Cabozantinib in Context – CABINET Rationale and Trial Design

The rationale for evaluating cabozantinib in neuroendocrine tumors (NETs) stems from the highly vascular nature of these tumors, particularly pancreatic NETs, which show strong arterial enhancement on imaging. This characteristic has long pointed to angiogenesis as a therapeutic target. Earlier studies with anti-angiogenic therapies such as bevacizumab and various tyrosine kinase inhibitors (TKIs), such as sunitinib and pazopanib, showed varying degrees of activity. Cabozantinib, a multitargeted oral TKI that inhibits VEGFR, MET, AXL, and other pathways, was considered a promising candidate given its broad spectrum and potential antitumor effects. While the impact of each individual target remains uncertain, the combination of activity across several pathways may contribute to its efficacy in a disease known for biological complexity and heterogeneity.

The CABINET trial was a phase 3, randomized, double-blind, placebo-controlled study led by a cooperative group rather than industry, enhancing its credibility. It included 2 cohorts—pancreatic and extrapancreatic NETs—acknowledging the biological and clinical differences between subtypes. Patients were required to have progressed on at least 1 prior therapy in addition to a somatostatin analogue. Importantly, once peptide receptor radionuclide therapy (PRRT) became an approved option during the trial period, prior PRRT was also allowed. The trial randomly assigned patients 2:1 to receive either 60 mg of cabozantinib or placebo, and a crossover option was added to ensure ethical access to treatment after progression.

Progression-free survival (PFS) was selected as the primary end point, a choice aligned with established guidance in NET research. Due to the indolent course of many NETs and the availability of multiple subsequent therapies, overall survival (OS) is often an impractical and confounded end point. With crossover permitted and extended survival common, measuring OS differences becomes less feasible. PFS provides a reliable indicator of clinical benefit in this context and is widely accepted as a meaningful outcome in NET trials.