Discovery of BLU-945, a Reversible, Potent, and Wild-Type-Sparing Next-Generation EGFR Mutant Inhibitor for Treatment-Resistant Non-Small-Cell Lung Cancer

While epidermal growth factor receptor (EGFR) tyrosine
kinase inhibitors
(TKIs) have changed the treatment landscape for EGFR mutant (L858R
and ex19del)-driven non-small-cell lung cancer (NSCLC), most patients
will eventually develop resistance to TKIs. In the case of first-
and second-generation TKIs, up to 60% of patients will develop an
EGFR T790M mutation, while third-generation irreversible TKIs, like
osimertinib, lead to C797S as the primary on-target resistance mutation.
The development of reversible inhibitors of these resistance mutants
is often hampered by poor selectivity against wild-type EGFR, resulting
in potentially dose-limiting toxicities and a sub-optimal profile
for use in combinations. BLU-945 (compound 30) is a potent,
reversible, wild-type-sparing inhibitor of EGFR+/T790M and EGFR+/​T790M/​C797S
resistance mutants that maintains activity against the sensitizing
mutations, especially L858R. Pre-clinical efficacy and safety studies
supported progression of BLU-945 into clinical studies, and it is
currently in phase 1/2 clinical trials for treatment-resistant EGFR-driven
NSCLC.