A phase II study of zanzalintinib for patients with advanced urothelial carcinoma following prior therapy.

Abstract

TPS889 Background: Advanced urothelial carcinoma (aUC) remains an aggressive malignancy with limited options in refractory disease. Multiple VEGF receptor tyrosine kinase inhibitors (TKIs), including cabozantinib, have demonstrated activity in the salvage setting of aUC alone and in combination with checkpoint inhibitors. Zanzalintinib, a second generation TKI, has a target profile similar to cabozantinib but with a significantly shorter half-life, which is expected to confer a better therapeutic index and reduce the time to resolution of toxicities. We hypothesize that given the important role of the VEGF pathway in UC, Zanzalintinib will demonstrate single-agent activity in refractory aUC. We propose a Phase II trial to evaluate the activity of Zanzalintinib for aUC progressing after prior therapy. Methods: This is a multicenter, open-label, single-arm investigator-initiated phase II trial conducted at four sites through the Hoosier Cancer Research Network. Patients receive oral zanzalintinib 60 mg once daily in 28-day cycles until disease progression or unacceptable toxicity. Major eligibility criteria include histologically confirmed aUC, prior treatment with EV and a PD1/L1 inhibitor, ECOG performance status 0-2, measurable disease, adequate hematologic, renal, and hepatic function. Exclusion criteria include prior exposure to VEGF inhibitors, >3 prior lines of therapy, active central nervous system metastases, uncontrolled hypertension, left ventricular ejection fraction <50% and serious cardiovascular events within 6 months. Radiographic imaging is done every 2 cycles x 3, then every 3 cycles. The primary endpoint is objective response rate (ORR) per RECIST v1.1. Secondary endpoints include progression-free survival (PFS), overall survival (OS), and safety. Exploratory endpoints include biomarker correlations with clinical outcomes. A Simon two-stage design will be used to assess efficacy, with an initial cohort of 25 patients and expansion to 40 if predefined criteria are met. ORR ≥20% is considered important, while ORR <10% is not considered clinically meaningful. Archival tumor is collected and blood is collected at baseline, cycle 2 day 1, and end of therapy for correlative studies of circulating tumor DNA, circulating markers of angiogenesis, and immune pathways. Funder: Exelixis, ClinicalTrials.gov Identifier: NCT07185945. Clinical trial information: NCT07185945 .