Functional Heterogeneity in MET Pathway Activation in PDX Models of Osimertinib Resistant EGFR-Driven Lung Cancer.

MET pathway activation is one of the most common mechanisms of resistance to osimertinib in epidermal growth factor receptor (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 PDXs from 9 patients with multi-region and temporal sampling of osimertinib resistant tumor tissue from EGFR-mutant NSCLC patients. 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.