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

Background

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).

Methods

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.

Results

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 (2^nd interim for epNET [109 events]; 1^st 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: LBA53

Conclusions

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.

Clinical trial identification

NCT03375320.

Editorial acknowledgement

Legal entity responsible for the study

Alliance for Clinical Trials in Oncology.

Funding

U.S. National Institutes of Health (U10CA180821, U10CA180882); Exelixis; Alliance for Clinical Trials in Oncology.

Disclosure

J. Chan: Financial Interests, Personal, Advisory Board: Ipsen, Crinetics; Financial Interests, Personal, Speaker, Consultant, Advisor: Novartis; Financial Interests, Personal, Stocks/Shares: Merck; Financial Interests, Institutional, Research Funding: Lilly, Sanofi; Financial Interests, Personal, Steering Committee Member: Camurus. S. Behr: Financial Interests, Personal, Speaker, Consultant, Advisor: Novartis, GenVivo. T.R. Halfdanarson: Financial Interests, Institutional, Research Funding: Thermo Fisher Scientific, Advanced Accelerator Applications/Novartis, Camurus, Crinetics, ITM; Financial Interests, Institutional, Advisory Board, unpaid or paid to institution: Ipsen, Advanced Accelerator Applications/Novartis, ITM, Crinetics, Viewpoint Molecular Targeting; Financial Interests, Personal, Advisory Board: TerSera, Terumo; Non-Financial Interests, Institutional, Steering Committee Member: Camurus. N. Trikalinos: Financial Interests, Institutional, Research Funding: Exelixis. B. Konda: Financial Interests, Institutional, Research Funding: Esai, Merck. N. Vijayvergia: Financial Interests, Personal, Speaker, Consultant, Advisor: Rayze Bio, ITM, AstraZeneca; Financial Interests, Institutional, Research Funding: Puma, Oryzon, BMS. N..A. Dasari: Financial Interests, Personal, Advisory Board: HutchMed, AAA, Personalis, Illumina, Takeda; Financial Interests, Institutional, Trial Chair: HutchMed, Eisai, Guardant Health, Natera, Xencor, Taiho; Financial Interests, Institutional, Coordinating PI: Enterome. J. Strosberg: Financial Interests, Personal, Speaker, Consultant, Advisor: Novartis; Financial Interests, Institutional, Principal Investigator: Alphamedix, Rayzebio, Novartis. E.M. O'Reilly: Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, BioNTech, Merck, AstraZeneca, Novartis, Fibrogen, Astellas, Tempus, Merus, BMS, Berry Genomics, Exelixis, Incyte, Neogene, Sevier, Thetis, Vector, Yiviva; Financial Interests, Personal, Advisory Board, +Spouse: Ipsen; Financial Interests, Personal, Advisory Board, Spouse: Genentech/Roche, Eisai; Financial Interests, Personal, Advisory Board, + spouse: Autem; Financial Interests, Institutional, Local PI: Genentech/Roche, Arcus, Elicio; Financial Interests, Personal and Institutional, Coordinating PI: BioNTech; Financial Interests, Institutional, Coordinating PI: AstraZenica, Pertzye; Financial Interests, Institutional, Research Grant: Parker Institute; Non-Financial Interests, Other, Scientific and Medical Advisory Board: Pancreas Cancer Action Network; Non-Financial Interests, Member of Board of Directors: National Pancreas Foundation; Other, Editor: American Society of Clinical Oncology, American Association of Cancer Research (AACR). All other authors have declared no conflicts of interest.