Editor’s Note: At the American Society of Clinical Oncology (ASCO) Annual Meeting, Dr. Toni K. Choueiri from the Dana-Farber Cancer Institute and Harvard Medical School presented the primary results of the LITESPARK-022 study (NCT05239728). As the largest randomized, double-blind, Phase 3 trial to date in the adjuvant immunotherapy setting, LITESPARK-022 evaluated the efficacy of pembrolizumab plus belzutifan versus pembrolizumab monotherapy for patients with clear cell renal cell carcinoma (ccRCC) at increased risk of recurrence post-nephrectomy.01 Clinical Context:
Unmet Needs Beyond KEYNOTE-564 While the KEYNOTE-564 study established pembrolizumab as the standard of care for adjuvant treatment in ccRCC—demonstrating a significant improvement in overall survival (OS)—approximately 40% of high-risk patients still experience recurrence or death within five years of surgery. Belzutifan, a potent and selective small-molecule inhibitor of hypoxia-inducible factor 2α (HIF-2α), has demonstrated established efficacy and safety in advanced renal cell carcinoma. LITESPARK-022 hypothesized that dual-mechanism inhibition (HIF-2α plus PD-1) would further reduce the risk of recurrence compared to immunotherapy alone.
02 Study Design:
The Largest Adjuvant Exploration in ccRCC LITESPARK-022 enrolled 1,841 patients with ccRCC following nephrectomy who were at intermediate-high risk (T2 grade 4 or T3), high risk (T4 or node-positive), or M1 NED (no evidence of disease after complete resection of metastases). Patients were randomized 1:1 to:
- Experimental Arm: Belzutifan (120 mg QD) plus pembrolizumab (400 mg Q6W) for approximately one year (up to 9 cycles).
- Control Arm: Placebo plus pembrolizumab for the same duration.
The primary endpoint was investigator-assessed disease-free survival (DFS). Secondary endpoints included OS and safety.
03 Efficacy Data:
Statistically Significant and Clinically Meaningful DFS Improvement At the first pre-specified interim analysis with a median follow-up of 28 months, the combination therapy demonstrated a clear superior benefit:
- DFS Benefit: The combination arm significantly reduced the risk of disease recurrence or death by 28% compared to the pembrolizumab monotherapy arm (HR=0.72; 95% CI: 0.59–0.88; P=0.0006). This result surpassed the pre-specified significance threshold of P=0.016.
- Subgroup Consistency: DFS benefits were consistent across all pre-specified subgroups, regardless of the baseline risk category.
- Curve Characteristics: The DFS curves began to separate as early as 3 months. Notably, the separation persisted even after the completion of the 1-year treatment period, suggesting a durable clinical impact.
04 Survival Trends:
Immature OS Data with Positive Early Signals The OS data remained immature at this interim analysis, with only 87 events (29% of the required information fraction). Early observations showed:
- A hazard ratio (HR) for OS of 0.78 (95% CI: 0.51–1.21).
- With a P-value of 0.238, the results did not meet the stringent pre-specified alpha of P=0.0003 for this interim analysis. No detrimental signal was observed, and follow-up for this key secondary endpoint is ongoing.
05 Safety Profile:
Manageable Class-Specific Adverse Events The addition of belzutifan increased the incidence of adverse events (AEs) as expected:
- Grade 3/4 AEs: 42% in the combination arm vs. 18% in the control arm.
- Discontinuation: 10% of patients in the combination arm discontinued any study treatment due to AEs, compared to 7.3% in the monotherapy arm.
- Specific AEs of Interest: Anemia, a known class effect of HIF-2α inhibitors, occurred in the majority of patients but was mostly Grade 1 or 2. Grade 3 anemia was reported in 12% of the combination group (vs. <1% in the control group) and was managed via dose interruptions, reductions, and occasionally erythropoiesis-stimulating agents (ESAs) or blood transfusions. Hypoxia (Grade 3 or higher) occurred in 4.6% of the combination group, leading to discontinuation of belzutifan in only 1.6% of patients.
06 Conclusion:
Entering the Era of Combination Adjuvant Therapy Dr. Toni K. Choueiri concluded that LITESPARK-022 is the first Phase 3 adjuvant trial in renal cell carcinoma to demonstrate a significant benefit for a combination therapy over an active immunotherapy comparator. The 28% reduction in recurrence risk represents a meaningful advancement in clinical practice. While OS data require further maturation, these results support the addition of belzutifan to the standard-of-care adjuvant pembrolizumab for patients with ccRCC at increased risk of recurrence.
