Abstract 1197TiP
Background
c-MET is a member of the receptor tyrosine kinase (RTK) family. As essential components of signal transduction pathways regulating cell proliferation, differentiation, migration, metabolism, and cell cycle control, RTKs are putative targets as treatment strategies for various cancers. c-MET is mainly expressed in epithelial tissues and is subject to dysregulation, manifesting as mutations, amplifications, and overexpression. c-MET has high affinity to its naturally occurring ligand, Hepatocyte Growth Factor (HGF). Binding of HGF to c-MET results in cell proliferation, survival, motility, induction of cells polarity, scattering, angiogenesis, and invasion, by inducing various signaling pathways. The dysregulation of HGF/c-MET pathway has been implicated in primary tumor and metastatic progression as well as drug resistance mechanisms. ABN401 competitively attaches to the ATP binding sites in the kinase domain of c-MET with high specificity to inhibit autophosphorylation of c-MET and its downstream signaling pathway. In preclinical studies, ABN401 exhibited anti-tumor activity as monotherapy and/or in combination with standard agents.
Trial design
ABN401 is being evaluated in an open-label, non-randomized, dose-escalation study in patients with advanced solid tumors, dose-extension and dose-expansion in patients with non-small cell lung cancer (NSCLC) harboring c-MET dysregulation. The extension study of phase I (pilot expansion) is ongoing in NSCLC patients with c-MET alteration at 800 mg as the recommended phase II dose (RP2D). With RP2D in phase I, phase II expansion cohort will be started and opened from cohort 1 in the US and Korea to recruit NSCLC patients with MET exon 14 skipping. During screening for patient enrollment, subjects will be tested to confirm MET exon 14 skipping using tissue-based NGS or RNA-based ddPCR with tissue or blood. We plan to open several cohorts to treat other types of cancers harboring MET alteration. In addition, combination therapies with different types of drugs are planned.
Clinical trial identification
NCT04052971.
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Abion.
Disclosure
D.H. Lee: Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, BMS, CJ Healthcare, Eli Lilly, ChongKeunDang, Janssen, Merck, MSD, Mundipharma, Novartis, Ono, Pfizer, Roche, Samyang Biopharm, ST Cube, AbbVie, Takeda, Genexine, Menarini, Blueprint Medicine, BC Pharma. A. Roohullah: Financial Interests, Institutional, Full or part-time Employment: Sydney Southwest Private Hospital. B.C. Cho: Financial Interests, Institutional, Full or part-time Employment: Yonsei University Health System; Financial Interests, Personal and Institutional, Research Grant: Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD, AbbVie, Medpacto, GI Innovation, Eli Lilly, Blueprint Medicines, Interpark Bio Convergence Corp; Financial Interests, Personal, Advisory Board: Kanaph Therapeutics Inc., BridgeBio Therapeutics, Cyrus Therapeutics, Guardant Health; Financial Interests, Personal, Stocks/Shares: TheraCanVac Inc., Gencurix Inc., BridgeBio Therapeutics, Kanaph Therapeutics Inc., Cyrus Therapeutics, Interpark Bio Convergence Corp.; Financial Interests, Personal, Advisory Role: Novartis, AstraZeneca, Boehringer Ingelheim, Roche, BMS, Ono, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, MSD, Medpacto, Blueprint Medicines; Financial Interests, Personal, Member of the Board of Directors: Interpark Bio Convergence Corp.; Financial Interests, Personal, Royalties: Champions Oncology; Financial Interests, Personal, Other, Founder: Daan Biotherapeutics. J. Choi: Financial Interests, Personal, Full or part-time Employment: Abion Inc.; Financial Interests, Personal, Stocks/Shares: Abion Inc. K.E. Park: Financial Interests, Personal, Full or part-time Employment: Abion Inc.; Financial Interests, Personal, Stocks/Shares: Abion Inc. E. Kim: Financial Interests, Personal, Full or part-time Employment: Abion Inc. N.Y. Kim: Financial Interests, Personal, Full or part-time Employment: Abion Inc.; Financial Interests, Personal, Stocks/Shares: Abion Inc. Y.K. Shin: Non-Financial Interests, Personal and Institutional, Member of the Board of Directors: Abion Inc.; Financial Interests, Personal, Stocks/Shares: Abion Inc. J. Han: Financial Interests, Personal, Other: Roche, AstraZeneca, Takeda; Financial Interests, Personal, Advisory Role: AstraZeneca, Lilly, MSD, BMS, Pfizer, Medpacto; Financial Interests, Personal, Research Grant: Novartis, Roche, Pfizer, Ono. All other authors have declared no conflicts of interest.