Background: The antibody-drug conjugate telisotuzumab vedotin (Teliso-V) is composed of the c-Met–targeting antibody telisotuzumab (ABT-700) linked to the microtubule inhibitor monomethyl auristatin E. In the LUMINOSITY study (NCT03539536), efficacy of Teliso-V was seen in patients (pts) with EGFR wildtype nonsquamous NSCLC and c-Met overexpression (≥25% tumor cells at 3+ intensity by IHC); overall response rate: 36.5%. Data are limited on whether specific driver oncogene states affect responses. We investigated genomic alterations in relation to response to Teliso-V in this population. Methods: Pts received 1.9 mg/kg Teliso-V monotherapy once every 2 weeks in LUMINOSITY. ctDNA was isolated from plasma collected at different timepoints. The PGDx elio plasma complete assay was used to identify genomic alterations in ctDNA samples. This assay included 521 genes for single nucleotide variants and insertion-deletion mutations, 38 for amplifications (amp), and 21 for translocations. Results: In total, 52 pts were included in the study; ctDNA from 48 pts was analyzed. The overall response rate among pts with ctDNA results was 37.5% (18 pts with partial response) compared with 36.5% for the ITT population of 52 pts. Genomic alterations are listed in the Table.Three out of 4 pts with MET amp at baseline responded, accounting for 17% of total responses. The observed MET amp frequency in this MET IHC preselected cohort was 8%, which is similar to the prevalence observed in tissue analysis by FISH. Of note, 1 nonresponder harbored a MET ex14del mutation at baseline, and a responder had a low-frequency mutation detected at the final visit. Mutations in KRAS were the most common genomic alteration and were detected in 13 (27%) pts at baseline. Three pts with a KRAS mutation were responders; among these, 2 out of 3 had a KRAS G12C mutation (seen in 3 pts total). Response rates were higher in pts with MET amp (75%; 95% CI: 0.30, 0.95) vs those without MET amp (34%; 0.22, 0.49), and higher in pts without KRAS mutations (43%; 0.28, 0.59) vs those with KRAS mutations (23%; 0.08, 0.50); however, confidence intervals were wide and larger sample sizes are needed. Conclusions:MET amp occurred more frequently in responders; however, Teliso-V activity was not restricted to these pts, as most responders were not MET amplified. Specific genomic alterations beyond MET may influence clinical response. The current analysis demonstrated numeric differences between pts with identified drivers who did or did not respond to Teliso-V. Additional research on this topic is needed in larger pt cohorts and/or with tissue-based NGS analyses.