Abstract 1141O
Background
VEGF pathway inhibitors are active against NET. We compared cabozantinib (CABO), a multi-kinase inhibitor targeting VEGFR, c-MET, AXL and RET, with placebo (PB) in a phase 3 trial including previously treated patients (pts) with advanced NET (NCT03375320). The study was stopped early and unblinded per DSMB recommendations based on interim results showing improvement in PFS by local radiology assessment (ESMO 2023). Updated and final results of PFS by BICR, objective response rate (ORR), subgroup analyses, and safety are now presented.
Methods
Pts with locally advanced or metastatic extra-pancreatic NET (epNET) or pancreatic NET (pNET) were randomized 2:1 in separately powered cohorts to receive CABO 60 mg daily vs PB. Eligibility included progression by RECIST within 12 months (mo) prior to registration, ≥ 1 prior therapy. Prespecified primary endpoint: PFS by BICR. Secondary endpoints: ORR, overall survival (OS), safety.
Results
203 pts with epNET and 95 pts with pNET were randomized through the data cutoff of 8/24/2023. Primary tumor sites for pts with epNET included GI tract 57%, lung 19%, unknown 12%. In both cohorts, CABO significantly improved PFS by BICR and resulted in higher confirmed ORR (Table). Across clinical subgroups, including primary tumor site and prior anticancer therapy, PFS favored CABO. Grade 3+ treatment-related adverse events (AEs) were higher in the CABO arm; no new safety signals were noted.
Table: 1141O
| epNET cohort | pNET cohort | ||||
| CABO (N=134) | PB (N=69) | CABO (N=64) | PB (N=31) | ||
| PFS (BICR) | Median PFS, mo | 8.5 | 4.0 | 13.8 | 4.5 |
| Stratified HR (95% CI) | 0.38 (0.25-0.58) | Ref | 0.23 (0.12-0.42) | Ref | |
| Stratified log-rank p-value | pConclusionsCABO demonstrates significant improvement in PFS by BICR in epNET and pNET. AEs are consistent with the known safety profile of CABO. CABO may be a new treatment option for pts with previously treated, advanced NET. Clinical trial identificationNCT03375320. Editorial acknowledgementLegal entity responsible for the studyAlliance for Clinical Trials in Oncology. FundingU.S. National Institutes of Health U10CA180821, U10CA180882; U10CA180820, U10CA180868, U10CA180888; Exelixis; https://acknowledgments.alliancefound.org. DisclosureJ. Chan: Financial Interests, Personal, Advisory Board: Curium, Ipsen, Novartis; Financial Interests, Personal, Stocks/Shares: Merck; Financial Interests, Personal, Royalties: UpToDate; Financial Interests, Personal and Institutional, Steering Committee Member: Camurus; Financial Interests, Institutional, Coordinating PI: Lilly; Non-Financial Interests, Member of Board of Directors: North American Neuroendocrine Tumor Society. S.C. Behr: Financial Interests, Personal, Speaker, Consultant, Advisor: Novartis, GenVivo. A. Shergill: Financial Interests, Personal, Advisory Board: Guardant, Pfizer; Financial Interests, Personal, Invited Speaker: Takeda, OSCO/ASCO Direct, ACPMP, Cholangiocarcinoma Summit, Cholangiocarcinoma Foundation, ASCO Advantage; Financial Interests, Institutional, Research Funding: Hutchison MediPharma, Takeda, Merck, Verastem Oncology, Turning Point Therapeutics, Gritstone, Bolt Therapeutics, BMS, Pfizer, Astellas, Oncologie, Macogenics, Seattle Genetics, Amgen, Daiichi Sankyo, Lilly, Jacobio, AstraZeneca. T.R. Halfdanarson: Financial Interests, Institutional, Research Funding: Thermo Fisher Scientific, Advanced Accelerator Applications/Novartis, Camurus, Crinetics, ITM; Financial Interests, Institutional, Advisory Board: Ipsen, Advanced Accelerator Applications/Novartis, ITM, Crinetics, Perspective Therapeutics, Exelixis, Curium, Abdera Therapeutics; Non-Financial Interests, Personal, Steering Committee Member: Camurus, ITM. B. Konda: Financial Interests, Institutional, Research Funding: Merck, Eisai, Xencor. N. Trikalinos: Financial Interests, Institutional, Research Funding: Exelixis. S. Shaheen: Financial Interests, Personal, Advisory Board, Consultation fee of one time $2,825.00 on March 1, 2024: Exelixis; Financial Interests, Institutional, Local PI, Institutional PI for the company's study: A phase 2, randomized, parallel-group study to evaluate the safety, pharmacokinetics, and dose response of paltusotine treatment in patients with carcinoid syndrome: Crinetics; Financial Interests, Personal, Steering Committee Member, Steering Committe Member for: A phase 2, randomized, parallel-group study to evaluate the safety, pharmacokinetics, and dose response of paltusotine treatment in patients with carcinoid syndrome: Crinetics. N. Vijayvergia: Financial Interests, Personal, Advisory Board: Rayze Bio, ITM, AstraZeneca, Exelixis; Financial Interests, Institutional, Research Funding: Puma, Oryzon, BMS. N.A. Dasari: Financial Interests, Personal, Advisory Board: HutchMed, Exelixis, 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. 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