A Phase 2, Single-Arm, Multicenter, Open-Label Study of Zanzalintinib in Participants With Recurrent or Progressive Meningioma

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)

• 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

• 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

• 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)

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

Key Inclusion Criteria:

* Histologically confirmed World Health Organization (WHO) grade 1, 2, or 3 meningioma.

* Developed recurrent disease or progressive disease (PD) after receiving standard therapy (for example, surgery and/or radiation) or have been deemed ineligible to receive these therapies. At least 1 prior course of meningioma-directed radiotherapy is required, if not contraindicated.

* Radiologically documented progression of any existing tumor (growth \> 15% of the bidimensional enhancing tumor within the prior 6 months or appearance of new lesions (including intra and extracranial manifestations).

* For participants treated with external beam radiation, interstitial brachytherapy, or radiosurgery, an interval ≥ 24 weeks must have elapsed from completion of therapy to initiation of treatment.

* Measurable disease by RANO meningioma criteria as determined by the investigator, obtained ≤ 14 days prior to initiation of treatment.

* Karnofsky performance status (KPS) ≥ 60%.

* Demonstrate adequate organ and marrow function within 14 days of treatment initiation

Key Exclusion Criteria:

* Prior history of hypertensive encephalopathy at any time.

* Extracranial lesions invading major blood vessels including, but not limited to, inferior vena cava, pulmonary artery, or aorta.

* Contraindication to magnetic resonance imaging (MRI).

* Local therapy (surgery and/or radiation therapy) is indicated per investigator

* Receipt of any type of cytotoxic, biologic or other systemic anticancer therapy (including investigational) within 4 weeks or 5 half-lives, whichever is shorter, before initiation of treatment. There is no limit on prior systemic therapies

* Prior Surgery - completed wound healing must occur prior to initiation of treatment; ≥ 8 weeks for major surgery, ≥ 7 days for minor surgery, including stereotactic biopsies.

* The participant has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:

* Cardiovascular disorders, including uncontrolled hypertension,

* Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation,

* Clinically significant hematuria, hematemesis, or hemoptysis of \> 0.5 teaspoon (2.5 milliliters \[mL\]) of red blood within 12 weeks before initiation of treatment or other history of significant bleeding (eg, intracranial hemorrhage/bleeding), or

* Other clinically significant disorders.

* Requirement for hemodialysis or peritoneal dialysis.

* History of solid organ or allogeneic stem cell transplant.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.