Cabozantinib for advanced grade 3 neuroendocrine tumors: subgroup analysis of the phase 3 CABINET trial (Alliance A021602)

Abstract: Well-differentiated grade 3 neuroendocrine tumors (NETs) have recently been described as a distinct category, and randomized data regarding efficacy of therapy for these patients are scarce. In the phase 3 CABINET trial, cabozantinib improved PFS compared with placebo in patients with advanced, previously treated, progressive extra-pancreatic NETs (epNETs) and pancreatic NETs (pNETs) of all grades. Here, we evaluate if these results remain consistent in a subgroup of patients with well-differentiated G3 NETs. Patients with locally advanced or metastatic epNETs or pNETs were randomized 2:1 in independent cohorts to receive cabozantinib 60 mg daily vs placebo. We analyzed outcomes of the subset of patients with G3 NETs (Ki-67 > 20%), combining patients in the pNET and epNET cohorts due to small sample sizes. Twenty-four patients had G3 NETs, 16 randomized to cabozantinib and 8 to placebo. Primary sites included pancreas (n = 12), GI tract (n = 7), unknown primary sites (n = 3), and lung/thymus (n = 2). Median PFS for patients with G3 NETs treated with cabozantinib was 7.9 vs 3 months with placebo (HR = 0.15, 95% CI: 0.04-0.57, 1-sided log-rank P = 0.0034). The confirmed overall radiographic response rate was 25% (4/16) with cabozantinib vs 0% (0/8) with placebo. Safety outcomes were consistent with published data for the trial as a whole. Subset analysis of the CABINET trial showed improved PFS associated with cabozantinib vs placebo for G3 NETs of pancreatic and extra-pancreatic origin. Despite limited numbers, these results suggest that cabozantinib can be an effective option for patients with advanced G3 NETs. ClinicalTrials.gov Identifier: NCT03375320.