Profiling Membrane Antigen Expression of Select Antibody-Drug Conjugate (ADC) Targets in EGFR-Altered Non-Small Cell Lung Cancer Treated With Osimertinib

Abstract

Background: Resistance to EGFR-Tyrosine Kinase Inhibitors (TKIs) in patients with NSCLC represents an unmet clinical need. Bypass pathway upregulation is a key mechanism of resistance and represents a potential target for therapeutic agents such as Antibody-Drug Conjugates (ADCs). This study evaluates the RNA expression of select ADC targets in NSCLC patients treated with osimertinib (osi).

Methods: The Tempus Lens Platform was used to identify a cohort (n=583 patients) of classical EGFR-altered NSCLC with DNA (xT) and RNA (xR) testing treated with first-line osi monotherapy (mono) or osi with chemotherapy (combo). RNA-seq data of select ADC membrane targets, including ERBB2, ERBB3, MET, NECTIN4, and TACSTD2 (TROP2) were quantified as transcripts per million (TPM), reported as log2(TPM + 1) and compared using Wilcoxon rank-sum test. Median RNA expression in each gene was defined relative to the pre-treatment EGFR-altered cohort. We examined real world overall survival (rwOS) and hazard ratio (HR) from Cox proportional hazards model.

Results: Among 583 patients, median (range) age at diagnosis was 66 (27-88) years old while 68% were female. In all samples, the highest median gene expression was identified in ERBB2, MET, and TACSTD2 (TROP2) (7.46, 7.38, 7.57). When comparing first-line pre- and post-treatment samples, there was a significant increase in median gene expression of MET (7.23 vs 7.85; p<0.001) however decreases in median expression of NECTIN4 (5.22 vs 4.90; p=0.005) and ERBB2 (7.48 vs 7.38; p=0.021). In pre-osi mono patients (n=378), median rwOS was 29.8 months. Of the five genes assessed, only MET expression was associated with worse rwOS (HR 1.25; p=0.001). In the mono group, those with above-median MET expression at pre-treatment had a worse rwOS than those with below-median expression (26.1 vs. 31.5 months; p=0.007). Above-median MET expression was associated with worse rwOS compared to below median (HR 1.52; p=0.008).

Conclusion: In patients with EGFR-altered NSCLC, we identified high expression of ERBB2, MET, and TACSTD2 (TROP2) in both pre- and post-treated samples. This may provide rationale for use of these ADC targets in second-line therapy, such as seen in recent approvals for trastuzumab deruxtecan in ERBB2-mutated, telisotuzumab vedotin in c-MET over-expressing, and datopotamab deruxtecan in EGFR-altered NSCLC. Notably, high MET pre-treatment expression was associated with poor survival outcome and appeared to be associated with post-osimertinib resistance. Further investigation is required to evaluate MET expression as a predictive biomarker for MET-targeting agents to overcome innate and acquired EGFR-TKI resistance.