Sponsor: Merck Sharp & Dohme LLC (industry)
Phase: 3
Start date: Nov. 26, 2025
Planned enrollment: 904
Zanzalintinib (XL092) is an investigational, oral multi‑target tyrosine kinase inhibitor (TKI) being developed by Exelixis. It is being studied across multiple solid tumors as monotherapy and in combination with immune checkpoint inhibitors. Key ongoing randomized programs include phase 3 trials in non–MSI‑H metastatic colorectal cancer (mCRC; STELLAR‑303), non–clear cell renal cell carcinoma (nccRCC; STELLAR‑304), and PD‑L1–positive recurrent/metastatic head and neck squamous cell carcinoma (HNSCC; STELLAR‑305). (ascopubs.org)
Zanzalintinib inhibits MET, VEGFR2, and the TAM family kinases (TYRO3, AXL, MER). Preclinical work shows on‑target inhibition of MET/AXL phosphorylation and >90% inhibition of VEGFR2 phosphorylation in vivo, anti‑angiogenic effects, and immune modulation that enhances activity with PD‑1/PD‑L1 blockade. These data support combining zanzalintinib with immune checkpoint inhibitors. (aacrjournals.org)
Recommended phase 2 dose from early clinical development is 100 mg once daily (maximum tolerated dose 120 mg). (businesswire.com)
n=32; objective response rate (ORR) 38% (all partial responses); disease control rate (DCR) 88%. Responses were observed despite prior VEGFR‑TKI exposure. (ir.exelixis.com)
Clear cell RCC (treatment‑naïve; combinations, phase 1b/2 STELLAR‑002 expansion; preliminary)
Zanzalintinib + nivolumab: reported ORR 63% and DCR 90% (non‑randomized cohort, n≈40). Zanzalintinib + nivolumab/relatlimab: reported ORR 33% and DCR 90%. Results were presented at ASCO 2025; a peer‑reviewed abstract is referenced by the sponsor release. (ir.exelixis.com)
Metastatic colorectal cancer, non–MSI‑H/dMMR, RAS‑WT (refractory; phase 1 STELLAR‑001 randomized expansion)
Zanzalintinib + atezolizumab (n=54) vs zanzalintinib (n=53): ORR 7.4% vs 1.9%; median PFS 4.0 vs 3.0 months (HR 0.68); median OS 14.3 vs 11.1 months (HR 0.75). In patients without liver metastases, ORR 18.0% vs 5.9% and median PFS 8.2 vs 3.3 months (HR 0.40). (ascopubs.org)
Ongoing randomized studies
In mCRC (STELLAR‑001 expansion), the most common treatment‑related adverse events (TRAEs) with zanzalintinib ± atezolizumab were diarrhea (52%/49%), nausea (54%/36%), and decreased appetite (41%/36%). Grade 3–4 TRAEs occurred in 48% (combo) and 40% (mono); grade 5 TRAEs occurred in 2% in each arm. Treatment discontinuation due to TRAEs: 11% (zanzalintinib) and 9% (atezolizumab in the combo). (ascopubs.org)
In early RCC combination cohorts, emerging tolerability appears consistent with VEGF/MET‑targeted TKIs plus PD‑1–based therapy; detailed peer‑reviewed safety tables are pending from ASCO 2025 presentations. (ir.exelixis.com)
Notes: Zanzalintinib remains investigational; efficacy and safety have not been established and are being evaluated in ongoing trials. Where only sponsor communications are available (e.g., STELLAR‑002 combinations), figures should be interpreted as preliminary pending full peer‑reviewed publications. (ir.exelixis.com)
Last updated: Oct 2025
Goal: To determine whether belzutifan plus zanzalintinib improves progression-free survival and overall survival compared with cabozantinib in recurrent advanced clear-cell renal cell carcinoma after adjuvant anti-PD-1/L1 therapy.
Patients: Patients have histologically confirmed unresectable stage IV RCC with a clear-cell component, measurable disease by RECIST 1.1, and recurrence during adjuvant anti-PD-1/L1 therapy or within 24 months after its last dose. No prior systemic RCC therapy other than adjuvant anti-PD-1/L1 treatment is permitted. Key exclusions include significant recent cardiovascular or thromboembolic disease, left ventricular ejection fraction of 50% or lower, current pneumonitis/interstitial lung disease, dialysis, active hepatitis B or C, HIV infection, high-risk gastrointestinal disorders, and recent major surgery.
Design: Randomized, open-label, active-controlled phase 3 trial. Participants receive treatment until a protocol-defined reason for discontinuation, with efficacy followed for up to approximately 73 months. Tumor responses and progression are assessed by blinded independent central review using RECIST 1.1.
Treatments: The experimental arm receives oral belzutifan plus oral zanzalintinib once daily. Belzutifan is a HIF-2α inhibitor with established antitumor activity in RCC. Zanzalintinib, also known as XL092, is an investigational multikinase inhibitor targeting VEGFR2, MET, and the TAM kinases TYRO3, AXL, and MER, thereby affecting angiogenesis, tumor growth, and tumor-associated immunosuppression. In an early study of 32 heavily pretreated patients with clear-cell RCC, 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. The comparator arm receives oral cabozantinib once daily, an established multikinase inhibitor used in advanced RCC.
Outcomes: The co-primary endpoints are progression-free survival by blinded independent central review and overall survival, assessed for up to approximately 73 months. Secondary endpoints include objective response rate, duration of response, adverse events, and treatment discontinuations due to adverse events. Patient-reported outcomes assess global health and quality of life, physical and role functioning, and kidney cancer symptoms using the EORTC QLQ-C30 and FKSI-DRS, including changes from baseline and time to clinically meaningful deterioration, for up to approximately 25 months.
Burden on patient: Estimated burden is moderate. Both regimens are taken orally once daily, avoiding routine infusion visits, and the protocol information does not specify mandatory research biopsies or intensive pharmacokinetic sampling. However, patients will require repeated clinic visits, laboratory and safety monitoring, cardiovascular assessment as appropriate, serial imaging for RECIST evaluation, adverse-event management, and regular quality-of-life questionnaires. The potentially prolonged treatment and follow-up period, along with toxicities associated with HIF-2α and multikinase inhibition, may create meaningful cumulative travel and monitoring demands.
Last updated: Jul 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 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
* Has pharmacologically uncompensated, symptomatic hypothyroidism
* Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention
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