FDA Approves Adjuvant Belzutifan Plus Pembro for Kidney Cancer

The FDA has approved belzutifan (Welireg) in combination with pembrolizumab (Keytruda) or pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex) for the adjuvant treatment of adults with renal cell carcinoma (RCC) with a clear cell component who are at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions.¹

The approval is based on the phase 3 LITESPARK-022 trial (NCT05239728), in which the combination led to a statistically significant and clinically meaningful improvement in disease-free survival (DFS) vs pembrolizumab alone as adjuvant therapy in this patient population.^1,2 The median investigator-assessed DFS was not reached (NR; 95% CI, 36.9-NR) with the combination (n = 921) vs NR (95% CI, NR-NR) with pembrolizumab alone in the intention-to-treat population (n = 920; HR, 0.72; 95% CI, 0.59-0.87; P =.0003). The landmark 12-, 24-, and 30-month DFS rates with the combination were 91.9%, 80.7%, and 75.8%, respectively; these rates were 85.2%, 73.7%, and 68.6% with pembrolizumab alone.

Prespecified subgroup analysis indicated that most subgroups benefited from the regimen. The sole group where the HR exceeded 1.00 was individuals with high-risk disease (HR, 1.10; 95% CI, 0.59-2.02).

The median overall survival (OS) was NR (95% CI, NR-NR) in both arms, and did not reach statistical significance (HR, 0.78; 95% CI, 0.51-1.19; P =.1220), with only 29% of expected events having occurred. The 12-, 24-, and 30-month OS rates in the combination arm were 98.3%, 96.2%, and 95.6%, respectively; these rates were 98.6%, 95.7%, and 93.8% in the pembrolizumab monotherapy arm.

“LITESPARK-022 is the first adjuvant phase 3 trial in RCC to show a significant benefit for a combination treatment vs an active immunotherapy comparator,” Toni Choueiri, MD, lead study author and 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, said when presenting the data at the 2026 ASCO Genitourinary Cancers Symposium.²

Trial Rationale

Adjuvant pembrolizumab became the standard of care (SOC) for patients with high-risk RCC based on the phase 3 KEYNOTE-564 trial (NCT03142334), which demonstrated improvements in DFS and OS with the checkpoint inhibitor vs placebo.³ However, approximately 40% of patients on the trial experienced death or recurrence within 5 years of nephrectomy, pointing to an existing gap in effective treatment options.

Belzutifan is a potent, selective HIF-2α inhibitor that has shown activity in the advanced setting in individuals with prior exposure to immunotherapy and VEGFR tyrosine kinase inhibitor therapy. As such, earlier exposure to the agent, in combination with the current SOC, was believed to improve outcomes in this population.

Patient Eligibility

Eligible patients had histologically confirmed clear cell RCC with no prior exposure to systemic therapy, had undergone surgery within 12 weeks prior to being randomly assigned, and had an ECOG performance status of 0 or 1. One of the following was also required:

• Intermediate-high risk of recurrence (M0) defined by pT2, grade 4/sarcomatoid, N0 disease, or pT3, N0 disease of any grade
• High risk of recurrence (M0) defined by pT4, N0 disease of any grade, or any pT, any grade, N+ disease
• M1 with no evidence of disease (NED)

A total of 1841 patients were randomly assigned 1:1 to receive 400 mg of pembrolizumab every 6 weeks for approximately 1 year and not exceeding 9 cycles, plus 120 mg of daily belzutifan for no more than 54 weeks; or the same dose and schedule of pembrolizumab plus matched placebo.

Patients were stratified by risk (intermediate-high vs high vs M1 NED) and tumor grade (1-2 vs 3-4).

The primary end point was investigator-assessed DFS. Secondary end points included OS and safety. The median follow-up was 28.4 months (range, 15.0-40.1) at the data cutoff date of August 23, 2025.

