Based on results from the phase III KEYNOTE-564 study,¹ adjuvant pembrolizumab is currently a standard of care for patients with clear cell renal cell carcinoma who have an increased risk of recurrence following a nephrectomy. Now, results from the phase III LITESPARK-022 study investigating the combination of adjuvant pembrolizumab plus the oral hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor belzutifan in high-risk patients show that the regimen demonstrated a statistically significant improvement in disease-free survival vs pembrolizumab plus placebo.²

The findings support the combination therapy as a potential new standard of care in patients at risk for recurrence, according to the study authors. The study by Toni K. Choueiri, MD, FASCO, Director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute, and colleagues, was presented during the 2026 ASCO Genitourinary Cancers Symposium.

Toni K. Choueiri, MD

The researchers enrolled 1,841 patients with clear cell renal cell carcinoma without metastases and intermediate-high or high risk of recurrence after a nephrectomy, or stage M1 with no evidence of disease (M1 NED) after surgery. The patients were randomly assigned 1:1 to receive nine doses of intravenous pembrolizumab 400 mg every 6 weeks (~1 year) with either oral belzutifan 120 mg once daily (921 patients) or placebo (920 patients).

The primary endpoint was disease-free survival. Secondary endpoints included overall survival and safety.

Results

As of August 23, 2025, the median follow-up of these patients was 28.4 months (range, 15.0–40.1). 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 disease-free survival 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 the first interim analysis (IA1) with a total of 87 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 the final overall survival analysis.

Seventy percent of patients in the pembrolizumab plus belzutifan arm and 71% of patients in the pembrolizumab plus 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 with belzutifan and 30.2% of the patients who received pembrolizumab with placebo, most commonly anemia (12.1% vs 0.4%), increased alanine aminotransferase (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%) 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 patient 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 renal cell carcinoma at increased risk of recurrence,” concluded the study authors.

ASCO Perspective

“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 ASCO expert Brian I. Rini, MD, FASCO, Medical Oncologist at Vanderbilt University Medical Center, in a statement. “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.

“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.”

— BRIAN I. RINI, MD, FASCO

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“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.”

Editor’s note: The HIF-2α inhibitor belzutifan helps to reduce risk of progression by blocking HIF-2α, which is overabundant in clear cell renal cell carcinoma cells and drives cancer growth. The Nobel Prize in Physiology or Medicine in 2019 was awarded to William G. Kaelin, Jr., MD, of Dana-Farber, for the science behind the development of belzutifan.

On March 2, 2026, the U.S. Food and Drug Administration (FDA) granted priority review to two supplemental applications seeking approval of belzutifan (Welireg) in combination with pembrolizumab (Keytruda) or pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex) for the adjuvant treatment of adult patients with clear cell renal cell carcinoma who are at an increased risk of recurrence following nephrectomy. The FDA has set a Prescription Drug User Fee Act, or target action date, of June 19, 2026. 

DISCLOSURE: Funding for this study was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. The study authors’ conflict of interest disclosures may be found at https://coi.asco.org/report/viewabstractcoi?id=521958.

REFERENCES

1. Choueiri TK, Tomczak P, Park S-H, et al: Overall survival with adjuvant pembrolizumab in renal-cell carcinoma. N Engl J Med 390:1359-1371, 2024.

2. Choueiri TK, Motzer RJ, Karam JA, et al: Adjuvant pembrolizumab plus belzutifan versus pembrolizumab for clear cell renal cell carcinoma (ccRCC): the randomized phase 3 LITESPARK-022 study. J Clin Oncol 44, (suppl 7; abstr LBA418), 2026.