Background Well-differentiated grade 3 neuroendocrine tumors (NET) 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 NET (epNET) and pancreatic NET (pNET) of all grades. Here, we evaluate if these results remain consistent in a subgroup of patients with well-differentiated G3 NET. Methods Patients with locally advanced or metastatic epNET or pNET 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 (Ki67>20%), combining patients in the pNET and epNET cohorts due to small sample sizes. Results 24 patients had G3 NETs, 16 randomized to cabozantinib and 8 to placebo. Primary sites included pancreas (n=12); GI tract (n=7); unknown primary (n=3); lung/ thymus (n=2). Median PFS for patients with G3 NET treated with cabozantinib was 7.9 months 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. Conclusion 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.
Strosberg et al. (2026) studied this question.