Zanzalintinib versus everolimus in patients with previously treated advanced neuroendocrine tumors: The phase 2/3, randomized STELLAR-311 trial.

Abstract

TPS647 Background: The targeted agents everolimus (a mammalian target of rapamycin [mTOR] inhibitor) as well as sunitinib and cabozantinib (vascular endothelial growth factor receptor [VEGFR] tyrosine kinase inhibitors [TKIs]) are standard treatment options for patients with previously treated advanced neuroendocrine tumors (NETs). Zanzalintinib is a novel, oral, multitargeted TKI that targets MET, VEGFR, and TAM kinases, AXL and MER. In preclinical studies, zanzalintinib has demonstrated a similar kinase inhibition profile, shorter half-life, and preferential in vivo tumor distribution compared with cabozantinib. In addition, zanzalintinib has shown encouraging antitumor activity and a consistent safety profile across multiple solid tumor types in early-phase clinical trials. Accordingly, the STELLAR-311 trial was designed to evaluate the efficacy and safety of zanzalintinib compared with everolimus in patients with locally advanced or metastatic NETs. Methods: STELLAR-311 is a phase 2/3, open-label, randomized, multicenter trial enrolling adult patients aged ≥18 years with locally advanced/unresectable or metastatic, well-differentiated grade 1–3 NETs of pancreatic or extra-pancreatic (gastrointestinal tract, lung, thymus, or other) origin. Patients are required to have measurable disease and documented radiographic disease progression within 12 months before randomization (both per Response Evaluation Criteria in Solid Tumors version 1.1). Requirements for prior systemic treatment are based on NET primary tumor site and functional status. Patients with pancreatic NET or nonfunctional extra-pancreatic NET must have received up to one prior line of therapy; patients with functional extra-pancreatic NET must have received one prior line. Somatostatin analogs do not count toward prior treatment requirements. Previous VEGFR-TKI or mTOR inhibitor treatment is not allowed. Patients will be randomized to zanzalintinib or everolimus, administered orally once daily. The primary endpoint is progression-free survival (PFS), assessed by blinded independent central review (BICR). Secondary efficacy endpoints include investigator-assessed PFS, overall survival, and BICR- and investigator-assessed objective response rate, duration of response, and disease control rate. Other secondary endpoints include safety and quality of life. STELLAR-311 is currently recruiting patients; planned enrollment is 440 patients. Clinical trial information: NCT06943755 .