FDA Approves Belzutifan Plus Pembrolizumab in Adjuvant ccRCC Treatment: The LITESPARK-022 Phase 3 Trial

KEY FINDINGS

• Approval: On 12 June 2026 the FDA approved belzutifan (Welireg) plus pembrolizumab (Keytruda) as adjuvant treatment for patients with intermediate-high or high risk ccRCC after nephrectomy.
• LITESPARK-022 phase 3: 1,841 patients, a disease-free survival (DFS) advantage with HR 0.72 (95% CI 0.59-0.87; p=0.0003).
• 24-month DFS rate: 80.7% in the combination arm versus 73.7% in the control arm.
• A historic first: The first combined approval of a HIF-2α inhibitor (belzutifan) and a PD-1 inhibitor (pembrolizumab) in early-stage ccRCC.
• Safety: Overall survival data are not yet mature; the grade ≥3 adverse event rate was 52.1% in the combination arm.

Background and Clinical Context

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma. In high-risk patients undergoing nephrectomy (T3-T4, regional lymph node involvement, or surgery after oligometastatic M1 disease), the risk of recurrence remains seriously elevated.

The adjuvant-stage approval of pembrolizumab in 2021 (based on the KEYNOTE-564 trial) was a turning point in this field. However, recurrence rates that remained at significant levels in 5-year follow-up data clearly demonstrated the need for new treatment combinations.

Belzutifan, as a hypoxia-inducible factor 2α (HIF-2α) inhibitor, directly targets the tumour biology of ccRCC. HIF-2α hyperactivation associated with VHL gene mutation is one of the fundamental drivers of ccRCC. The hypothesis that belzutifan could act synergistically with pembrolizumab is based on this mechanism.

Study Design - LITESPARK-022

LITESPARK-022 (NCT05239728), a double-blind, randomized, placebo-controlled phase 3 trial, used the following criteria to define its patient population: histologically confirmed ccRCC (no prior systemic therapy), nephrectomy performed no more than 12 weeks before randomization, ECOG performance status 0-1, intermediate-high risk, high risk of recurrence, or M1 disease (after nephrectomy plus resection of metastases).

Key Results

Median DFS was not reached in either arm. The combination therapy achieved a 28% relative reduction in the risk of recurrence compared with placebo. Overall survival data were immature at the time of the interim analysis but were reported as HR 0.78 (95% CI 0.51-1.19; p=0.1220).

Safety Profile

Grade ≥3 anaemia and hypoxia specific to belzutifan are findings that require attention. Hypoxia is known to be related to belzutifan's suppressive effect on erythropoietin. Prescribing warnings include embryo-fetal toxicity and anaemia/hypoxia.

Dosing recommended by the FDA: Belzutifan (Welireg) 120 mg orally once daily - until recurrence or unacceptable toxicity, or ≤54 weeks. Pembrolizumab (Keytruda) 200 mg IV every 3 weeks or 400 mg IV every 6 weeks, ≤12 months. Pembrolizumab plus berahyaluronidase alfa-pmph (Keytruda Qlex) 395 mg/4,800 units SC every 3 weeks or 790 mg/9,600 units every 6 weeks, ≤12 months.

Implications for Clinical Practice

1. Historical significance

This approval is a historic milestone in that it is belzutifan's first approval in early-stage ccRCC and the first combination of a PD-1 inhibitor with a HIF-2α inhibitor to be approved together.

2. Expanding treatment options

Adjuvant treatment options after nephrectomy in intermediate-high and high risk ccRCC have expanded. HIF-2α inhibition plus PD-1 blockade showed a synergistic effect; however, the burden of grade ≥3 adverse events increased with combined use (52.1% versus 30.2%). Monitoring for anaemia and hypoxia should now be a routine part of adjuvant treatment.

3. The M1 NED population

The approval also covers the M1 NED population (minimal disease, operated); it is particularly valuable for this patient group. OS data are not yet mature; whether the disease-free survival advantage translates into overall survival will be monitored in follow-up studies.

Conclusion

Data from the LITESPARK-022 trial demonstrate that the HIF-2α plus PD-1 combination provides a meaningful DFS advantage beyond PD-1 monotherapy in adjuvant ccRCC treatment. This statistically and clinically meaningful result, with an HR of 0.72, made the FDA's rapid approval decision possible.

The increase in adverse event burden should not be overlooked and patient selection must be careful. As OS data mature, the long-term effect of this combination will become clearer. Nevertheless, this approval is already fundamentally changing the treatment approach in high-risk ccRCC patients after nephrectomy.

Toni K. Choueiri, MD (Dana-Farber Cancer Institute) commented: "With pembrolizumab we gained, in 2021, a systemic therapy that could reduce recurrence. Belzutifan can reduce the risk of recurrence, metastasis or death by roughly a further 30% on top of that."

References

• Clarke H. FDA approves adjuvant belzutifan with pembrolizumab for ccRCC. Urology Times. 12 June 2026. - urologytimes.com
• FDA approves adjuvant belzutifan plus pembrolizumab in ccRCC. OncLive. 2026. - onclive.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, Abstract LBA418. - ascopubs.org
• ASCO GU 2026: Adjuvant Pembrolizumab + Belzutifan versus Pembrolizumab for Clear Cell RCC. UroToday. 2026. - urotoday.com
• Dana-Farber Research Supports FDA Approval of Pembrolizumab-Belzutifan Combination for Higher-Risk Clear Cell Kidney Cancer After Surgery. Dana-Farber Cancer Institute. 2026. - dana-farber.org
• FDA approves belzutifan with pembrolizumab for adjuvant treatment of renal cell carcinoma. U.S. Food and Drug Administration. 12 June 2026. - fda.gov