Next-Generation EGFR Tyrosine Kinase Inhibitors for Treating EGFR -Mutant Lung Cancer beyond First Line

Tyrosine kinase inhibitors (TKIs) against the human epidermal growth factor receptor ( ) are now standard treatment in the clinic for patients with advanced mutant non-small-cell lung cancer (NSCLC). First-generation TKIs, binding competitively and reversibly to the ATP-binding site of the tyrosine kinase domain, have resulted in a significant improvement in outcome for NSCLC patients with activating mutations (L858R and Del19). However, after a median duration of response of ~12 months, all patients develop tumor resistance, and in over half of these patients this is due to the emergence of the T790M resistance mutation. The second-generation TKIs were developed to treat resistant disease, targeting not only T790M but -activating mutations and wild-type . Although they exhibited promising anti-T790M activity in the laboratory, their clinical activity among T790M+ NSCLC was poor mainly because of dose-limiting toxicity due to simultaneous inhibition of wild-type . The third-generation TKIs selectively and irreversibly target T790M and activating mutations, showing promising efficacy in NSCLC resistant to the first- and second-generation TKIs. They also appear to have lower incidences of toxicity due to the limited inhibitory effect on wild-type . Currently, the first-generation gefitinib and erlotinib and second-generation afatinib have been approved for first-line treatment of metastatic NSCLC with activating mutations. Among the third-generation TKIs, osimertinib is today the only drug approved by the Food and Drug Administration and the European Medicines Agency to treat metastatic T790M NSCLC patients who have progressed on or after TKI therapy. In this review, we summarize the available post-progression therapies including third-generation inhibitors and combination treatment strategies for treating patients with NSCLC harboring mutations and address the known mechanisms of resistance.