of which have been previously reported with belzutifan in the metastatic renal cell carcinoma (RCC) setting, he said. Importantly, the majority of AEs were grade 1 or 2 in severity, indicating that they were generally mild to moderate and could be managed with appropriate monitoring and supportive care, he added.

Investigators attributed the manageable safety profile, in part, to growing clinical experience with belzutifan in advanced disease. As oncologists have become more familiar with identifying patients at risk for treatment-related toxicities and managing AEs such as anemia, these strategies have translated effectively into the adjuvant setting.

LITESPARK-022 represents a landmark study because it is the first adjuvant trial in RCC to demonstrate a significant benefit for a combination regimen compared with an active control rather than placebo or observation, Choueiri said. Pembrolizumab alone was already an established standard of care based on the phase 3 KEYNOTE-564 trial (NCT03142334), making the positive findings particularly meaningful, he concluded.