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posted on 2024-02-08, 14:20 authored by Nitin Roper, Rajaa El Meskini, Tapan Maity, Devon Atkinson, Amanda Day, Nathan Pate, Constance M. Cultraro, Svetlana Pack, Valerie Zgonc, Zoe Weaver Ohler, Udayan Guha Efficacy and determinants of response to osimertinib and savolitinib combination among osimertinib-resistant EGFR-mutant NSCLC PDX models with spatially and temporally heterogenous MET pathway activation. Tumor growth inhibition studies in MET polysomy (A) and MET amplified (B) PDXs. Dashed vertical lines delineate when treatment was stopped. Asterisks signify statistical significance between osimertinib and savolitinib combination and osimertinib alone treatment arms. P values were calculated by t test. P values < 0.05 were considered significant. C, Association between response to osimertinib and savolitinib combination and IHC features (phospho-MET, c-MET), copy number and FISH parameters (number of MET copies and MET/CEP7 ratio). Response is defined as >25 days until reaching tumor size endpoint in osimertinib and savolitinib combination compared with osimertinib treatment alone. Individual circles represent a unique tumor for each represented PDX model. D, Representative c-MET and phospho-MET IHC images of PDX tumors with and without response to osimertinib and savolitinib combination. Scale bars, 50 µm.
Funding
HHS | National Institutes of Health (NIH)
History
ARTICLE ABSTRACT
MET pathway activation is one of the most common mechanisms of resistance to osimertinib in EGFR-mutant non–small cell lung cancer (NSCLC). We previously demonstrated spatial and temporal heterogeneity in MET pathway activation upon osimertinib resistance in EGFR-mutant NSCLC; however, the functional relevance of these findings is unclear. Here, we generated 19 patient-derived xenografts (PDX) from 9 patients with multi-region and temporal sampling of osimertinib-resistant tumor tissue from patients with EGFR-mutant NSCLC. MET pathway activation was a putative mechanism of osimertinib resistance in 66% (n = 6/9) patients from whom PDXs were generated. Significant spatial and temporal heterogeneity in MET pathway activation was evident. Osimertinib-resistant PDXs with MET amplification by FISH (defined as MET/CEP7 ratio ≥2.0 or mean MET ≥ 6.0 copies/cell) and high-level phospho-MET, but not c-MET expression, had better responses to osimertinib and savolitinib combination than to osimertinib alone. MET polysomy tumors by FISH from both PDXs and patients had evidence of subclonal phospho-MET expression. Select MET polysomy PDX tumors with phospho-MET expression responded better to osimertinib and savolitinib combination than MET polysomy PDX tumors without phospho-MET expression. Our results suggest osimertinib and savolitinib combination is most effective for osimertinib-resistant EGFR-mutant tumors with MET pathway activation as evidenced by phospho-MET. As subclonal MET amplification may be evident in MET polysomy tumor progression, MET polysomy warrants close clinical follow-up with phospho-MET IHC in parallel with FISH diagnostic.
Using a novel cohort of in vivo PDX models of MET pathway activation with acquired resistance to osimertinib in EGFR-mutant lung cancer, we demonstrate that phospho-MET may be a clinically relevant assay to guide treatment selection with osimertinib and savolitinib combination. In addition, our work shows that patients with MET polysomy tumors may have subclonal MET amplification and therefore require close follow up for the use of osimertinib and savolitinib combination.
