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Belzutifan plus zanzalintinib versus cabozantinib for recurrent advanced kidney cancer after adjuvant PD-1/L1 therapy

A Phase 3, Randomized, Open-label Study of Belzutifan + Zanzalintinib Versus Cabozantinib in Participants With Advanced RCC Who Experienced Disease Recurrence During or After Prior Adjuvant Anti-PD-1/L1 Therapy (LITESPARK-033)

Phase 3 Interventional Merck Sharp & Dohme LLC · NCT07227402

This study will test whether taking belzutifan together with zanzalintinib helps people with recurrent advanced kidney cancer live longer and keep the cancer from getting worse compared with cabozantinib after prior adjuvant PD-1/L1 therapy.

Quick facts

PhasePhase 3
Study typeInterventional
Enrollment904 (estimated)
Ages18 Years and up
SexAll
SponsorMerck Sharp & Dohme LLC Industry-sponsored
Drugs / interventionszanzalintinib, cabozantinib
Locations108 sites (CABA, Buenos Aires and 107 other locations)
Trial IDNCT07227402 on ClinicalTrials.gov

What this trial studies

This is a randomized Phase 3 trial comparing the combination of belzutifan and zanzalintinib to cabozantinib in patients with recurrent advanced renal cell carcinoma after prior adjuvant PD-1/L1 therapy. Eligible participants have unresectable Stage IV disease with a clear cell component, measurable disease by RECIST 1.1, and recurrence during or within 24 months after adjuvant PD-1/L1, with no other prior systemic RCC therapy allowed. The primary outcomes include overall survival and progression-free survival, with patients followed by regular imaging and clinical assessments. Study sites for enrollment are located in Buenos Aires, Argentina.

Who should consider this trial

Good fit: Adults with unresectable, advanced clear-cell renal cell carcinoma that recurred during or within 24 months after adjuvant PD-1/L1 therapy, who have measurable disease and have not received prior systemic therapy other than adjuvant PD-1/L1, are the intended candidates.

Not a fit: Patients with significant recent cardiovascular disease, non–clear-cell histology, prior systemic RCC treatments beyond adjuvant PD-1/L1, or who cannot travel to the Buenos Aires sites are unlikely to be eligible or receive benefit.

Why it matters

Potential benefit: If successful, the belzutifan plus zanzalintinib combination could help patients live longer and delay cancer progression compared with current cabozantinib treatment.

How similar studies have performed: Cabozantinib is an established approved therapy for advanced RCC and belzutifan has shown activity in RCC settings, but the specific belzutifan plus zanzalintinib combination compared directly to cabozantinib is novel and has not been proven in large Phase 3 trials.

Eligibility criteria

Show full inclusion / exclusion criteria 
Inclusion Criteria:

The main inclusion criteria include but are not limited to the following:

* Has a histologically confirmed diagnosis of unresectable, advanced renal cell cancer (RCC) with clear cell component (with or without sarcomatoid features) i.e., Stage IV renal cell cancer per American Joint Committee on Cancer (AJCC) (8th Edition)
* Has measurable disease per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1)
* Has disease recurrence during adjuvant anti-programmed cell death 1/programmed cell death ligand 1 (PD-1/L1) therapy or recurrence ≤24 months following the last dose of adjuvant anti-PD-1/L1 therapy
* Has received no other prior systemic therapy for their RCC except for their adjuvant anti-PD-1/L1 therapy

Exclusion Criteria:

The main exclusion criteria include but are not limited to the following:

* Has clinically significant cardiovascular disease within 12 months from first dose of study intervention, including New York Heart Association Class III or IV congestive heart failure, unstable angina, new-onset angina, pulmonary embolism, myocardial infarction, cerebral vascular accident, or cardiac arrhythmia associated with hemodynamic instability
* Had deep vein thrombosis within 3 months before randomization unless stable, asymptomatic, and treated with therapeutic anticoagulation for at least 4 weeks before randomization
* Has a left ventricular ejection fraction ≤50% or below the institutional (or local laboratory) normal range as determined by multigated acquisition or echocardiogram
* Has had major surgery within 8 weeks before randomization or has not adequately recovered from major surgery or has ongoing surgical complications
* Has current pneumonitis/interstitial lung disease
* Has symptomatic pleural effusion (for example cough, dyspnea, pleuritic chest pain), ascites, or pericardial fluid requiring drainage within 4 weeks prior to randomization
* Has a gastrointestinal disorder including those associated with a high risk of perforation or fistula formation
* Has a serious active nonhealing wound/ulcer/bone fracture
* Has a requirement for hemodialysis or peritoneal dialysis
* Has history of human immunodeficiency virus infection
* Has hepatitis B or hepatitis C virus
* Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention

Where this trial is running

CABA, Buenos Aires and 107 other locations

+58 more sites — see ClinicalTrials.gov for the full list.

Study contacts

How to participate

  1. Review the eligibility criteria above with your treating physician.
  2. Visit the official trial page on ClinicalTrials.gov for the most current contact information and recruitment status.
  3. Contact the listed study coordinator or principal investigator to request pre-screening. Pre-screening is free and never obligates you to enroll.
View on ClinicalTrials.gov → Find more trials like this →
Conditions Renal Cell CarcinomaCarcinomaRenal cellBelzutifanZanzalintinib
Last reviewed 2026-06-13 by the Find a Trial editorial team. Information on this page is for educational purposes and is not medical advice. Always consult qualified healthcare professionals about clinical trial participation.