*September 2020*

Additionally, the findings showed that BLU-945 potently and selectively inhibited triple-mutant EGFR, harboring the most common on-target resistance mutations to standard EGFR-targeted therapies, including the third-generation EGFR TKI osimertinib (Tagrisso). Specifically, BLU-945 inhibited triple-mutant EGFR with sub-nanomolar potency and it also showed a greater than 900-fold selectivity over wild-type EGFR plus overall kinome selectivity.

Curently, no FDA-approved treatments are available for patients with EGFR-mutant NSCLC who develop resistance to osimertinib, which is available for the first-line treatment of patients with EGFR-mutant NSCLC, and as a second-line treatment for patients with EGFR-mutant disease who acquire the T790M mutation. Therefore, there is an unmet need for novel therapies that can address this tumor resistance, according to Blueprint Medicines, the developer of BLU-945.2 For example, C797S is the most frequent on-target resistance mechanism to osimertinib.

BLU-945 is a fourth-generation EGFR TKI that potently inhibits triple-mutant EGFR that harbors either activated L858R or exon 19 deletion mutations, plus acquired T790M and C797S mutations, and selective to wild-type EGFR and kinome. BLU-945 is found to inhibit 1% of the kinome at more than 90% at a concentration of 3 μM, and a selectivity profile that enables combinations to cover a wide spectrum of resistant mechanisms. Read more.