Background: Teliso-V is a first-in-class anti–c-Met antibody-drug conjugate composed of the monoclonal antibody telisotuzumab (ABT-700), a cleavable valine-citrulline (dipeptide) linker, and cytotoxic monomethylauristatin E (MMAE; potent microtubule polymerization inhibitor). Direct MMAE payload delivery to c-Met protein overexpressing (OE) cells enables Teliso-V to work independently of c-Met signaling. In NSCLC, while c-Met OE is more common than MET gene amplification (Amp), about 90% of MET Amp tumors will also be c-Met OE. In an ongoing phase 2 trial, Teliso-V showed encouraging efficacy and acceptable safety in previously treated c-Met OE NSQ NSCLC population (Camidge et al. JCO.2022.40.16_suppl.9016). From this study, a retrospective analysis of 10 patients with MET Amp (≥1.8 MET gene to chromosome 7 copy number ratio by fluorescence in situ hybridization [FISH]) demonstrated an objective response rate (ORR) of 80%. Described here is an ongoing phase 2 study evaluating efficacy and safety of Teliso-V monotherapy in patients with previously untreated MET Amp locally advanced/metastatic NSQ NSCLC. Methods: This is a phase 2, single-arm, open-label, global study (NCT05513703). Eligible patients (≥18 years) have histologically documented advanced/metastatic NSQ NSCLC, measurable disease by RECIST v1.1, confirmed MET Amp determined centrally by FISH or locally by FISH, tissue next-generation sequencing (NGS), or plasma NGS using sponsor-approved assays. Additional eligibility criteria include Eastern Cooperative Oncology Group performance status 0 or 1, no alterations in EGFR, ALK, ROS1, or BRAF that predict sensitivity to targeted therapy, no prior systemic therapy for locally advanced or metastatic NSCLC, no prior c-Met–targeted antibody therapy. Teliso-V is administered intravenously at 1.9 mg/kg every 2 weeks until disease progression, intolerable toxicity, or other study drug discontinuation criteria are met. Primary endpoint is ORR assessed by independent central review (ICR). Secondary endpoints include duration of response and disease control rate, progression-free survival per ICR, overall survival, patient-reported outcomes (PROs). Tumor assessments (per RECIST v1.1) are performed at baseline and approx. every 6 (year 1), 8 (year 2), and 12 weeks (year 3 and beyond). PROs are assessed through validated questionnaires (EORTC QLQ-LC13, EORTC QLQ-C30, EQ-5D-5L). Safety and tolerability are evaluated by adverse events, physical examinations, laboratory data, and vital signs. Pharmacokinetic and biomarker evaluations may be used for exploratory analyses. The trial intends to enroll approx. 70 efficacy-evaluable patients, with interim analyses planned after 20 and 50 patients are able to be followed for ≥6 months. The study was open to enrollment as of Nov 2022. Clinical trial information: NCT05513703.