Novel treatment strategies for EGFR mutant lung cancer

Abstract

Abstract Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the standard of care for patients with advanced EGFR mutant non-small cell lung cancer (NSCLC). Osimertinib, a mutant selective EGFR TKI, when used as initial therapy, results in median progression free survival (PFS) of 18.9 months. However, all patients ultimately develop resistance to osimertinib and new strategies to enhance the initial efficacy of osimertinib or treat acquired resistance mechanisms are needed. Acquired resistance to osimertinib is heterogenous and can be mediated by both on-target resistance mechanisms (EGFR C797S) or activation of parallel (MET or HER2 amplification or acquired oncogenic rearrangements) or downstream (KRAS or BRAF mutations) signaling pathways. Strategies to treat these resistance mechanisms include 1st/2nd generation EGFR inhibitors or concomitant targeting of the activated signaling pathway. Novel treatment approaches including the development of allosteric EGFR inhibitors and more comprehensive means of targeting resistance using a HER3 antibody drug conjugate (ADC; U3-1402) will be discussed. A complementary approach is to enhance the initial efficacy of osimertinib. Preclinical studies demonstrate that reactivation of ERK 1/2 signaling occurs within just a few days of osimertinib treatment. EGFR inhibitor mediated apoptosis requires upregulation of the proapoptotic protein BIM and this process is controlled by ERK 1/2 signaling. Thus ERK 1/2 reactivation following osimertinib treatment decouples EGFR inhibition from apoptosis. Concomitant EGFR and MEK inhibition prevents this process and leads to a greater apoptotic response than osimertinib alone. Strategies to translate these observations and other first line osimertinib combination studies will be discussed.