LITESPARK-022 DFS data make case for belzutifan/pembrolizumab as new standard in ccRCC

The addition of belzutifan (Welireg) to adjuvant pembrolizumab (Keytruda) significantly improved disease-free survival (DFS) compared with pembrolizumab alone in patients with high-risk clear cell renal cell carcinoma (RCC) after undergoing nephrectomy.^1,2

Data from the phase 3 LITESPARK-022 study (NCT05239728) were presented at the 2026 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium by Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute, coleader of the Kidney Cancer Program at Dana-Farber/Harvard Cancer Center, and the Jerome and Nancy Kohlberg Chair and Professor of Medicine at Harvard Medical School in Boston, Massachusetts.

Introducing the study, Choueiri said, “In 2021, [during] the ASCO plenary session, pembrolizumab showed a disease-free survival benefit and was introduced to the world as one of the first adjuvant therapies and the first immunotherapy to gain approval.³ Two years ago…we presented the data from overall survival from KEYNOTE-564 [NCT03142334].^4,5 Pembrolizumab then became the first adjuvant therapy to have an overall survival benefit since the first attempt to do these studies in 1973. Still, we have a problem. And the problem is that 40% of patients treated with adjuvant pembrolizumab will experience death or recurrence within 5 years of nephrectomy because they have a high-risk disease.”⁶

Choueiri then discussed belzutifan, a selective HIF-2α inhibitor that has demonstrated efficacy in advanced RCC in patients previously treated with immunotherapy and VEGFR-TKI therapy.⁷

“We hypothesized that 2 mechanisms of action would be better than 1 and launched LITESPARK-022,” Choueiri commented.

Patients were eligible for LITESPARK-022 if they had histologically confirmed ccRCC with no prior systemic therapy, had undergone surgery 12 weeks or sooner prior to randomization, ECOG Performance Status of 0 or 1, and had 1 of either intermediate-high risk of recurrence, high risk of recurrence, or M1 no evidence of disease. Patients were randomly assigned 1:1 to either pembrolizumab 400 mg every 6 weeks for approximately 1 year (9 or fewer cycles) plus belzutifan 120 mg once daily for 54 weeks or less (921 patients), or to pembrolizumab 400 mg every 6 weeks for approximately 1 year (9 or fewer cycles) plus placebo once daily for 54 weeks or less (920 patients). The primary end point was DFS by investigator assessment, and OS was the key secondary end point. Safety was another secondary end point.

In the belzutifan arm, 6 patients did not receive treatment; in the placebo arm, 7 were not treated. A total of 636 (69.5%) patients completed treatment in the belzutifan arm; 649 (71.1%) completed treatment in the placebo arm. Most patients were male (73.1% of the belzutifan arm and 69.8% of the placebo arm) and White (62.5% in the belzutifan arm and 63.2% in the placebo arm). The majority of patients in each arm had intermediate-to-high risk disease (84.6% in the belzutifan arm vs 85.0% in the placebo arm). In the belzutifan arm, 65.0% of patients had a tumor grade of 3-4 compared with 64.3% in the placebo arm.

“After 28 months’ follow-up, the combination of pembrolizumab and belzutifan resulted in a statistically significant and clinically meaningful improvement in disease-free survival over pembrolizumab single agent,” Choueiri said. The HR was 0.72 (95% CI, 0.59-0.87; P = .0003). Examining DFS in subgroups such as age, sex, race, ECOG Performance Status, geographic region, PD-L1 status, risk category, and tumor grade, Choueiri reported that most HRs were below 1.0. Choueiri also shared interim OS results; the HR was 0.78 (95% CI, 0.51-1.19; P = .1220).

Turning to safety, there was a 42.2% incidence of grade 3 or higher treatment-related adverse events (AEs) in the belzutifan arm vs 17.9% in the placebo arm. In the belzutifan arm, 10.2% of patients experienced a treatment-related AE resulting in discontinuation of all study treatment, vs 7.3% in the placebo arm. In each arm, there were 3 treatment-related AEs that led to death.

Choueiri then examined treatment-emergent AEs related to the HIF-2α inhibitor class. Anemia was reported in 84% of patients in the belzutifan arm, although these events were largely grade 1 and 2. The incidence of the grade 3 or higher anemia was 12.1% in the belzutifan arm vs 0.5% in the placebo arm.

“Anemia was managed in this protocol mostly by dose interruption, reduction, or discontinuation, and occasionally by blood transfusion, ESA [erythropoiesis-stimulating agent], or both,” Choueiri said.

Choueiri then touched on hypoxia; grade 3 or higher hypoxia was reported in 4.6% of the belzutifan arm and no patients in the placebo arm.

“Hypoxia was managed by interruption, dose reduction, and, [in] 1.6% of patients, discontinuation completely, but also by oxygen therapy. The median onset of oxygen therapy was 100 days,” Choueiri said.

“LITESPARK-022 is the first adjuvant phase 3 trial in renal cell cancer to show a significant benefit for a combination treatment vs an active immunotherapy comparator. These results, I believe, support the addition of belzutifan to standard-of-care adjuvant pembrolizumab for patients with clear cell RCC at increased risk of recurrence,” Choueiri concluded.

REFERENCES

1. 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. ). Presented at: 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium. February 26-28, 2026. San Francisco, California. Abstract LBA418. https://meetings.asco.org/meetings/2026-asco-genitourinary-cancers-symposium/334/16925?presentation=256660

2. KEYTRUDA® (pembrolizumab) plus WELIREG® (belzutifan) given as adjuvant therapy reduced the risk of disease recurrence or death by 28% compared to KEYTRUDA monotherapy in certain patients with earlier-stage renal cell carcinoma (RCC). News release. Merck. February 28, 2026. Accessed February 28, 2026. https://www.businesswire.com/news/home/20260228025853/en/KEYTRUDA-pembrolizumab-Plus-WELIREG-belzutifan-Given-as-Adjuvant-Therapy-Reduced-the-Risk-of-Disease-Recurrence-or-Death-by-28-Compared-to-KEYTRUDA-Monotherapy-in-Certain-Patients-With-Earlier-Stage-Renal-Cell-Carcinoma-RCC

3. National Comprehensive Cancer Network. Kidney Cancer (Version 1.2026). NCCN Clinical Practice Guidelines in Oncology. Accessed February 28, 2026. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1440

4. Choueiri TK, Tomczak P, Park SH, et al. Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. N Engl J Med. 2021;385(8):683-694. doi:10.1056/NEJMoa2106391

5. Choueiri TK, Tomczak P, Park SH, et al. Overall survival with adjuvant pembrolizumab in renal-cell carcinoma. N Engl J Med. 2024;390(15):1359-1371. doi:10.1056/NEJMoa2312695

6. Haas NB, Powles T, Tomczak P, et al. Five-year follow-up results from the phase 3 KEYNOTE-564 study of adjuvant pembrolizumab (pembro) for the treatment of clear cell renal cell carcinoma (ccRCC). J Clin Oncol. 2025;43(suppl_16):4514. doi:10.1200/JCO.2025.43.16_suppl.4514

7. Choueiri TK, Powles T, Peltola K, et al. Belzutifan versus everolimus for advanced renal-cell carcinoma. N Engl J Med. 2024;391(8):710-721. doi:10.1056/NEJMoa2313906