Statistical Plan

The study initially planned to enroll 1800 patients. With DFS as the primary end point, 496 events were estimated to provide 95% power to detect an HR of 0.72 at a 1-sided α of 2.5%. The first prespecified interim analysis was planned after approximately 396 DFS events and a minimum of 15 months had elapsed since the last patient had been randomly assigned. With respect to OS, an α of 2.5% was to be used to determine whether to reject the null hypothesis for DFS. The P value boundaries were 0.01632 for DFS and 0.00003 for OS.'

Baseline Characteristics

Between March 2022 and May 2024, 1841 patients were randomly assigned to study therapy: 921 to the investigational arm and 920 to the control arm. In the combination arm, 6 patients were not treated, and 69.5% of patients completed therapy; 2 (0.2%) remain on therapy. Reasons for discontinuation (30.3%) included adverse effects (AEs; 17.8%), patient withdrawal (4.9%), recurrence or relapse (4.7%), physician decision (1.1%), nonadherence to the study drug (0.8%), nonadherence to the protocol (0.7%), protocol violation (0.2%), and being lost to follow-up (0.1%). In the monotherapy arm, 7 patients were not treated, and 71.1% completed therapy; 0 remain on treatment. The top 3 reasons for discontinuation (28.9%) were AEs (11.4%), recurrence or relapse (11.5%), and patient withdrawal (3.1%).

The baseline characteristics were well balanced, Choueiri noted. In the combination arm, the median age was 59.0 years (range, 20-91), and most patients were male (73.1%), White (62.5%), and from regions outside of the US (84.8%). Most patients had an ECOG performance status of 0 (85.6%) and had intermediate-high risk (84.6%). Sarcomatoid features were absent in most cases (79.3%), and most patients had a grade 3 or 4 tumor (65.0%) and PD-L1 combined positive score of 1 or greater (59.4%).

Safety and Tolerability

The median duration of study therapy was 12.4 months (range, 0.03-20.10) in the combination arm (n = 915) vs 12.4 months (range, 0.30-18.90) in the monotherapy arm (n = 913). Treatment-emergent AEs (TEAEs; 98.9%) that were grade 3 or greater, led to discontinuation of all study therapy, led to death, were classified as serious, or were serious and led to discontinuation of all study treatment occurred in 52.1%, 11.9%, 1.1%, 29.5%, and 6.4% of patients in the combination arm, respectively; the corresponding rates of TEAEs (94.5%) in the monotherapy arm were 30.2%, 9.0%, 1.2%, 19.9%, and 4.7%.

Treatment-related AEs (TRAEs) in the combination arm (96.6%) were grade 3 or greater, led to discontinuation of all study treatment, or led to death in 42.2%, 10.2%, and 0.3% of patients, respectively; these rates of TRAEs (80.7%) were 17.9%, 7.3%, and 0.3% in the monotherapy arm. Immune-mediated AEs or infusion reactions occurred in 35.4% (grade ≥3, 9.4%) and 38.7% (grade ≥3, 8.3%) of patients in the combination and monotherapy arms, respectively.

The following TEAEs occurred in the combination and monotherapy arms, respectively: anemia (84.0%; 11.4%), fatigue (36.4%; 26.3%), increased alanine aminotransferase levels (28.9%; 14.1%), increased aspartate aminotransferase levels (22.0%; 11.9%), diarrhea (20.9%; 16.2%), pruritus (20.3%; 23.5%), dizziness (19.3%; 8.2%), headache (16.9%; 10.8%), nausea (16.3%; 12.2%), arthralgia (15.1%; 16.9%), hypothyroidism (14.9%; 18.8%), asthenia (12.9%; 7.4%), rash (12.3%; 15.4%), increased blood creatinine levels (12.0%; 12.3%), dyspnea (10.7%; 4.4%), hyperthyroidism (7.7%; 11.4%), and cough (7.5%; 10.2%).

REFERENCES

1. US Food and Drug Administration. FDA approves belzutifan with pembrolizumab for adjuvant treatment of renal cell carcinoma. June 12, 2026. Accessed June 12, 2026. https://tinyurl.com/ctdeyjpw

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. 2026;44(suppl 7):LBA418. doi:10.1200/JCO.2026.44.7_suppl.LBA418

3. 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