Based on the results from the phase III KEYNOTE-564 study, adjuvant pembrolizumab is currently standard of care for patients with clear cell renal cell carcinoma at increased risk of recurrence following a nephrectomy.
Now, the results from the phase III LITESPARK-022 study—which investigated the combination of adjuvant pembrolizumab plus the HIF-2α inhibitor belzutifan in high-risk patients—show that the doublet demonstrated a statistically significant and clinically meaningful improvement in disease-free survival vs pembrolizumab plus placebo.
The findings support the combination therapy as a potential new standard of care in patients at risk for recurrence, according to the study authors. Toni K. Choueiri, MD, FASCO, presented the data during the 2026 ASCO Genitourinary Cancers Symposium (Abstract LBA418).
Toni K. Choueiri, MD, FASCO
Study Methodology
Researchers enrolled 1,841 patients with stage M0 clear cell renal cell carcinoma and intermediate-high or high risk of recurrence after a nephrectomy, or with stage M1 disease with no evidence of disease (M1 NED) after surgery. The patients were randomly assigned 1:1 to receive nine doses of intravenous pembrolizumab at 400 mg every 6 weeks for approximately 1 year with either oral belzutifan at 120 mg once daily (n = 921) or placebo (n = 920).
The primary endpoint of the trial was disease-free survival; secondary endpoints included overall survival and safety.
Results
As of August 2025, the median follow-up was 28.4 months (range = 15.0–40.1 months). The researchers found that pembrolizumab plus belzutifan significantly improved disease-free survival vs pembrolizumab plus placebo (hazard ratio [HR] = 0.72, 95% confidence interval [CI] = 0.59–0.87; P = .0003). Median disease-free survival was not reached in either arm; the estimated 24-month rate was 80.7% (95% CI = 77.7%–83.2%) vs 73.7% (95% CI = 70.6%–76.6%), respectively.
Overall survival was immature at first interim analysis, with a total of 87 overall survival 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 = .1220) at 29% of the events needed for final overall survival analysis.
Seventy percent of patients in the pembrolizumab/belzutifan arm and 71% of patients in the pembrolizumab/placebo arm completed the assigned treatment. Among the treated patients, grade ≥ 3 treatment-emergent adverse events occurred in 52.1% of the patients who received pembrolizumab/belzutifan and 30.2% of the patients who received pembrolizumab/placebo, most commonly anemia (12.1% vs 0.4%), increased alanine aminotransferase (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%) adverse events were similar between the two arms. No new safety signals were seen.
“Adjuvant pembrolizumab plus belzutifan demonstrated a statistically significant and clinically meaningful improvement in disease-free survival vs pembrolizumab plus placebo in patients with clear cell renal cell carcinoma at increased risk of recurrence postnephrectomy, 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,” concluded the study authors.
ASCO Perspective
Brian I. Rini, MD, FASCO
“The LITESPARK-022 data are both exciting and somewhat surprising, as previous research has not shown a clear benefit to giving targeted therapy after surgery to remove kidney cancer with a high risk of recurring,” commented Brian I. Rini, MD, FASCO, an ASCO Expert in kidney cancer and a medical oncologist at Vanderbilt University Medical Center. “The combination of belzutifan and pembrolizumab showed a significant improvement in the duration of time patients with kidney cancer remained cancer-free after surgery compared to those receiving pembrolizumab alone.
“While these results are encouraging, the combination treatment was associated with increased toxicity, and we are still awaiting long-term data to determine if this regimen translates into a definitive overall survival benefit.”
DISCLOSURE: Funding for this study was provided by Merck sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. For full disclosures of the study authors, visit coi.asco.org.
