The FDA has approved belzutifan plus pembrolizumab as adjuvant treatment for ccRCC. LITESPARK-022: a 28% improvement in DFS, with 24-month DFS of 80.7% versus 73.7% (HR 0.72).
On 12 June 2026 the FDA approved the combination of belzutifan and pembrolizumab as adjuvant treatment for patients with clear cell renal cell carcinoma (ccRCC) at high or intermediate-high risk of recurrence after nephrectomy
16 June 2026 | Source: FDA, Urology Times, ASCO GU 2026, Dana-Farber Cancer Institute | Topic: Kidney Cancer / Uro-Oncology
KEY FINDINGS
- Approval: On 12 June 2026 the FDA approved belzutifan (Welireg) plus pembrolizumab (Keytruda) as adjuvant treatment in ccRCC at high risk of recurrence after nephrectomy - the first FDA approval for a PD-1 plus HIF-2α inhibitor combination.
- LITESPARK-022 phase 3: Adding belzutifan significantly improved disease-free survival (DFS) by 28% compared with pembrolizumab monotherapy (HR 0.72; 95% CI 0.59-0.87; p=0.0003).
- 24-month DFS rate: 80.7% (combination) versus 73.7% (monotherapy).
- Review process: Conducted under Project Orbis with the participation of Australia's TGA and Health Canada.
Background and Study Design
Clear cell renal cell carcinoma (ccRCC) accounts for approximately 75% of renal cell carcinoma cases. For patients at intermediate-high or high risk of recurrence after nephrectomy, systemic adjuvant treatment remained inadequate for many years. The adjuvant approval of pembrolizumab in 2021 was an important first step; however, recurrence risk still remained significant.
Belzutifan (Welireg) is an oral inhibitor targeting HIF-2α (hypoxia-inducible factor 2 alpha). Suppressing the HIF-2α pathway, which is hyperactivated in ccRCC because of VHL mutation, stands out as a strategy specific to this tumour type.
Study Design
LITESPARK-022 (NCT05239728) is a multicentre, double-blind, randomized controlled phase 3 trial. It enrolled 1,841 patients with histologically confirmed ccRCC who had undergone nephrectomy and were at intermediate-high or high risk of recurrence, or who had undergone metastasectomy for M1 disease.
| Parameter | Value |
|---|---|
| Total number of patients | 1,841 patients |
| Randomization | 1:1 |
| Combination arm | Pembrolizumab 400 mg every 6 weeks (≤9 cycles, ~12 months) + belzutifan 120 mg orally once daily (≤54 weeks) (n=921) |
| Control arm | Pembrolizumab 400 mg every 6 weeks + placebo once daily (n=920) |
| Primary endpoint | Investigator-assessed disease-free survival (DFS) |
| Secondary endpoints | Overall survival (OS) and safety |
| Median follow-up | 28.4 months |
Key Results
Median DFS was not reached in either arm, a finding that points to the long-term efficacy of the combination. Overall survival (OS) data are not yet mature.
| Endpoint | Belzutifan + Pembrolizumab | Placebo + Pembrolizumab |
|---|---|---|
| Median DFS | Not reached | Not reached |
| 24-month DFS rate | 80.7% (95% CI 77.7-83.2) | 73.7% (95% CI 70.6-76.6) |
| DFS hazard ratio | 0.72 (95% CI 0.59-0.87) - p=0.0003 | |
| OS hazard ratio (immature) | 0.78 (95% CI 0.51-1.19) - p=0.1220 | |
| Patients completing treatment | 69.5% (n=636) | 71.1% (n=649) |
Safety Profile
| Safety Parameter | Belzutifan + Pembro | Placebo + Pembro |
|---|---|---|
| Grade ≥3 adverse events | 52.1% | 30.2% |
| Serious treatment-related AEs | 29.5% | 19.9% |
| Anaemia (grade ≥3) | 12.1% | 0.5% |
| ALT elevation (grade ≥3) | 6.4% | 2.0% |
| Hypoxia (grade ≥3) | 4.6% | 0% |
| Grade 5 treatment-related AEs | 1.1% | 1.2% |
Important safety warnings: The belzutifan prescribing information includes a boxed warning for embryo-fetal toxicity and warnings for anaemia and hypoxia. For pembrolizumab there are warnings regarding immune-mediated adverse reactions, infusion reactions and complications of allogeneic haematopoietic stem cell transplantation.
FDA-approved dosing regimens: Belzutifan (Welireg) 120 mg orally once daily - until disease recurrence, unacceptable toxicity or a maximum of 54 weeks. Pembrolizumab (Keytruda) IV: 200 mg every 3 weeks or 400 mg every 6 weeks, for up to 12 months. Pembrolizumab plus berahyaluronidase alfa-pmph (Keytruda Qlex) SC: 395 mg/4,800 units every 3 weeks or 790 mg/9,600 units every 6 weeks, for up to 12 months.
Implications for Clinical Practice
1. A candidate for a new standard
Adding belzutifan to adjuvant pembrolizumab after nephrectomy in ccRCC at intermediate-high or high risk of recurrence improves DFS by 28%, making it a candidate for a new treatment standard.
2. Toxicity management comes to the fore
The rise in grade ≥3 adverse events to 52.1% in the combination arm (control: 30.2%) makes monitoring for anaemia and hypoxia in particular mandatory. Routine full blood count and oxygenation monitoring take on critical clinical importance.
3. Patient selection
The approval is limited to the intermediate-high/high risk or M1-NED population; the place of this combination in low-risk patients is not clear.
Conclusion
This FDA approval on 12 June 2026 represents an important turning point in adjuvant ccRCC treatment. Data from the LITESPARK-022 trial demonstrate that belzutifan plus pembrolizumab provides a significant DFS advantage over pembrolizumab monotherapy (HR 0.72; p=0.0003). While the toxicity profile is manageable, it requires intensified monitoring; maturation of the overall survival data remains critical for this combination to take a full place in clinical algorithms.
For urologists and oncologists, this approval is set to reshape post-nephrectomy treatment planning in high-risk ccRCC patients.
Dr Toni K. Choueiri of the Dana-Farber Cancer Institute commented: "We waited for decades and we finally have a systemic therapy that can reduce the risk of kidney cancer recurrence and death. Belzutifan reduces the risk of recurrence by roughly a further 30%; this is an extremely welcome development."
References
- FDA approves belzutifan with pembrolizumab for adjuvant treatment of renal cell carcinoma. U.S. Food and Drug Administration. 12 June 2026. - fda.gov
- Clarke H. FDA approves adjuvant belzutifan with pembrolizumab for ccRCC. Urology Times. 12 June 2026. - urologytimes.com
- 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. 2026 ASCO GU Cancers Symposium, Abstract LBA418. - ascopubs.org
- Dana-Farber Research Supports FDA Approval of Pembrolizumab-Belzutifan Combination for Higher-Risk Clear Cell Kidney Cancer After Surgery. Dana-Farber Cancer Institute. 12 June 2026. - dana-farber.org
Important Note: This article is compiled from scientific publications for general information purposes only and does not constitute individual medical advice. Always consult your physician regarding treatment decisions.
Dr. Murat Binbay - Urology, Uro-Oncology and Robotic Surgery
