Therapy for EGFR tyrosine kinase inhibitor-resistant NSCLC with a focus on the T790M-resistant mutation

The molecular characterisation of nonsquamous lung cancer has now become a standard procedure. In addition to the rare EML4-ALK and ROS-1 mutations, the detection of an epidermal growth factor receptor (EGFR) mutation has become a crucial factor in the selection of an optimal targeted therapy. Deletion of exon 19 and the L858R point mutation account for approximately 90 % of activating EGFR mutations and patients with these mutations are highly sensitive to treatment with EGFR tyrosine kinase inhibitors (EGFR TKIs). First-generation EGFR TKIs (gefitinib, erlotinib) reversibly inhibit the EGFR tyrosine kinase, while second-generation EGFR TKIs (afatinib, dacomitinib) are irreversible EGFR TKIs. However, despite an often excellent initial response to treatment with first- or second-generation EGFR TKIs, patients eventually develop drug resistance after approximately 9–12 months of treatment. T790M-targeting third-generation EGFR TKIs as osimertinib and rociletinib have shown high response rates of about 60 % in EGFR T790M-positive pretreated patients with a favourable toxicity profile. Unfortunately, patients eventually developed resistance to these drugs after approximately 10 months and the third-generation EGF R Cys797S mutation was recently reported to be a potential mechanism of resistance to third-EGFR TKIs.