Skip to content

LITESPARK-022 — Adjuvant pembrolizumab + belzutifan vs pembrolizumab monotherapy in high-risk clear cell RCC

Abstract: LBA418 · Session: Oral Abstract Session — RCC, Day 1 (Thu Feb 26, 2026), Moscone West · Embargo: lifted on presentation

Headline: Adding belzutifan to adjuvant pembrolizumab cut the risk of disease recurrence or death by 28% (DFS HR 0.72, 95% CI 0.59–0.87, p=0.0003) in resected high-risk ccRCC — the first IO + HIF-2α adjuvant combination to clear a Ph3 primary endpoint.

At a glance

  • Sponsor: Merck
  • PI / presenter: Toni Choueiri (Dana-Farber Cancer Institute)
  • NCT ID: NCT05239728
  • Phase: 3
  • Design: Double-blind, 1:1 randomization, adjuvant pembro + belzutifan vs pembro + placebo for up to ~17 cycles post-nephrectomy
  • N: ~1,600 randomized, high-risk ccRCC (post-nephrectomy ± metastasectomy)
  • Primary endpoint(s): DFS by investigator assessment
  • Comparator: Pembrolizumab monotherapy (the post-KEYNOTE-564 adjuvant SOC)
  • Indication: High-risk clear cell RCC, post-nephrectomy
  • Line: Adjuvant

Headline result

DFS HR 0.72 (95% CI 0.59–0.87, p=0.0003), reported at the protocol-specified interim. OS event count immature; trend reportedly favors the combination but not formally tested. Safety: known belzutifan anemia / hypoxia signal additive with pembro; treatment discontinuation rates manageable, no new safety signals.

Mechanism / class

Belzutifan: oral HIF-2α inhibitor, first-in-class. Approved 2021 for VHL-associated tumors; expanded to 3L+ advanced ccRCC (LITESPARK-005) in 2023. Pembrolizumab adjuvant established by KEYNOTE-564 (DFS positive 2021; OS positive ESMO 2024). LITESPARK-022 combines two mechanistically complementary classes — checkpoint inhibition + hypoxia-pathway disruption.

Trial design deep dive

Study architecture. Double-blind, placebo-controlled Ph3, 1:1 randomization, ~1,600 post-nephrectomy high-risk ccRCC patients. Experimental arm: pembrolizumab 400 mg IV q6w + belzutifan 120 mg PO daily for up to ~17 cycles (~12 months); control arm: pembro + matched placebo on the same schedule. Stratification factors (per ClinicalTrials.gov): geographic region, recurrence-risk category (intermediate-high vs high vs M1 NED post-metastasectomy), and PD-L1 status.

Endpoint definitions. Primary: investigator-assessed DFS (time from randomization to first documented local/regional recurrence, distant metastasis, second primary, or death). Key secondaries: OS, DFS by BICR, safety, PRO (FKSI-DRS, EORTC QLQ-C30).

Key subgroup analyses. - Risk-category strata (intermediate-high vs high vs M1 NED) — DFS benefit reportedly consistent; M1 NED magnitude TBD given small N. - PD-L1 CPS — TBD in abstract; expected supportive subgroup. - Sarcomatoid histology — TBD; KEYNOTE-564 showed enhanced pembro benefit here. - Prior metastasectomy vs nephrectomy-only — TBD.

Comparator context. Pembrolizumab monotherapy became adjuvant SOC after KEYNOTE-564 (DFS positive 2021; OS positive ESMO 2024, NEJM 2024). LITESPARK-022 is the first trial to add a second mechanism on top of an already-effective adjuvant IO, raising the bar above an active comparator rather than placebo.

FDA / regulatory implications. Merck sNDA was under FDA priority review at time of GU readout (per pre-meeting press release); PDUFA action anticipated mid-2026. Filing leverages the LITESPARK-005 mCRPC-equivalent (3L+ ccRCC) accelerated approval and the new adjuvant Ph3. NCCN kidney guideline anticipated to add the combination as a preferred adjuvant option following FDA action; OS-mature data still needed for category-1 listing.

Discussant takeaway

Discussant (Robert J. Motzer, MSK) framed it as the "second pillar" of adjuvant ccRCC after KEYNOTE-564 — but cautioned that the absolute DFS benefit is modest in a population where pembro monotherapy is already effective. David McDermott (BIDMC) emphasized the tolerability question for an ~12-month adjuvant course.

Practice-changing verdict

Yes — with caveats. Merck's sNDA was already under FDA priority review at time of GU readout, with PDUFA action anticipated mid-2026. NCCN kidney guideline anticipated to add the combination as a preferred adjuvant option following FDA action. Open question: OS magnitude — the DFS-to-OS conversion for adjuvant ccRCC has historically been uncertain (KEYNOTE-564 took ~5 years for OS).

  • ASCO 2026 main: OS interim update expected (forward-looking)
  • ESMO 2026: likely venue for OS-mature readout
  • AACR 2026 GU sessions: HIF-2α mechanism / belzutifan biology
  • Other ASCO GU 2026 trials: LITESPARK-011 (2L belzutifan + lenvatinib vs cabozantinib)

Sources