Synergy Between Kinase Inhibitors And Antibodies Enables Upfront Prevention Of Recurring Secondary Resistance In Egfr-Mutated Lung Cancer

NSCLC (non-small cell lung cancer) patients harboring activating mutations (i.e., exon 19 deletion, L858R mutation) in the epidermal growth factor receptor(EGFR) gain sensitivity to EGFR tyrosine kinase inhibitors (TKIs). Despite the initial great response to 1st and 2nd generation EGFR TKIs (e.g., erlotinib,afatinib), eventually most patients become resistant, mainly due to the appearance of a secondary mutation, namely T790M, followed by c-Met or HER2 gene amplification, overexpression of AXL, mutations in downstream effectors, as well as phenotypic changes. When the T790M mutation is detected, patients can be treated with the 3rd generation EGFR-TKI osimertinib. Unfortunately, also in this case, following an initial phase of response, patients become resistant and even though 4th generation EGFR-TKIs are under development, most likely they will provide yet again a temporary solution. In order to avoid several cycles of response/resistance, we propose to combine monoclonal antibodies against EGFR and HER2, (cetuximab and trastuzumab, 2XmAbs), withone of the three EGFR TKIs already approved as first line therapy (i.e., erlotinib, afatinib and osimertinib).