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, 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)

Mechanism of action

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)

Efficacy

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)

Safety

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)

Further reading

• Phase 3 STELLAR-303 results in The Lancet
• Phase 1 STELLAR-001 colorectal-cancer results
• STELLAR-002 renal-cell carcinoma results
• Peer-reviewed review of zanzalintinib
• NCI Drug Dictionary entry

Last updated: Sep 2026

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.