Phase II Trial of Cabozantinib in Combination with Nivolumab for Advanced Extrapancreatic Neuroendocrine Tumors

Cabozantinib, a multi-kinase inhibitor, improves progression-free survival (PFS) in patients with advanced extrapancreatic neuroendocrine tumors (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.

This was an open-label, single-arm, phase II trial, which enrolled patients with advanced epNET. Patients received nivolumab 240 mg i.v. 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 two-stage design, 19 patients were enrolled in the first stage. Secondary objectives included ORR by immune-related RECIST, PFS, and safety. Exploratory objectives included correlation between immune and angiogenic proteomic profile and clinical outcomes.

Eighteen of the 19 enrolled patients were evaluable for response. Best response was partial response in one (5%), stable disease in 16 (90%), and progressive disease in one patient (5%). The ORR did not meet goal for the first stage, so enrollment was terminated. The median PFS was 5.6 months (95% confidence interval, 3.5-9.9). 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.

Cabozantinib and nivolumab were associated with limited response in patients with epNET. Alternative strategies to enhance the immune response in epNET are needed.