Sponsor: Merck Sharp & Dohme LLC (industry)
Phase: 3
Start date: April 9, 2026
Planned enrollment: 758
Zanzalintinib (XL092) is an investigational, orally administered multikinase inhibitor being developed for solid tumors, both alone and with immune-checkpoint inhibitors. The most mature evidence comes from metastatic colorectal cancer (mCRC); studies are also evaluating renal cell, head and neck, prostate, liver, and other cancers. (pubmed.ncbi.nlm.nih.gov)
Zanzalintinib inhibits receptor tyrosine kinases involved in angiogenesis, tumor growth, metastasis, treatment resistance, and immune suppression—notably VEGFR2, MET, and the TAM-family kinases TYRO3, AXL, and MER. This profile provides the rationale for combining it with PD-1/PD-L1 checkpoint inhibitors. Its reported half-life of approximately 16–22 hours supports once-daily dosing. (cancer.gov)
Metastatic colorectal cancer: In the randomized phase 3 STELLAR-303 trial, 901 previously treated patients with non-MSI-H/non-dMMR mCRC received zanzalintinib plus atezolizumab or regorafenib. Median overall survival was 10.9 versus 9.4 months, respectively (hazard ratio 0.80; 95% CI 0.69–0.93; p=0.0045). Objective response rates were 4% versus 1%, and disease-control rates were 54% versus 41%. In the subgroup without liver metastases, final median survival was 15.9 versus 12.7 months, but the difference was not statistically significant (HR 0.83; p=0.1185). (pubmed.ncbi.nlm.nih.gov)
Earlier phase 1 STELLAR-001 results in refractory mCRC found response rates of 7.4% with zanzalintinib–atezolizumab and 1.9% with zanzalintinib alone; median progression-free survival was 4.0 and 3.0 months, respectively. (ascopubs.org)
Renal cell carcinoma: Early, nonrandomized results also suggest activity. Single-agent zanzalintinib produced a 38% response rate and 88% disease-control rate in 32 previously treated patients with clear-cell RCC. In first-line STELLAR-002, zanzalintinib plus nivolumab produced a 63% response rate in 40 patients, whereas the combination with nivolumab and relatlimab produced a 33% response rate in a separate 40-patient cohort. These findings remain preliminary and require confirmation in randomized trials. (ascopubs.org)
In STELLAR-303, grade 3 or worse treatment-related adverse events occurred in 60% of patients receiving zanzalintinib–atezolizumab and 37% receiving regorafenib. The most common severe treatment-related events with the combination were hypertension (15%), proteinuria (6%), fatigue (6%), and diarrhea (6%). Treatment-related deaths occurred in five patients (1%) receiving the combination and one patient receiving regorafenib. (pubmed.ncbi.nlm.nih.gov)
Across early studies, frequently reported toxicities included diarrhea, nausea, decreased appetite, fatigue, and hypertension. Dose reductions were common in the renal-cell carcinoma combinations, although treatment discontinuation rates were relatively low in the zanzalintinib–nivolumab cohort. (ascopubs.org)
Last updated: Sep 2026
Goal: To determine whether adding zanzalintinib to belzutifan improves progression-free survival and overall survival compared with belzutifan alone in advanced renal cell carcinoma previously treated with both PD-1/PD-L1 and VEGF-targeted tyrosine kinase inhibitor therapy.
Patients: Participants have unresectable stage IV renal cell carcinoma with a clear-cell component, with or without sarcomatoid features, measurable disease by RECIST 1.1, and progression on or after both PD-1/PD-L1 and VEGF-TKI therapy given sequentially or in combination. No more than three prior systemic regimens are permitted, including only one prior anti-PD-1/PD-L1 therapy. Important exclusions include resting oxygen saturation below 92% or supplemental oxygen use, current pneumonitis/interstitial lung disease, clinically significant cardiovascular disease, left ventricular ejection fraction of 50% or lower, recent major surgery or deep-vein thrombosis, active hepatitis B or C, HIV infection, solid-organ transplantation, and another recently active malignancy.
Design: Phase 3, randomized, double-blind, placebo-controlled treatment study. Participants are assigned to belzutifan plus zanzalintinib or belzutifan plus a matching placebo. Tumor progression and responses are assessed by blinded independent central review using RECIST 1.1.
Treatments: The experimental arm receives oral belzutifan 120 mg plus oral zanzalintinib 60 mg once daily for approximately 24 months. The comparator arm receives oral belzutifan 120 mg plus zanzalintinib-matching placebo once daily for approximately 24 months. Belzutifan is an oral HIF-2α inhibitor and an established targeted treatment option in advanced clear-cell RCC. Zanzalintinib, also called XL092, is an investigational oral multikinase inhibitor targeting VEGFR2, MET, and the TAM kinases TYRO3, AXL, and MER, pathways involved in angiogenesis, tumor growth, and tumor-associated immunosuppression. In an early-phase cohort of 32 heavily pretreated clear-cell RCC patients, zanzalintinib produced a 38% objective response rate, an 88% disease-control rate, and median progression-free survival of 9 months; grade 3 treatment-related adverse events occurred in 44%, with no grade 4 or 5 treatment-related events reported.
Outcomes: The co-primary outcomes are progression-free survival by blinded independent central review, assessed for up to approximately 30 months, and overall survival, assessed for up to approximately 50 months. Secondary outcomes include confirmed objective response rate, duration of response, adverse events, and treatment discontinuations due to adverse events. Patient-reported outcomes include changes and time to deterioration in global health and quality of life, physical functioning, and role functioning using the EORTC QLQ-C30, as well as kidney cancer symptoms using the FKSI-DRS.
Burden on patient: Estimated burden is moderate. Both regimens are once-daily oral therapies, avoiding routine infusion visits, but treatment may continue for approximately two years and requires regular clinic assessments, laboratory monitoring, safety evaluations, and serial imaging for RECIST-based disease assessment. Participants must also complete repeated quality-of-life and symptom questionnaires. No mandatory research biopsy or intensive pharmacokinetic blood-draw schedule is described, so the procedural burden appears broadly comparable to that of a closely monitored oral systemic therapy trial, although travel and follow-up may continue for survival assessment for about four years.
Last updated: Sep 2026
Inclusion Criteria:
The main inclusion criteria include but are not limited to the following:
* Has a histologically confirmed diagnosis of unresectable, advanced renal cell carcinoma (RCC) with clear cell component (with or without sarcomatoid features) ie, Stage IV RCC per American Joint Committee on Cancer (8th Edition)
* Has measurable disease per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1)
* Has received no more than 3 prior systemic regimens for RCC, including only 1 prior anti-Programmed Cell Death-1/Programmed Cell Death 1 Ligand 1 therapy
Exclusion Criteria:
For exclusion criteria: The main exclusion criteria include but are not limited to the following:
* Has any of the following: a pulse oximeter reading \<92% at rest, requires intermittent supplemental oxygen, or required chronic supplemental oxygen
* Has clinically significant cardiovascular disease within 12 months from first dose of study intervention
* Has 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
* Has current pneumonitis/interstitial lung disease
* Has a history of human immunodeficiency virus infection
* Has Hepatitis B or Hepatitis C virus infection
* Has a known additional malignancy that is progressing or has required active treatment within the past 3 years
* Has a history of solid organ transplant
* Has not adequately recovered from major surgery or has ongoing surgical complications
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