Abstract 4033: Pan-exon mutant KIT inhibitor DCC-3009 demonstrates tumor regressions in preclinical gastrointestinal stromal tumor models

Abstract

Abstract Introduction: Gastrointestinal stromal tumors (GISTs) are typically driven by primary mutations in KIT exons 9 or 11. Heterogeneous drug-resistant secondary mutations arise in patients treated with FDA approved KIT inhibitors, including imatinib and sunitinib. Drug resistant secondary mutations are found at multiple regions in the ATP pocket (encoded by exons 13 and 14) or activation switch (encoded by exons 17 and 18) of KIT kinase. In addition, multiple drug-resistant clones can arise within a tumor or in metastatic tumor sites. An inhibitor that can broadly and potently inhibit the spectrum of KIT mutations is highly sought. Ripretinib has been FDA approved as a 4th line treatment for GIST and has broad activity against KIT mutations, including clinical potency in patients with mutations in KIT exons 11, 17, or 18. DCC-3009 was designed as a next generation KIT inhibitor that broadly and potently inhibits primary KIT mutations in exons 9 and 11 and secondary drug-resistant mutations across exons 13, 14, 17, and 18. DCC-3009 is a potent and selective inhibitor in enzyme and cell-based assays, and has demonstrated efficacy in xenograft models driven by drug resistant KIT mutations. Methods: DCC-3009 was tested for inhibition of KIT mutants using standard enzyme and cell-based assays. Levels of phosphorylated KIT were determined by Western blot or ELISA. Proliferation was measured using the fluorescent dye resazurin. KIT mutant xenograft or patient-derived xenograft models were performed at Crown Biosciences or Labcorp, AAALAC accredited facilities, with the approval of Animal Care and Use Committees. Results: In BaF3 cells transfected with KIT mutants, DCC-3009 was shown to potently inhibit the spectrum of known primary and secondary drug-resistant mutations in GIST. The pan-mutant KIT profile of DCC-3009 was shown in vitro to be superior to 2nd and 3rd line standard of care therapies sunitinib and regorafenib. DCC-3009 was selective for KIT when screened against a large panel of kinases. DCC-3009 has optimized pharmaceutical properties for oral administration. In pharmacokinetic/pharmacodynamic studies DCC-3009 achieved sufficient free drug levels to significantly inhibit drug-resistant KIT mutants for 12 hr post dose. In xenograft studies, treatment with DCC-3009 twice daily led to tumor regression in drug-resistant models with KIT exon 9/13, 11/13 or 11/17 mutations. Conclusions: DCC-3009 is a pan-exon mutant KIT inhibitor exhibiting high potency in KIT mutants in pre-clinical models spanning exons 9, 11, 13, 14, 17 and 18. In vivo, DCC-3009 exhibited efficacy in drug-resistant models with KIT exon 9/13, 11/13 or 11/17 mutations. Based on this profile, DCC-3009 has entered formal preclinical development. Citation Format: Bryan D. Smith, Subha Vogeti, Timothy M. Caldwell, Hanumaiah Telikepalli, Yu Mi Ahn, Gada Al-Ani, Stacie L. Bulfer, Andrew Greenwood, Cale L. Heiniger, Joshua W. Large, Cynthia B. Leary, Wei-Ping Lu, Kylie Luther, William C. Patt, Max D. Petty, Yeni K. Romero, Forrest A. Stanley, Kristen L. Stoltz, Daniel C. Tanner, Sihyung Yang, Yu Zhan, Bertrand Le Bourdonnec, Daniel L. Flynn. Pan-exon mutant KIT inhibitor DCC-3009 demonstrates tumor regressions in preclinical gastrointestinal stromal tumor models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4033.