Investigational Drug
Zanzalintinib
HealthScout AI Analysis
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Overview
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)
Mechanism of action
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)
Efficacy
- Clear cell RCC (previously treated; monotherapy, phase 1b STELLAR‑001 expansion)
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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)
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Clear cell RCC (treatment‑naïve; combinations, phase 1b/2 STELLAR‑002 expansion; preliminary)
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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)
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Metastatic colorectal cancer, non–MSI‑H/dMMR, RAS‑WT (refractory; phase 1 STELLAR‑001 randomized expansion)
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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)
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Ongoing randomized studies
- STELLAR‑303 (phase 3): zanzalintinib + atezolizumab vs regorafenib in previously treated non–MSI‑H mCRC; primary endpoint OS (patients without liver metastases). (ascopubs.org)
- STELLAR‑304 (phase 3): zanzalintinib + nivolumab vs sunitinib in treatment‑naïve nccRCC. (ascopubs.org)
- STELLAR‑305 (phase 2/3): zanzalintinib + pembrolizumab vs pembrolizumab in PD‑L1–positive recurrent/metastatic HNSCC. (ascopubs.org)
- Additional investigator‑initiated phase 2 in mCRPC after 177Lu‑PSMA‑617 progression (single‑arm; enrolling). (ascopubs.org)
Safety
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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)
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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)
Further reading
- Preclinical characterization of XL092 (mechanism, immune effects). (aacrjournals.org)
- STELLAR‑001 mCRC randomized expansion results (ASCO GI 2025). (ascopubs.org)
- STELLAR‑303 phase 3 design in non–MSI‑H mCRC (ASCO 2024). (ascopubs.org)
- STELLAR‑001 ccRCC expansion biomarker analysis and summary of monotherapy activity. (ascopubs.org)
- STELLAR‑304 phase 3 design in nccRCC (ASCO 2024). (ascopubs.org)
- STELLAR‑305 phase 2/3 design in HNSCC (ASCO 2024). (ascopubs.org)
- Sponsor summary of STELLAR‑002 RCC combination expansion (ASCO 2025). (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
Active trials using Zanzalintinib
Found 9 active trials using this drug:
HealthScout AI summary: Adults with unresectable/metastatic leiomyosarcoma or adipocytic sarcoma (excluding pure WD LPS and low‑grade LMS), ECOG 0–1, after 1–4 prior lines receive eribulin (D1,8 q21d) plus oral zanzalintinib (XL092), a multi‑target TKI of VEGFR2/MET/TAM kinases aimed at anti‑angiogenic and immunomodulatory effects. Allows treated/stable brain mets; key exclusions include significant CV disease, bleeding risk, GI perforation risk, moderate–severe hepatic impairment, and prior zanzalintinib.
ClinicalTrials.gov ID: NCT06957431
HealthScout AI summary: Adults with unresectable or metastatic clear cell RCC (± sarcomatoid) that recurred during adjuvant anti–PD-(L)1 or within 24 months after completion, without prior VEGF/TKI or HIF-2α therapy, receive oral zanzalintinib (VEGFR2/MET/TAM multi-TKI) plus belzutifan (HIF‑2α inhibitor). Open-label, nonrandomized cohorts explore two zanzalintinib dose levels to assess safety and preliminary efficacy (ORR by BICR).
ClinicalTrials.gov ID: NCT07049926
HealthScout AI summary: Single-arm study of zanzalintinib (XL092), an oral multikinase inhibitor of VEGFR2, MET, and TAM (TYRO3/AXL/MER), as first-line systemic therapy in adults with locally advanced or metastatic radioiodine-refractory differentiated thyroid cancer (papillary, follicular, oncocytic/Hürthle, or poorly differentiated) with RECIST-measurable disease and recent progression. Excludes prior systemic therapy in the RAI-refractory setting and patients with active brain mets or significant cardiovascular/GI risk; daily dosing in 21-day cycles until progression or toxicity.
ClinicalTrials.gov ID: NCT06959641
HealthScout AI summary: Adults with well-differentiated (Grade 1–3) unresectable or metastatic pancreatic or extra-pancreatic NETs with recent RECIST-defined progression and no prior VEGFR TKI or mTOR inhibitor are randomized to zanzalintinib (XL092, an oral multi-kinase inhibitor of VEGFR2/MET/TAM) versus everolimus. Excludes NECs and select NET subtypes; primary endpoint is PFS by blinded central review.
ClinicalTrials.gov ID: NCT06943755
HealthScout AI summary: Adults with advanced/metastatic clear cell RCC who progressed on or after adjuvant anti–PD-1/PD-L1 therapy (no prior systemic therapy otherwise) are randomized to zanzalintinib (XL092), an oral multi-targeted TKI of VEGFR2/MET/TAM kinases, versus XL092 plus nivolumab (PD-1 inhibitor). Key exclusions include untreated/unstable CNS mets and active autoimmune disease requiring immunosuppression.
ClinicalTrials.gov ID: NCT06863311
HealthScout AI summary: Adults with recurrent high-grade uterine/endometrial cancers (FIGO grade 3 endometrioid, serous, mixed high-grade, or carcinosarcoma) after platinum, ECOG 0–2, measurable disease, and prior HER2- or immune-therapy as appropriate, receive paclitaxel plus zanzalintinib (XL092), an oral multi-targeted TKI inhibiting VEGFR2, MET, and TAM kinases, with maintenance zanzalintinib for responders/stable disease. Excludes prior TKIs/bevacizumab, uncontrolled CV disease, high-risk bleeding/GI conditions, and untreated/unstable CNS disease.
ClinicalTrials.gov ID: NCT06795009
HealthScout AI summary: Adults with unresectable, systemic therapy–naïve HCC (ECOG 0–1, Child-Pugh A) receive triplet therapy with zanzalintinib (XL-092; oral multikinase TKI targeting VEGFR2/MET/TAM), durvalumab (PD-L1 inhibitor) every 4 weeks, and a single priming dose of tremelimumab (CTLA-4 inhibitor), with cohorts exploring sequencing (TKI lead-in vs immediate I/O). Excludes prior PD-1/PD-L1/CTLA-4 or MET/VEGFR TKIs, significant autoimmune disease, active viral hepatitis/HIV, and high bleeding risk; mandatory baseline tumor tissue required.
ClinicalTrials.gov ID: NCT06698250
HealthScout AI summary: Adults with radiographic mCRPC who have progressed after 177Lu‑PSMA‑617 receive oral zanzalintinib (XL092) monotherapy once daily. XL092 is an investigational multikinase TKI targeting VEGFR2, MET, and TAM kinases (TYRO3/AXL/MER) to inhibit angiogenesis and tumor growth; primary endpoint is 16‑week disease control.
ClinicalTrials.gov ID: NCT06568562
HealthScout AI summary: Adults with metastatic or unresectable leiomyosarcoma after at least two prior systemic regimens (≤2 prior TKIs), ECOG 0–1, receive oral zanzalintinib (XL092), a multi-kinase inhibitor of VEGFR2, MET, and TAM (TYRO3/AXL/MER), given continuously in 14‑day cycles until progression/toxicity. Key exclusions include prior XL092, significant cardiovascular/bleeding risk, unstable CNS disease, and concurrent oral anticoagulants.
ClinicalTrials.gov ID: NCT06571734
