18EXACT: a randomized phase II trial of XL092 (zanzalintinib) in combination with immunotherapy in patients who progress on adjuvant therapy in clear cell RCC [NCT06863311]

Abstract Background The randomized phase III KEYNOTE-564 trial demonstrated that adjuvant pembrolizumab improves disease-free survival and overall survival compared to placebo in patients with clear cell renal cell carcinoma (ccRCC) at intermediate-high and high risk for recurrence after surgery with curative intent. At 2 years of follow-up about 20% of patients on KEYNOTE-564 had disease recurrence. Treatment options post adjuvant progression are not well established. Zanzalintinib (Zanza) is a next-generation anti-VEGFR multi-targeted tyrosine kinase inhibitor which has demonstrated safety and activity in ccRCC including treatment-refractory disease. Pre-clinical data shows that anti-PD-1 immune checkpoint inhibition is synergistic with Zanza. Nivolumab (nivo) is an anti-PD-1 immune checkpoint inhibitor that is well tolerated and approved in advanced ccRCC. We hypothesize that Zanza and Zanza + Nivo in combination are well tolerated and improve the overall response rate at 6 months in patients who have progressed on or after adjuvant pembrolizumab compared to the historical control of cabozantinib post- ICI. Methods This is a multicenter open-label randomized phase II trial evaluating Zanza and Zanza plus Nivo both compared to the historical control, cabozantinib, in subjects who progress on or after adjuvant pembrolizumab. Eligible patients include those patients with measurable disease per RECIST 1.1 who progress on or after adjuvant pembrolizumab . 70 patients will be randomized 1:1 to receive either Zanza 100 mg by mouth daily or Zanza 100 mg by mouth daily in combination with Nivolumab 480 mg intravenously every 4 weeks until disease progression. The primary endpoint is overall response rate at 6 months as per investigator assessed RECIST 1.1. Secondary endpoints include progression- free survival at 6 months, overall survival, duration of response and adverse events as per CTCAE v5. 10 patients will undergo paired baseline and on treatment biopsies to evaluate tissue based molecular predictors of response and resistance and serial ctDNA will be evaluated. For each arm, a single stage design will be used to test the null hypothesis that the population partial and complete response proportion (P) ≤ 0.330 versus the alternative that P ≥ 0.530 via Z test. To assure a minimum of 85% power for a one-sided 0.10 level of significance test, we need to recruit 33 patients per arm. This trial is enrolling patients through the Hoosier Cancer Research Network. The study is activated at Columbia University. Sites pending activation include The Ohio State University, University of California, San Diego, University of Indiana, University of Minnesota, and Washington University in St. Louis. Significance & Vision Zanzalintinib is a multitargeted tyrosine kinase inhibitor which has demonstrated efficacy and tolerability in metastatic ccRCC. Treatment options for patients who progress on adjuvant pembrolizumab are ambiguous. The EXACT Trial seeks to determine if Zanzalitinib and Zanzalitinib plus Nivolumab are effective treatments in patients who progress on adjuvant pembrolizumab. Trial Schema This study is in collaboration with Exelixis Inc.