Abstract 1652: Preclinical characterization of ICT-011, a first-in-class, highly selective, potent and orally bioavailable MET degrader for the treatment of NSCLC harboring MET amplification

Abstract Background: The MET (also known as c-MET) tyrosine kinase receptor plays important roles in cancer cell growth, survival, migration, and invasion/metastasis. More importantly, MET alterations, including MET gene exon 14 skipping mutation, amplification and protein overexpression are recognized as oncogenic drivers for non-small cell lung cancer (NSCLC). MET amplification is the most common acquired resistance mechanism to EGFR tyrosine kinase inhibitor (TKI) treatment in EGFR-mutated NSCLC. Although MET TKIs are approved for the treatment of NSCLC patients with MET exon 14 skipping mutation, there are currently no effective treatments for those with MET amplification and overexpression. We discovered and evaluated ICT-011, which is a potent, selective, oral degrader of MET for treatment of NSCLC with MET amplification. Results: ICT-011 potently induced the degradation of MET protein in vitro in CRBN and ubiquitin-proteosome-dependent manners and demonstrated its selectivity for MET degradation when evaluated with proteome profiling analyses. In addition, in vitro cell-based analyses exhibited that ICT-011 induced protein proximity between MET and CRBN proteins. ICT-011 showed strong anti-proliferative activity against cancer cells with MET alterations, including MET amplification, but not normal cells. ICT-011 potently suppressed MET downstream signals and sustained the prolonged degradation of MET for 48 hours post-washout. ICT-011 had favorable PK profile suitable for oral administration in mouse, rat, and dog. ICT-011 exhibited rapid and robust anti-tumor activity, which was sustained after discontinuing its treatment in MET-amplified EBC-1 NSCLC xenograft models. ICT-011 also demonstrated superior anti-tumor activities compared with MET TKI, Tepotinib, and showed durable anti-tumor activities after discontinuing its treatment in patient-derived xenograft models of MET-amplified and EGFR-mutant (exon19 del) NSCLC. Conclusions: These results demonstrate that ICT-011 is a first-in-class, highly selective, potent and orally bioavailable MET degrader for the treatment of NSCLC harboring MET amplification. Citation Format: Jong Seok Kang, Yo Han Hong, Yong Hwan Kim, Hyeji Lee, Ji-Seong Yoon, Kyusic Jang, Bo Kyoung Kim, Young-Jun Shin, Moon Hwan Kim, Hye-Dong Yoo. Preclinical characterization of ICT-011, a first-in-class, highly selective, potent and orally bioavailable MET degrader for the treatment of NSCLC harboring MET amplification [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1652.