| Autor: |
Lim, Sun Min, Schalm, Stefanie S., Lee, Eun Ji, Park, Sewon, Conti, Chiara, Millet, Yves A., Woessner, Rich, Zhang, Zhuo, Tavera-Mendoza, Luz E., Stevison, Faith, Albayya, Faris, Dineen, Thomas A., Hsieh, John, Oh, Seung Yeon, Zalutskaya, Alena, Rotow, Julia, Goto, Koichi, Lee, Dae-Ho, Yun, Mi Ran, Cho, Byoung Chul |
| Zdroj: |
Therapeutic Advances in Medical Oncology; 10/21/2024, p1-20, 20p |
| Abstrakt: |
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 (EGFR 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 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 EGFR m NSCLC progressing on previous EGFR-TKIs. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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