236 (PB116) - Preclinical characterization of CNS-active, mutant-selective fourth-generation EGFR inhibitors with potent activity against single, double, and triple mutant EGFR variants including T790M and C797S

Abstract

Background: EGFR activating mutations are observed in 10–50% of NSCLC patients and the common mutations (L858R [L] and exon 19 deletions [D]) are initially sensitive to first- second- and third-generation EGFR inhibitors (e.g., erlotinib [1G], afatinib [2G], and osimertinib [3G], respectively). However, on-target resistance is observed in a substantial percentage of patients, with T790M (T) and C797S (C) mutations observed most frequently (post-1G/2G and post-3G, respectively). Furthermore, EGFR mutational heterogeneity can increase during treatment with existing inhibitors, activity against wild type (WT) EGFR leads to dose-limiting toxicities, and tumors commonly metastasize to the brain.