Preclinical Development of Therapeutics in Murine Models of Lung Cancer

Division Of Basic Sciences - Nci

Investigators

Abstract

The key goal of the collaborative project between CAPR Lung Cancer modelling program and Dr. Udayan Guha's lab (Thoracic and GI Malignancies Branch) was to establish PDX models as part of the clinical trial NCI IRB-16-C-0092 "A pilot study of local ablative therapy (LAT) for treatment of oligoprogressive, EGFR mutated, non-small cell lung cancer (NSCLC) after treatment with osimertinib (AZD9291)," to generate additional material for biomarker analysis, and to create cohorts for "co-clinical" trials assessing therapeutic combinations for efficacy against EGFR TKI-resistant tumors. We generated PDX models using multi-region spatial and temporal sampling of osimertinib-resistant EGFR mutant lung tumors from patients enrolled in the clinical trial. A total of 19 PDXs from 8 patients with EGFR mutant lung cancer were generated, including longitudinally sampled patients before and after LAT and metastatic sites. All PDX tumors were characterized by CAPR for MET amplification or polysomy as a mechanism of resistance as well as other NSCLC markers. We found that heterogeneity for MET amplification observed in patients was maintained in the PDXs. We evaluated the combination of osimertinib and the MET inhibitor savolitinib in a subset of patient tumor PDXs and analyzed the correlation between amplification or polysomy and response to combination therapy. At CAPR we also proposed IHC detection of phospho-MET as an indicator of MET activity. We found that a low H-score for phospho-MET indicated sensitivity of tumors to osimertinib alone, despite gene amplification by FISH. When phospho-MET was high, tumors regressed in response to the combination of osimertinib and savolitinb. Thus, incorporation of a phospho-MET IHC assay, particularly among patients with MET FISH polysomy or otherwise equivocal MET FISH report, should be considered prior to therapy. Our study, resulting in a joint manuscript soon to be submitted, provided functional, in vivo evidence supporting the use of combination osimertinib and savolitinib in patients with osimertinib resistant EGFR-mutant tumors with MET amplification, or polysomy contingent on phospho-MET activation. The data may help inform ongoing prospective studies of osimertinib plus savolitinib such as SAVANNAH (NCT03778229) and ORCHARD (NCT03944772). Additionally, we generated a PDX tumor bank from patients with EGFR-driven NSCLC, including tumors representing progression from sensitivity to resistance to osimertinib, that will be valuable as a research tool for the scientific community seeking access to informative preclinical models in support of therapeutic development efforts.