Phase II trial of cabozantinib in combination with nivolumab for advanced extrapancreatic neuroendocrine tumors (epNET)

Abstract Background: Cabozantinib, a multi-kinase inhibitor, improves progression-free survival (PFS) in patients with advanced extrapancreatic NET (epNET). Cabozantinib alters the tumor microenvironment to be more permissive to immune cells by reducing the presence of regulatory T cells and CD14+ monocytes. This trial investigated the efficacy and safety of cabozantinib in combination with nivolumab in patients with advanced epNET. Methods: Open-label, single-arm, phase II trial, which enrolled patients with advanced epNET. Patients received nivolumab 240 mg intravenously on days 1 and 15 and cabozantinib 40 mg orally once daily on a 28-day cycle. The primary endpoint was objective response rate (ORR) by RECIST v1.1. Using a Simon’s two-stage design 19 patients were enrolled in the first stage. Secondary objectives included ORR by immune-related response criteria (irRECIST), PFS, and safety. Exploratory objectives included correlation between immune and angiogenic proteomic profile, and clinical outcomes. Results: Eighteen of the 19 enrolled patients were evaluable for response. Best response was partial response 1(5%), stable disease 16 (90%), and progressive disease 1 (5%). ORR did not meet goal for the first stage, so enrollment was terminated. Median PFS was 5.6 months (95% CI, 3.5 to 9.9). Grade 3 toxicities attributed to the combination included tumor lysis (n= 1, 5%), elevated transaminases (n= 1, 5%), and fatigue (n= 2, 10%). Immune and angiogenic proteomic profiles demonstrated trends associated with longer time on therapy. Conclusion: Cabozantinib and nivolumab was associated with limited response in patients with epNET. Alternative strategies to enhance the immune response in epNET are needed.