Abstract 1964: Furmonertinib is a brain-penetrant EGFR TKI highly active in uncommon EGFR mutations, including PACC and exon 20 insertions

Abstract Background: Furmonertinib (AST2818, furmo) is an oral, highly brain-penetrant, and broadly active mutation-selective EGFR inhibitor against both classical and uncommon EGFR mutations (mts). Furmo has demonstrated promising interim efficacy and safety in non-small cell lung cancer (NSCLC) patients (pts) with EGFR exon 20 insertion (ex20ins) mts (Han et al., 2023). Furmo is currently being studied in a global Phase 3 trial for 1st line pts with ex20ins in NSCLC (FURVENT; NCT05607550) and has received FDA Breakthrough Designation in this pt population. P-loop and αC-helix Compressing (PACC) mts represent another subset of uncommon EGFR mts (Robichaux et al., 2021) that are similar to ex20ins in narrowing the drug binding pocket; include e.g. G719X, S768I, E709X, L747X, V774M; and are found as single or compound EGFR mts. Treatment options for pts with PACC mts remain limited. In this study, we further characterized PACC mts as cancer drivers in NSCLC and evaluated the pre-clinical activity and binding mechanisms of furmo in PACC and ex20ins mts. Methods: AACR Project GENIE and TEMPUS databases were used for mutation analysis. In vitro potency was determined in Ba/F3 cell lines for 33 PACC and 16 ex20ins mts. In vivo efficacy was conducted in pt-derived xenografts (PDXs). Molecular modeling was performed using MOE software. Results: PACC prevalence was 2.4% vs. 1.6% for ex20ins and 14% for classical EGFR mts in all NSCLC, corresponding to 10.4% PACC and 7% ex20ins of all EGFR mts. Co-mutation analysis revealed that other oncogenes, such as p53, co-occurred alongside PACC to a similar rate as with ex20ins and classical EGFR mts which further supports the role of PACC mts as a similar cancer driver as other EGFR mts in NSCLC. Ba/F3 cell lines harboring PACC mts were highly sensitive to furmo which showed overall superior potency vs. osimertinib and similar activity to afatinib. When comparing the mutant/wild-type IC50 ratio, furmo showed promising and high activity against single (e.g. G719X) and compound (e.g. ex19del+L718V) PACC mts. IC50 values were similar for PACC as compared to ex20ins mts. Therefore, furmo is predicted to be broadly active across both PACC and ex20ins mutant pt populations at clinically achievable drug levels. Molecular modelling revealed that furmo’s interaction with ex20ins and PACC mts is stabilized through hydrogen bonds with specific sites and its proximity to hydrophobic residues including L792 and P794 in the drug binding pocket. To further characterize furmo sensitivity in vivo against PACC mts, studies in PDXs are ongoing to evaluate efficacy, pharmacokinetics and pharmacodynamics and will be presented. Conclusions: PACC mts are important and prevalent cancer drivers in NSCLC and furmo is similarly active preclinically against both PACC and ex20ins mts. The activity of furmo in EGFR PACC mutant NSCLC is currently being evaluated in a global study FURTHER (NCT05364073). Citation Format: Monique B. Nilsson, Zineb Mounir, Luna Musib, Junqin He, Xiaoxing Yu, Qing Li, Huibing Luo, John V. Heymach, Jerry Y. Hsu, Stuart Lutzker, Xiuning Le, Marcin Kowanetz. Furmonertinib is a brain-penetrant EGFR TKI highly active in uncommon EGFR mutations, including PACC and exon 20 insertions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1964.