LBA53 Alliance A021602: Phase III, double-blinded study of cabozantinib versus placebo for advanced neuroendocrine tumors (NET) after progression on prior therapy (CABINET)

VEGF pathway inhibitors are active against NET. We assessed the efficacy of cabozantinib (CABO), a multi-kinase inhibitor targeting VEGFR, c-MET, AXL, and RET, in previously treated patients (pts) with advanced extra-pancreatic NET (epNET) or pancreatic NET (pNET). Pts with locally advanced or metastatic well or moderately differentiated epNET or pNET were randomized (2:1) in separately powered cohorts to receive CABO 60 mg daily vs placebo (PB). Eligibility included progression by RECIST within 12 months (mo) prior to registration, ≥ 1 prior therapy including everolimus, sunitinib or Lu-177 dotatate. Randomization was stratified by concurrent somatostatin analog (SSA) and primary site in epNET and by concurrent SSA and prior sunitinib in pNET. Primary endpoint: progression-free survival (PFS), with preplanned interim analyses for futility after 33% and 66% of events and alpha spending of 0.001 per interim analysis. Secondary endpoints: response rate (RR), overall survival (OS), safety. 197 pts (129 CABO, 68 PB) with epNET and 93 pts (62 CABO, 31 PB) with pNET were randomized between 10/2018-6/2023. For epNET: 55% midgut/unknown primary; 70% concurrent SSA. For pNET: 55% concurrent SSA; 28% prior sunitinib. Median follow-up: 12.6 mo for epNET; 10.1 mo for pNET. An independent DSMB requested and reviewed interim analyses for PFS based on local radiology assessment (2nd interim for epNET [109 events]; 1st for pNET [50 events]). Efficacy analyses in both cohorts noted significantly improved PFS for pts receiving CABO vs placebo (Table). No new safety signals were noted. DSMB voted to terminate accrual and unblind pts on 7/28/2023. RR, OS data will be presented.Table: LBA53epNET cohortpNET cohortCABOPBCABOPBPFSMedian PFS8.2 mo3.2 mo13.7 mo3.0 moStratified HR (95% CI)0.41 (0.27 – 0.62)Ref0.25 (0.12 – 0.49)Refp-valuep<0.0001p<0.0001Safety# Evaluable for safety124636030Grade 3+ adverse event94 (75.8%)27 (42.9%)41 (68.3%)13 (43.3%)Grade 3+ hypertension34 (27.4%)3 (4.8%)16 (26.7%)6 (20.0%)Grade 3+ hand-foot syndrome4 (3.2%)0 (0%)6 (10%)0 (0%) Open table in a new tab CABO demonstrates statistically significant and clinically meaningful improvement in PFS in epNET and pNET. CABO may be a new treatment option for pts with previously treated, progressive NET.