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

[PURPOSE] 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.

[PATIENTS AND METHODS] 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.

[RESULTS] 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.

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