Background: Teliso-V is an antibody-drug conjugate composed of a c-Met antibody (ABT-700) and a microtubule inhibitor (monomethyl auristatin E). The phase 2 M14-239 trial (LUMINOSITY, NCT03539536) aims to identify the c-Met OE NSCLC populations best suited to Teliso-V (Stage 1) and expand selected groups for further evaluation of efficacy (Stage 2). In Stage 1, pts were enrolled into cohorts defined by histopathology (non-squamous [NSQ] or squamous [SQ]) and EGFR mutation status (mutant or wild type [WT]); NSQ cohorts were further divided in groups on the basis of c-Met expression (high or intermediate). Updated data from the fourth interim analysis (IA4) are presented. Methods: Pts had locally advanced/metastatic NSCLC, ≤2 prior lines of systemic therapy, ≤1 line of chemotherapy, and tumors that were c-Met OE by central immunohistochemistry (IHC; Ventana; Tucson, AZ). c-Met OE was defined for the NSQ cohort as ≥25% 3+ by IHC (high, ≥50% 3+; intermediate, 25 to <50% 3+) and for the SQ cohort as ≥75% 1+ by IHC. The planned enrollment was up to approximately 150 pts in Stage 1 and 160 pts in Stage 2. Teliso-V was dosed at 1.9 mg/kg IV Q2W. The primary endpoint is objective response rate (ORR) by independent central review. Secondary endpoints include duration of response (DOR). Results: As of data cutoff (27 May 2021), 136 pts were treated with Teliso-V; 122 were evaluable for ORR. ORR was 36.5% in the NSQ EGFR WT cohort (52.2% in c-Met high group and 24.1% in c-Met intermediate group), but was modest in the NSQ EGFR mutant and SQ cohorts. Efficacy data in groups/cohorts are in the Table. The most common any-grade adverse events (AEs) were peripheral sensory neuropathy (25.0%), nausea (22.1%), and hypoalbuminemia (20.6%). Grade 5 AEs considered possibly related to Teliso-V occurred in 2 pts (sudden death and pneumonitis in 1 pt each in the SQ cohort). Conclusions: Teliso-V demonstrated a promising ORR in pts with previously treated c-Met OE NSQ EGFR WT NSCLC; this cohort is currently expanding in Stage 2. ORR was modest in the cohorts of pts with c-Met OE NSQ EGFR mutant NSCLC and with c-Met OE SQ NSCLC; both cohorts have now met the protocol-specified stopping criteria and are no longer enrolling. The safety profile observed was consistent with IA3. Clinical trial information: NCT03539536.