Journal Article

BLU-945, a potent and selective next-generation EGFR TKI, has antitumor activity in models of osimertinib-resistant non-small-cell lung cancer

Albayya, Faris, Rotow, Julia, Cho, Byoung Chul, Lee, Dae-Ho, Schalm, Stefanie S., Millet, Yves A., Tavera-Mendoza, Luz E., Zalutskaya, Alena, Goto, Koichi, Yun, Mi Ran, Park, Sewon, Stevison, Faith, Lim, Sun Min, Zhang, Zhuo, Lee, Eun Ji, Hsieh, John, Dineen, Thomas A., Woessner, Rich, Oh, Seung Yeon, Conti, Chiara

2024

Overview

Introduction: Despite the availability of several epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), most patients with non-small-cell lung cancer (NSCLC) eventually develop resistance to these agents. Notably, EGFR_C797S mutations confer resistance to the third-generation EGFR-TKI osimertinib and no approved post-osimertinib targeted pharmacology options are currently available. BLU-945 is a novel, reversible, and orally available next-generation EGFR-TKI that selectively targets EGFR-activating (EGFRm) and resistance mutations (including EGFR_C797S) with nanomolar potency while sparing wild-type EGFR in vitro. Methods: In vitro activity of BLU-945 as a single agent and in combination with osimertinib was tested in engineered EGFR-mutant cell lines as well as patient-derived cells and patient-derived organoids. In vivo activity was evaluated in osimertinib-resistant patient-derived xenograft mouse models. Three patient cases from the global, first-in-human, phase I/II SYMPHONY trial (NCT04862780) demonstrating the clinical efficacy of BLU-945 were reported. Results: In vitro BLU-945 demonstrated inhibited cell viability and growth of EGFR-mutant/osimertinib-resistant cell lines. BLU-945 demonstrated in vivo tumor shrinkage in osimertinib-resistant models of NSCLC (osimertinib second line: EGFR_L858R/C797S and third line: EGFR_ex19del/T790M/C797S and L858R/T790M/C797S) both as monotherapy and in combination with osimertinib. BLU-945 also demonstrated tumor shrinkage in patients from the SYMPHONY trial. Conclusion: Our findings demonstrate the preclinical and early clinical activity of BLU-945 in EGFRm NSCLC progressing on previous EGFR-TKIs.

• Publisher: SAGE Publications,Sage Publications Ltd,SAGE Publishing
• Subject: Animal models / Antitumor activity / Cell culture / Cell viability / Epidermal growth factor receptors / Lung cancer / Mutants / Mutation / Non-small cell lung carcinoma / Organoids / Original Research / Small cell lung carcinoma / Targeted cancer therapy / Tumor cell lines / Tumors / Tyrosine kinase inhibitors