Abstract PR004: Brain penetrant allosteric EGFR inhibitors for NSCLC

Abstract

Abstract Approximately 30-50% of Non-Small Cell Lung Cancer (NSCLC) patients already have CNS disease at time of diagnosis or else develop it during treatment, and there remains a need for better outcomes in these patients. The 3rd-generation covalent EGFR inhibitor osimertinib is an effective therapy for NSCLC patients, improving upon 1st-generation inhibitors gefitinib and erlotinib, and achieving enhanced brain penetration relative to those agents. However, the survival benefit relative to the 1st-generation inhibitors is observed primarily in patients with exon19 deletions rather than the L858R mutation. We developed a series of mutant-selective allosteric EGFR inhibitors that specifically target the L858R mutation (and subsequent resistance mutations), with high selectivity over wt EGFR and across the kinome. Early compounds including the isoindolinone JBJ-09-063 demonstrated good in vivo efficacy in mouse tumor models, despite limited bioavailability. Diversification and optimization of the chemistry, involving a scaffold hopping approach and the replacement of the thiazole amide with benzimidazole, delivered a set of compounds with promising potency and rodent PK. A subset of these achieved good brain exposure in mice and efficacy in an intracranial H1975 brain metastasis model. The mutant-selectivity and ability to co-bind with osimertinib makes an allosteric EGFR inhibitor an ideal partner for combination therapy, with the potential to deliver enhanced outcomes in L858R-driven NSCLC, especially for patients with CNS disease. Citation Format: David Scott, Courtney Cullis, Tyler Beyett, Frederic Feru, Thomas Gero, Krista Gipson, Praful Gokhalle, Nathanael Gray, David Heppner, Sampson Huang, Pasi Jänne, Sandeepraj Pusalkar, Michael Eck. Brain penetrant allosteric EGFR inhibitors for NSCLC [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr PR004