450P Proteogenomics refines the molecular classification of leptomeningeal metastases in EGFR+ NSCLC

Background: Dato-DXd, a TROP2-directed antibody-drug conjugate, has shown efficacy in patients with EGFRm NSCLC.Elucidating the biological basis could clarify the molecular features that regulate Dato-DXd anti-tumor efficacy.We investigated Dato-DXd and DXd sensitivity biomarkers and impact of prior osimertinib treatment in preclinical models of NSCLC. Methods:In vitro viability screening performed in non-squamous (NSQ) and squamous (SQ) NSCLC cell lines (n=58) including 7 EGFRm cell lines.Internalization assays performed via live-cell imaging after osimertinib pre-treatment in EGFRm cell lines.In vivo studies evaluated single-dose Dato-DXd (10 mg/kg) in NSCLC patient-derived xenografts (PDX) models (n=38, including 15 EGFRm).Results: Dato-DXd activity was observed in EGFRwt (10/36 responders (R), 28%) and EGFRm (3/7 R, 43%) NSQ NSCLC cell lines.In this panel of models, SQ EGFRwt cell lines showed limited sensitivity to Dato-DXd (1/15 R, 7%).In addition, Dato-DXd demonstrated broader activity in EGFRm (11/15 R, 73%) compared to EGFRwt (11/23 R, 48%) NSCLC PDX models.Dato-DXd efficacy was observed in classical and atypical EGFRm PDX models.Mechanistically, TROP2 gene expression was necessary, but not sufficient for Dato-DXd response, suggesting additional biological factors are important.A NRF2 pathway signature and ABCC1 gene expression, putative DXd resistance markers, were associated with lower sensitivity to DXd and Dato-DXd.Interestingly, these were less prevalent in EGFRm compared to EGFRwt models, providing further preclinical rationale regarding the differential sensitivity of EGFRm tumors.Importantly, data also indicated the potential of osimertinib pre-treatment to enhance TROP2 expression and Dato-DXd internalization in EGFRm models.Conclusions: These preclinical data support the notable clinical activity of Dato-DXd in EGFRm NSCLC and provide a potential mechanistic rationale for why EGFRm disease has broad inherent sensitivity to Dato-DXd.Further validation in clinical cohorts is warranted.