FIGURE 1 from Functional Heterogeneity in MET Pathway Activation in PDX Models of Osimertinib-resistant EGFR-driven Lung Cancer

Generation of spatial and temporally heterogenous osimertinib-resistant EGFR-mutant NSCLC PDX models and treatment study design. A, Schematic diagram of the prospective clinical trial of LAT for osimertinib-treated EGFR-mutant lung cancer (RT: radiotherapy). PDXs were generated from osimertinib-resistant tumor tissue either at first or second progression on osimertinib or after standard of care (S.O.C) therapy. B, Multi-region and temporal tumor samples from surgical resections or biopsies used for PDX generation are shown for each individual patient. Putative mechanism of resistance to osimertinib as evidenced by exome and or transcriptome sequencing (Roper et al., Cell Reports Medicine 2020) is shown below each set of PDXs. Color denotes timing of sample acquisition. Red: first progression on osimertinib; Green: second progression on osimertinib; Blue: progression on S.O.C treatment. C, Illustrations of PDX generation from 3 patients with EGFR-mutant lung cancer with MET polysomy by FISH (MET ≥ 4.0 and <6.0 copies/cell if MET/CEP7 ratio is <2) or MET amplification by FISH (MET/CEP7 ratio ≥2.0 or ≥6 MET copies per cell) as a mechanism of resistance to osimertinib. D, Study design for treatment with MET inhibitor (savolitinib) with a third-generation EGFR TKI (osimertinib). PDXs with spatial heterogeneity in MET pathway activation (LAT001_6B and LAT001_9B), PDXs with temporal heterogeneity in MET pathway activation (LAT006_2B and LAT006_0118) and an additional validation PDX (LAT015_6B) were treated with vehicle, osimertinib, savolitinib, and osimertinib plus savolitinib combination followed by assessment of efficacy and identification of predictive markers.