e21105 Background: Biomarker-targeted antibody-drug conjugates (ADCs) have shown promise in treating lung cancer. Telisotuzumab vedotin (Teliso-V; ABBV-399) is a first-in-class MET (also known as c-Met)-directed ADC comprising the monoclonal antibody telisotuzumab (ABT-700) conjugated to a cytotoxic microtubule inhibitor, monomethyl auristatin E (MMAE), via a cleavable dipeptide linker. In the phase 2 LUMINOSITY study (NCT03539536), Teliso-V demonstrated promising anticancer activity in previously treated patients with MET-overexpressing (OE), non-squamous epidermal growth factor receptor wild type ( EGFR WT) non-small cell lung cancer (NSCLC; 52.2% overall response rate in MET OE high group, 36.5% in all MET OE cohort [intermediate and high]) and an acceptable safety profile (Camidge et al. J Clin Oncol. 2022;40:16 suppl, 9016). These data provide proof of concept that biomarker-selected MMAE-based ADCs could be beneficial to patients with NSCLC. Cofetuzumab pelidotin (ABBV-647), an ADC with a similar composition to Teliso-V, contains an anti-protein tyrosine kinase 7 (PTK7) monoclonal antibody (hu6MO24) conjugated to a microtubule-inhibiting cytotoxin, Aur0101 auristatin, via a cleavable cysteine-reactive linker. PTK7 expression and oncogenic functions have been reported in several cancers. We sought to establish the co-prevalence of MET OE and PTK7 in NSCLC to understand if both these antigens targeted by ADCs are co-expressed or present in distinct tumors. Methods: Antigen prevalence was analyzed in tumor samples from patients at the City of Hope National Medical Center with non-squamous NSCLC and EGFR WT or unknown status. Immunohistochemistry (IHC) assays used were MET (SP44) Assay for MET OE (Roche Tissue Diagnostics; positive if ≥25% cells at 3+ intensity) and an AbbVie-developed assay for PTK7 expression (positive if ≥90% cells at ≥2+ intensity). Results: A total of 148 patients (median age 67 years, 52% stage ≥III at diagnosis, 68% ECOG 0–2) were screened (data shown in table). About 24% of the patients were MET IHC positive, whereas 11% were PTK7 IHC positive. Further, MET OE and PTK7 had complementary prevalence with only 3% of the patients co-expressing both antigens. Conclusions: MET OE and PTK7 expression by IHC were found to be complementary in patients with non-squamous EGFR WT/unknown NSCLC. About 32% of patients were positive for MET OE or PTK7 expression or both. Data represent patients from a single center and more pre-treatment tissue samples that were viable and available. These IHC findings suggest that MET OE and PTK7 are indeed complementary NSCLC biomarkers. [Table: see text]