Overcoming resistance to EGFR tyrosine kinase inhibitors in lung cancer, focusing on non-T790M mechanisms.

INTRODUCTION: despite initial dramatic efficacy of EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutant lung cancer patients, emergence of acquired resistance is almost inevitable. The EGFR T790M secondary mutation that accounts for ~50% of resistance is now treatable with osimertinib. However, for the remaining 50% of patients who develop resistance mechanisms other than T790M mutation, cytotoxic chemotherapies are still the standard of care and novel treatment strategies are urgently needed. Areas covered: In this review, we discuss current experimental and clinical evidence to develop better treatment strategies to overcome or prevent acquired resistance to EGFR-TKIs in lung cancers, focusing on non-T790M mechanisms. Expert commentary: There are numerous non-T790M resistant mechanisms to EGFR-TKIs, and therefore, strategies that can be applied to many of these resistance mechanisms may be reasonable and useful in clinical practice. Although the combination of cytotoxic chemotherapy plus an EGFR-TKI has proved to be detrimental following front-line EGFR-TKI treatment failure, promising experimental and/or early clinical data have been reported for the combination of bevacizumab or anti-EGFR monoclonal antibody plus EGFR-TKIs. Upfront polytherapy, which co-targets potential resistance mechanisms or other important signaling for EGFR-mutant lung cancer cells, is also a promising strategy.