A Phase 2/3, Multicenter, Randomized Open-Label Study of Zanzalintinib vs Everolimus in Participants With Previously Treated, Unresectable, Locally Advanced or Metastatic Neuroendocrine Tumors

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, locally advanced/unresectable or metastatic, well-differentiated Grade 1, 2, or 3 NETs of pancreatic origin or extra-pancreatic origin.

* Allowed prior lines of therapy, based on the site of NET and functional status.

* Documented radiographic disease progression per RECIST 1.1, as assessed by the Investigator based on imaging assessments (computed tomography \[CT\] or magnetic resonance imaging \[MRI\]) within 12 months before randomization.

* Measurable disease according to RECIST 1.1 as determined by the Investigator.

* Archival tumor tissue is required, if available. If archival tumor tissue is not available, a fresh biopsy may be submitted if it can be safely and feasibly obtained. Every attempt should be made to provide tumor tissue.

Key Exclusion Criteria:

* Histologically confirmed neuroendocrine carcinomas (including small cell lung cancer), medullary thyroid cancer, pheochromocytoma, paraganglioma, Merkel cell carcinoma, and mixed neuroendocrine non-neuroendocrine neoplasm (MiNEN).

* Prior treatment with a vascular endothelial growth factor receptor (VEGFR) -targeting tyrosine kinase inhibitor or a mammalian target of rapamycin (mTOR) inhibitor.

* Systemic chemotherapy and any liver-directed or other ablative therapy within 4 weeks before randomization.

* Systemic radionuclide therapy within 6 weeks before randomization.

* Radiation therapy for bone metastases within 2 weeks, any other radiation therapy, except as indicated above, within 4 weeks before randomization.

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