Abstract 2960: MYTX-011: A pH-dependent anti-cMET ADC exhibits potent activity in multiple epithelial tumor models with clinically actionable mutations and varying levels of cMET expression

Abstract Small-molecule inhibitors (SMI) of acquired genetic alterations in cancer-driver genes have advanced patient care, especially in non-small cell lung cancer (NSCLC). Tyrosine kinase inhibitors (TKI) targeting the cMET receptor currently benefit a subset of patients whose tumors are dependent on cMET signaling. However, tumors frequently become refractory to SMI therapy. Antibody-drug conjugates (ADCs) targeting cMET have shown promising efficacy in a subset of NSCLC patients whose tumors express high levels of cMET. MYTX-011, an investigational, pH-sensitive, vcMMAE-based ADC targeting cMET, is designed to benefit a broader set of patients whose tumors express low to moderate levels of cMET and are not dependent on cMET signaling, in addition to patients that express high levels of cMET. We previously demonstrated that MYTX-011, which is engineered to rapidly dissociate from cMET at the acidic pH of endolysosomes, drives increased net internalization and cytotoxicity in tumor cells expressing low or moderate levels of cMET compared to a matched non-engineered ADC. Moreover, MYTX-011 was efficacious in NSCLC, gastric, esophageal, and HNSCC xenograft models with various cMET adenocarcinoma/squamous histology. Here, we demonstrate by live cell imaging that the pH-dependent binding of the antibody component of MYTX-011 leads to its rapid dissociation from cMET in the early endosomal lumen, whereas the non-engineered antibody remains localized to the endosomal membrane. These data support a model where MYTX-011 avoids non-productive recycling to the cell surface thereby enhancing delivery to lysosomes, payload release and cytotoxicity. To further study the mechanism of MYTX-011 across multiple tumor mutational backgrounds, we showed potent efficacy of MYTX-011 in tumor xenografts harboring clinically relevant mutations such as MET exon 14 skipping (METex14), KRAS, and EGFR, demonstrating that pH-dependent binding of MYTX-011 translated to potent efficacy regardless of actionable mutation status. MYTX-011 was active in low or moderate cMET-expressing NSCLC KRAS mutant (G12C) xenografts as well as in TKI-resistant xenograft models bearing EGFR mutation (T790M), whereas a benchmark ADC was either inactive or had greatly reduced efficacy. We also show that MYTX-011 was highly active in a METex14 Hs746T cell line derived xenograft (CDX) and NSCLC patient-derived xenografts (PDX) including a model derived from a patient with acquired resistance to MET TKI. Further, there were no antagonistic effects of combining MET TKI and MYTX-011 in METex14 PDX models, indicating the potential of MYTX-011 in combination with approved MET TKIs. Together, these findings highlight the potential of MYTX-011 as a therapeutic candidate for treating a broad range of cMET-expressing cancers with clinically actionable mutations. Citation Format: Deepak Kanojia, Federico Colombo, William J. Israelsen, Vijay Ramesh, Nimish Gera, Thomas Chittenden, Brian P. Fiske. MYTX-011: A pH-dependent anti-cMET ADC exhibits potent activity in multiple epithelial tumor models with clinically actionable mutations and varying levels of cMET expression. [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 2960.