BLU-945, a potent and selective next-generation EGFR TKI, has antitumor activity in models of osimertinib-resistant non-small-cell lung cancer
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 treatments. A key mechanism of resistance is the EGFR_C797S mutation, which renders tumors resistant to the third-generation EGFR-TKI osimertinib. Currently, there are no approved targeted therapies for patients who have progressed on osimertinib. BLU-945 is a novel, reversible, and orally available next-generation EGFR-TKI designed to selectively target both EGFR-activating mutations and resistance mutations (including EGFR_C797S) with nanomolar potency, while sparing wild-type EGFR in vitro.
Methods:
The in vitro activity of BLU-945 as a monotherapy and in combination with osimertinib was assessed in engineered EGFR-mutant cell lines, as well as in patient-derived cells and organoids. In vivo efficacy was evaluated using patient-derived xenograft (PDX) mouse models of osimertinib-resistant NSCLC. Additionally, clinical efficacy was explored in three patient cases from the global, first-in-human, Phase I/II SYMPHONY trial (NCT04862780), where BLU-945 was administered.
Results:
In vitro, BLU-945 inhibited cell viability and growth in EGFR-mutant cell lines that were resistant to osimertinib. In osimertinib-resistant PDX models of NSCLC (second-line EGFR_L858R/C797S, third-line EGFR_ex19del/T790M/C797S, and L858R/T790M/C797S), BLU-945 demonstrated significant tumor shrinkage, both as a monotherapy and in combination with osimertinib. Clinical activity was also observed in patients enrolled in the SYMPHONY trial, with tumor shrinkage seen in treated individuals.
Conclusion:
These findings highlight the preclinical and early clinical activity of BLU-945 as a promising treatment option for patients with EGFR-mutant NSCLC who have developed resistance to previous EGFR-TKI therapies. BLU-945’s ability to target both activating and resistance mutations, including EGFR_C797S, positions it as a potential solution for overcoming osimertinib resistance in NSCLC.