Phase 1 multicenter dose escalation and dose expansion study of antibody-drug conjugate (ADC) MYTX-011 in subjects with non-small cell lung cancer.

Abstract

TPS9147 Background: cMET is a receptor tyrosine kinase and proto-oncogene whose activity is upregulated across a wide range of cancers. In NSCLC, expression of cMET is upregulated by DNA amplification (2% to 5%), exon 14 skipping mutations (2% to 4%), and overexpression (30% to 60%). In NSCLC, cMET upregulation has also been demonstrated to be a resistance mechanism for several approved EGFR-targeted kinase inhibitors, and this may limit their effectiveness. Despite the approval of MET tyrosine kinase inhibitors, almost half of patients do not respond to these inhibitors and resistance is inevitable. MYTX-011 is an ADC incorporating the clinically validated vcMMAE linker-payload conjugated to a novel, pH-dependent anti-cMET antibody. In preclinical studies, MYTX-011, compared to a surrogate of an advanced clinical stage cMET ADC, showed markedly higher ( > 3 fold) internalization and increased cytotoxicity in cMET+ tumor cells in vitro, which translates to greater (≥3 fold) efficacy in high or moderate c-Met+ xenograft models in vivo. PK and toxicity studies revealed that MYTX-011 exhibited favorable PK characteristics, and a toxicity profile similar to previously described MMAE-based ADCs. Methods: MYTX-011-01 (ClinicalTrials.gov Identifier: NCT05652868) is a first-in-human Phase 1 dose escalation and dose expansion study. MYTX-011 will be administered intravenously every 21 days for a maximum of 2 years. Part 1 (dose escalation) will assess the safety and tolerability of MYTX-011 in patients with advanced NSCLC and identify the recommended Phase 2 dose (RP2D). Part 2 (dose expansion) will include subjects with NSCLC with cMET overexpression or MET amplification/exon 14 skipping mutations. In Part 1, subjects will be enrolled to evaluate the safety of escalating doses of MYTX-011 as a single-agent and to establish the RP2D and/or MTD. The dose escalation scheme is based on a 3-subject cohort minimum Bayesian Optimal Interval (BOIN) design. The RP2D will be selected as a biologically active dose at or below the MTD (or the highest dose tested if an MTD is not identified during the study) and will be informed by safety, tolerability, pharmacokinetic data, and preliminary anti-tumor activity of MYTX-011 based on RECIST 1.1. Part 2 of the study will be initiated once the RP2D has been determined and will enroll subjects into different cohorts based on cMET IHC positivity cutoff and/or presence of MET genetic alterations ( MET amplification or exon 14 skipping). All cohorts are defined to explore preliminary antitumor activity in populations with different thresholds of cMET positivity that were selected based on data for cMET expression and efficacy observed with MYTX-011 in preclinical models, published data for responses to cMET targeting agents, and on the prevalence of subject tumors with different expression levels. Enrollment in the MYTX-011-01 study is ongoing. Clinical trial information: NCT05652868 .