Abstract 1287: Clinical relevance and translatability of NSCLC patient-derived xenograft (PDX) models for evaluating cMET-targeted therapies

Adoption of tyrosine kinase inhibitors (TKIs) has improved outcomes for Non-Small Cell Lung Cancer (NSCLC) by disrupting tumor-promoting growth factors, but patients develop resistance to these therapies through acquired alterations in other receptors. MET amplification is a common mechanism of resistance to FDA-approved small molecule EGFR inhibitors. Antibody Drug Conjugates (ADCs), such as c-MET targeting telisotuzumab-vedotin, are emerging as a promising therapy for EGFR inhibitor-progressed NSCLC, but understanding ADC efficacy across diverse profiles of advanced tumors remains a challenge. There is a need to develop more translational preclinical models to understand next-generation experimental agent efficacy prior to clinical trial enrollment. Here, we investigate the therapeutic potential of an experimental anti-cMET ADC in a panel of NSCLC low-passage patient-derived xenograft (PDX) models derived from patients pre-treated with EGFR therapies.10 NSCLC PDX models from Champions Oncology’s tumor bank were established In Vivo from patient tumors and maintained at a low passage. Genomic and pharmacologic profiling was conducted on established models to characterize EGFR resistance. Models were then treated with 1 or 3 mg/ kg experimental agent every 4 days for 8 doses, with tumor volume and survival data collected over a 4-week treatment period. The experimental anti-cMET ADC demonstrated a range of tumor growth inhibition across the selected models, which is reflective of the heterogeneity seen in NSCLC patients in the clinic. Several cMET-amplified models showed significant tumor regression, while other cMET-amplified models exhibited more variability ranging from partial response to full resistance to treatment. The use of low-passage NSCLC PDX models is essential in preserving the clonal heterogeneity and molecular landscape of patient tumors, making them highly relevant for the preclinical evaluation of novel therapies. Notably, Champions low-passage models preserved the molecular and histological features of the original patient tumors, including mutations and copy number variations, which were critical for understanding the response to therapy. Our study highlights the translational potential of Champions PDX models, serving as a platform for investigating the efficacy and mechanisms of resistance to targeted therapies. Citation Format: Nathlie Leger, Kayla Tyskiewicz, Hanna Koster, Paul Heverly, Mara Gilardi, Stefano Cairo, Frank Smith. Clinical relevance and translatability of NSCLC patient-derived xenograft (PDX) models for evaluating cMET-targeted therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1287.