BLU-945, a Potent and Selective Next-generation EGFR TKI, Has Antitumor Activity in Models of Osimertinib-resistant Non-small-cell Lung Cancer

Overview

Journal Ther Adv Med Oncol

Specialty Oncology

Date 2024 Oct 24

PMID 39444426

Authors

Sun Min Lim

Stefanie S Schalm

Eun Ji Lee

Sewon Park

Chiara Conti

Yves A Millet

Rich Woessner

Zhuo Zhang

Luz E Tavera-Mendoza

Faith Stevison

Faris Albayya

Thomas A Dineen

John Hsieh

Seung Yeon Oh

Alena Zalutskaya

Julia Rotow

Koichi Goto

Dae-Ho Lee

Mi Ran Yun

Byoung Chul Cho

Affiliations

Soon will be listed here.

Abstract

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, _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 (m) 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 -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 -mutant/osimertinib-resistant cell lines. BLU-945 demonstrated in vivo tumor shrinkage in osimertinib-resistant models of NSCLC (osimertinib second line: _L858R/C797S and third line: _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 m NSCLC progressing on previous EGFR-TKIs.

Citing Articles

Drug Resistance in Late-Stage Epidermal Growth Factor Receptor (EGFR)-Mutant Non-Small Cell Lung Cancer Patients After First-Line Treatment with Tyrosine Kinase Inhibitors.

Lee C, Lee S, Hsu Y Int J Mol Sci. 2025; 26(5).

PMID: 40076686 PMC: 11900297. DOI: 10.3390/ijms26052042.

References

Mok T, Wu Y, Thongprasert S, Yang C, Chu D, Saijo N . Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009; 361(10):947-57. DOI: 10.1056/NEJMoa0810699. View

Eisenhauer E, Therasse P, Bogaerts J, Schwartz L, Sargent D, Ford R . New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2008; 45(2):228-47. DOI: 10.1016/j.ejca.2008.10.026. View

Planchard D, Janne P, Cheng Y, Yang J, Yanagitani N, Kim S . Osimertinib with or without Chemotherapy in -Mutated Advanced NSCLC. N Engl J Med. 2023; 389(21):1935-1948. DOI: 10.1056/NEJMoa2306434. View

Park K, Tan E, OByrne K, Zhang L, Boyer M, Mok T . Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol. 2016; 17(5):577-89. DOI: 10.1016/S1470-2045(16)30033-X. View

Wang S, Tsui S, Liu C, Song Y, Liu D . EGFR C797S mutation mediates resistance to third-generation inhibitors in T790M-positive non-small cell lung cancer. J Hematol Oncol. 2016; 9(1):59. PMC: 4957905. DOI: 10.1186/s13045-016-0290-1. View

Thress K, Paweletz C, Felip E, Cho B, Stetson D, Dougherty B . Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat Med. 2015; 21(6):560-2. PMC: 4771182. DOI: 10.1038/nm.3854. View

Kang H, Choi J, Shim H, Kim J, Kim D, Lee C . Establishment of a platform of non-small-cell lung cancer patient-derived xenografts with clinical and genomic annotation. Lung Cancer. 2018; 124:168-178. DOI: 10.1016/j.lungcan.2018.08.008. View

Fu K, Xie F, Wang F, Fu L . Therapeutic strategies for EGFR-mutated non-small cell lung cancer patients with osimertinib resistance. J Hematol Oncol. 2022; 15(1):173. PMC: 9733018. DOI: 10.1186/s13045-022-01391-4. View

Wee P, Wang Z . Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways. Cancers (Basel). 2017; 9(5). PMC: 5447962. DOI: 10.3390/cancers9050052. View

10.

Shi C, Wang Y, Xue J, Zhou X . Immunotherapy for EGFR-mutant advanced non-small-cell lung cancer: Current status, possible mechanisms and application prospects. Front Immunol. 2022; 13:940288. PMC: 9353115. DOI: 10.3389/fimmu.2022.940288. View

11.

Leonetti A, Sharma S, Minari R, Perego P, Giovannetti E, Tiseo M . Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer. Br J Cancer. 2019; 121(9):725-737. PMC: 6889286. DOI: 10.1038/s41416-019-0573-8. View

12.

Hsu W, Yang J, Mok T, Loong H . Overview of current systemic management of EGFR-mutant NSCLC. Ann Oncol. 2018; 29(suppl_1):i3-i9. DOI: 10.1093/annonc/mdx702. View

13.

Wang Y, Guo Z, Li Y, Zhou Q . Development of epidermal growth factor receptor tyrosine kinase inhibitors against EGFR T790M. Mutation in non small-cell lung carcinoma. Open Med (Wars). 2017; 11(1):68-77. PMC: 5329801. DOI: 10.1515/med-2016-0014. View

14.

Cross D, Ashton S, Ghiorghiu S, Eberlein C, Nebhan C, Spitzler P . AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014; 4(9):1046-61. PMC: 4315625. DOI: 10.1158/2159-8290.CD-14-0337. View

15.

Kim S, Lee J, Kim D, Joo H, Yun M, Jung D . Patient-Derived Cells to Guide Targeted Therapy for Advanced Lung Adenocarcinoma. Sci Rep. 2019; 9(1):19909. PMC: 6934824. DOI: 10.1038/s41598-019-56356-4. View

16.

Rangachari D, To C, Shpilsky J, VanderLaan P, Kobayashi S, Mushajiang M . EGFR-Mutated Lung Cancers Resistant to Osimertinib through EGFR C797S Respond to First-Generation Reversible EGFR Inhibitors but Eventually Acquire EGFR T790M/C797S in Preclinical Models and Clinical Samples. J Thorac Oncol. 2019; 14(11):1995-2002. PMC: 6823139. DOI: 10.1016/j.jtho.2019.07.016. View

17.

Ma C, Wei S, Song Y . T790M and acquired resistance of EGFR TKI: a literature review of clinical reports. J Thorac Dis. 2012; 3(1):10-8. PMC: 3256494. DOI: 10.3978/j.issn.2072-1439.2010.12.02. View

18.

Lee J, Piotrowska Z, Soo R, Cho B, Lim S . Combatting acquired resistance to osimertinib in EGFR-mutant lung cancer. Ther Adv Med Oncol. 2022; 14:17588359221144099. PMC: 9761802. DOI: 10.1177/17588359221144099. View

19.

Yu H, Arcila M, Rekhtman N, Sima C, Zakowski M, Pao W . Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013; 19(8):2240-7. PMC: 3630270. DOI: 10.1158/1078-0432.CCR-12-2246. View

20.

Sung H, Ferlay J, Siegel R, Laversanne M, Soerjomataram I, Jemal A . Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 71(3):209-249. DOI: 10.3322/caac.21660. View