Abstract LB458: Osimertinib treatment drives expression of TROP2, and combination treatment with datopotamab deruxtecan (Dato-DXd), a TROP2-directed antibody-drug conjugate, enhances its efficacy in PDX models of EGFR mutant non small-cell lung cance

Abstract Osimertinib is a 3rd generation EGFR tyrosine kinase inhibitor with proven efficacy in the first-line advanced or metastatic EGFR-mutant (EGFRm) non-small cell lung cancer setting. Despite clinical benefit, most patients become refractory to drug, highlighting the need for combination strategies to maximize the duration of response. To understand the signaling changes induced by prolonged osimertinib treatment we characterised the mRNA expression of cell surface markers by RNAseq. We found that acute and prolonged osimertinib treatment leads to significant upregulation of TACSTD2, the transcript encoding the TROP2 protein. We further found that levels of TROP2 protein on the cell surface were increased by prolonged osimertinib treatment, but returned to baseline upon drug cessation, both in vitro and in vivo. Moreover, single-cell RNAseq analysis of osimertinib-treated tumours showed a specific cell subpopulation that upregulated TACSTD2 expression, which was eliminated when xenograft-bearing animals were treated with the combination of osimertinib and the TROP2-directed antibody-drug conjugate (ADC) Dato-DXd. Critically, we found that in vivo Dato-DXd/osimertinib combination treatment showed improved in vivo efficacy over osimertinib monotherapy in 4 out of 9 EGFRm patient-derived xenograft (PDX) models. Expanding these studies to PDX models derived from osimertinib-resistant patients showed superior efficacy of the combination compared to either agent alone, in 3 out of 4 models. Taken together these preclinical data highlight the ability for long-term osimertinib treatment to enhance TROP2 expression and demonstrate the potential utility of a novel combination treatment strategy with a TROP2-targeting ADC. Citation Format: Matthew J. Martin, Alex Koers, Fernando Calero, Sara Talbot, Adina Hughes, Lukasz Magiera, Lucy Ireland, Nicolas Floc'h. Osimertinib treatment drives expression of TROP2, and combination treatment with datopotamab deruxtecan (Dato-DXd), a TROP2-directed antibody-drug conjugate, enhances its efficacy in PDX models of EGFR mutant non small-cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB458.