Adjuvant pembrolizumab plus belzutifan versus pembrolizumab for clear cell renal cell carcinoma (ccRCC): The randomized phase 3 LITESPARK-022 study.

Abstract

LBA418 Background: Adjuvant pembrolizumab is a standard of care for patients with ccRCC at increased risk of recurrence following nephrectomy based on the phase 3 KEYNOTE-564 study (N Engl J Med 385:683; N Engl J Med 390:1359). Combination strategies may further improve outcomes in this setting. We present results from the phase 3, double-blind LITESPARK-022 study (NCT05239728) of pembrolizumab + belzutifan vs pembrolizumab + placebo in pts with ccRCC at increased risk of recurrence post nephrectomy. Methods: Pts had ccRCC stage M0 and intermediate-high (pT2 Gr 4 or sarcomatoid, or pT3 any Gr, N0) or high (pT4 any Gr, N0, or any pT and Gr, N+) risk of recurrence after nephrectomy, or ccRCC stage M1 with no evidence of disease (M1 NED) after surgery. Pts were randomized 1:1 to receive 9 doses of IV pembrolizumab 400 mg Q6W (~1 year) with either oral belzutifan 120 mg QD or placebo. The primary endpoint was DFS by investigator. Secondary endpoints included OS (key) and safety. Results are presented from the first interim analysis (IA1; after 87% of DFS events occurred with a minimum of 15 mo of follow-up). Results: Overall, 1841 pts were randomized (921 to pembrolizumab + belzutifan and 920 to pembrolizumab + placebo). As of Aug 23, 2025, median follow-up was 28.4 mo (range, 15.0–40.1). Pembrolizumab + belzutifan significantly improved DFS vs pembrolizumab + placebo (HR 0.72, 95% CI 0.59–0.87; P = 0.0003). Median DFS was not reached in both arms; estimated 24-mo DFS rate was 80.7% (95% CI, 77.7–83.2) vs 73.7% (95% CI, 70.6–76.6), respectively. OS was immature at IA1 with a total of 87 OS events (38 in the pembrolizumab + belzutifan arm vs 49 in the pembrolizumab + placebo arm) and did not reach statistical significance (HR 0.78, 95% CI 0.51–1.19; P = 0.1220) at 29% of the events needed for final OS analysis. 70% of the pembrolizumab + belzutifan arm and 71% of the pembrolizumab + placebo arm completed the assigned treatment. Among treated pts, grade ≥3 treatment-emergent AEs occurred in 52.1% of pts who received pembrolizumab + belzutifan and 30.2% who received pembrolizumab + placebo, most commonly anemia (12.1% vs 0.4%), increased ALT (6.4% vs 2.0%), and hypoxia (4.6% vs 0%). Grade 5 treatment-emergent (1.1% vs 1.2%, respectively) and treatment-related (0.3% vs 0.3%) AEs were similar between arms. No new safety signals were seen. Conclusions: Adjuvant pembrolizumab plus belzutifan demonstrated a statistically significant and clinically meaningful improvement in DFS vs pembrolizumab plus placebo in pts with ccRCC at increased risk of recurrence post nephrectomy, with a safety profile consistent with the known profiles of each drug. These results support adjuvant pembrolizumab plus belzutifan as a potential new standard of care in RCC at increased risk of recurrence. Clinical trial information: NCT05239728 .