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Combination belzutifan plus zanzalintinib for recurrent clear cell renal cell carcinoma after anti‑PD‑(L)1 adjuvant therapy

A Phase 1b/2 Study of Immune and Targeted Combination Therapies in Participants With RCC (KEYMAKER-U03): Substudy 03C in Participants With Recurrent Disease During or After Anti-PD-(L)1 Adjuvant Therapy

Phase1; Phase2 Interventional Merck Sharp & Dohme LLC · NCT07049926

This study tests whether combining belzutifan and zanzalintinib is safe and active for people whose clear cell renal cell carcinoma came back during or within 24 months after anti‑PD‑(L)1 adjuvant therapy.

Quick facts

PhasePhase1; Phase2
Study typeInterventional
Enrollment140 (estimated)
Ages18 Years to 120 Years
SexAll
SponsorMerck Sharp & Dohme LLC Industry-sponsored
Drugs / interventionsradiation
Locations28 sites (San Francisco, California and 27 other locations)
Trial IDNCT07049926 on ClinicalTrials.gov

What this trial studies

Substudy 03C enrolls participants with recurrent clear cell renal cell carcinoma after prior adjuvant anti‑PD‑(L)1 therapy and gives an oral combination of belzutifan (a HIF‑2α inhibitor) and zanzalintinib (a VEGFR‑targeted agent). The trial includes a safety lead‑in phase to establish a tolerable dose and an efficacy phase to measure clinical activity such as response and duration. Participants must provide tumor tissue, be able to take oral medication, and have controlled blood pressure among other eligibility requirements. There is no formal hypothesis testing; the focus is on safety, tolerability, and signals of anti‑tumor activity to inform further development.

Who should consider this trial

Good fit: Adults with unresectable locally advanced or metastatic clear cell RCC whose disease recurred during or within 24 months after finishing adjuvant anti‑PD‑(L)1 therapy, who have had no other prior systemic therapy for advanced disease (aside from that adjuvant PD‑(L)1), can swallow oral meds, and can provide tumor tissue are ideal candidates.

Not a fit: Patients with non‑clear cell histology, those who received prior systemic therapy for advanced RCC beyond adjuvant PD‑(L)1, those with recurrence more than 24 months after adjuvant PD‑(L)1, or those with uncontrolled hypertension or inability to provide tumor tissue are unlikely to benefit from this substudy.

Why it matters

Potential benefit: If successful, this combination could offer a new treatment option that controls recurrent ccRCC after prior adjuvant anti‑PD‑(L)1 therapy.

How similar studies have performed: HIF‑2α inhibitors and VEGFR‑targeted agents have shown single‑agent and combination activity in RCC in prior studies, but this specific belzutifan plus zanzalintinib approach in the setting of recurrence after adjuvant PD‑(L)1 remains largely investigational.

Eligibility criteria

Show full inclusion / exclusion criteria 
The main inclusion criteria include but are not limited to the following:

* Has a histologically confirmed diagnosis of unresectable locally advanced/metastatic renal cell carcinoma (RCC) with clear cell component
* Has received no other prior systemic therapy for treatment of advanced/metastatic clear cell renal cell carcinoma (ccRCC) except for adjuvant programmed cell death ligand 1 (PD-(L)1) therapy
* Has disease recurrence during adjuvant anti- PD-(L)1 therapy or ≤24 months following the last dose of adjuvant anti-PD-(L)1 therapy
* Is able to swallow oral medication
* Submits an archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated
* Participants receiving bone resorptive therapy (must have therapy initiated at least 2 weeks before allocation/randomization)
* Has adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP ≤140/90 mm Hg with no change in antihypertensive medications within 1 week before allocation/randomization
* Has adequate organ function

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

* Has clinically significant hematuria, hematemesis, or hemoptysis of (\>2.5 mL) of red blood, or other history of significant bleeding
* Has clinically significant cardiovascular disease within 12 months from first dose of study intervention
* Has deep vein thrombosis within 3 months before allocation/randomization unless stable, asymptomatic, and treated with therapeutic anticoagulation for at least 4 weeks before allocation/randomization
* Has history of idiopathic pulmonary fibrosis, organizing pneumonia, or evidence of active pneumonitis
* Has serious wound, ulcer or bone fracture or has had major surgery within 8 weeks before first dose of study intervention
* Has symptomatic pleural effusion (for example cough, dyspnea, pleuritic chest pain), ascites, or pericardial fluid requiring drainage in the last 4 weeks before allocation/randomization
* Has gastrointestinal (GI) disorders, including those associated with a high risk of perforation or fistula formation
* Has malabsorption due to prior GI surgery or GI disease
* Has moderate to severe hepatic impairment
* Has received colony-stimulating factors within 28 days prior to intervention allocation/randomization
* Has received prior radiotherapy within 2 weeks of start of study intervention, or has radiation-related toxicities, requiring corticosteroids
* Is currently receiving strong inhibitors of cytochrome P450 3A4 (CYP3A4) that cannot be discontinued for the duration of the study
* Has received a live or live attenuated vaccine within 30 days before the first dose of study intervention
* Is currently receiving anticoagulants or platelet inhibitors that cannot be discontinued for the duration of the study
* Have been previously allocated/randomized to study intervention in any sub study of protocol MK-3475-U03
* Has a known additional malignancy that is progressing or has required active treatment within the past 3 years
* Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis
* Has radiographic evidence of encasement or invasion of a major blood vessel, or of intratumoral cavitation
* Has active autoimmune disease that has required systemic treatment in the past 2 years
* Has an active infection requiring systemic therapy
* Has history of human immunodeficiency virus (HIV) infection
* Has hepatitis B or hepatitis C virus infection

Where this trial is running

San Francisco, California and 27 other locations

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 →
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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.