A phase II trial of neoadjuvant zanzalintinib (ZANZA) plus nivolumab (NIVO) in patients with locally advanced and/or surgically challenging clear cell renal cell carcinoma (EXPLORE-RCC).

TPS4629 Background: Immunotherapy doublet combinations (+/- vascular endothelial growth factor receptor-tyrosine kinase inhibitor [VEGFR-TKI]) are established for front-line treatment of metastatic, clear cell renal cell carcinoma (ccRCC). However, their role in the perioperative setting for locoregional ccRCC remains to be defined. We designed the EXPLORE-RCC trial to evaluate neoadjuvant ZANZA (novel, next generation VEGFR-TKI with short half-life) plus NIVO (PD-1 inhibitor) in patients with locally advanced ccRCC, where the combination has the potential to shrink the primary tumor, increase resectability, and/or allow a partial nephrectomy or minimally invasive approach. Methods: In this multisite, phase 2, open-label, single-arm trial coordinated by the Hoosier Cancer Research Network, subjects will receive ZANZA 60mg orally once daily plus NIVO intravenously per standard of care (SOC) dosing for 12 weeks (w), followed by restaging scans and an adaptive approach: (1) subjects who are deemed operable will undergo resection (Cohort A); (2) subjects who remain inoperable can receive up to 48w total of ZANZA plus NIVO (Cohort B1) with the option to undergo resection when deemed operable; or (3) subjects who have disease progression will stop protocol mandated therapy and receive subsequent SOC treatment (Cohort B2). The main inclusion criteria include age ≥ 18 years, ECOG Performance Status of 0-1, histologically confirmed ccRCC, and locally advanced (cT3/4, N0-1, with or without tumor thrombus) disease and/or deemed surgically challenging per surgeon discretion. Non-measurable metastasis per RECIST 1.1 criteria, including soft tissue metastasis with longest diameter <10mm or distant lymph nodes <15 mm in short axis are allowed. Main exclusion criteria are non-clear cell histology, measurable metastatic disease per RECIST 1.1 criteria, and prior systemic treatment for ccRCC. The primary endpoint is overall response rate (ORR) after 12w of therapy. This single arm trial is powered to detect an improvement in ORR from a historical rate of 30% to 45%, with 80% power and a 0.05 one-sided type I error. Estimating 10% drop out, 69 subjects will be enrolled. Key secondary/exploratory endpoints include efficacy outcomes (conversion to operable, disease free survival, overall survival, pathologic response), safety, surgery-related complications (including Clavien-Dindo), and biomarker correlatives. The trial is actively enrolling (ClinicalTrials.gov NCT06794229) at UT Southwestern and opening at Ohio State, Fox Chase Cancer Center, Virginia Commonwealth, Northwestern University, and Washington University in St Louis. Clinical trial information: NCT06794229 .