BLU-451, a CNS-Active, Potent, and Selective Small-Molecule Inhibitor Against Uncommon EGFR Mutations.

BLU-451 is a potent and selective tyrosine kinase inhibitor designed to target uncommon epidermal growth factor receptor (EGFR) mutations, spare wild-type EGFR, and be active in the central nervous system (CNS). In vitro EGFR enzyme assays and engineered cell line models revealed selectivity and anti-proliferative potency of BLU-451 against a wide range of EGFR mutations in non-small cell lung cancer, including common mutations, atypical mutations, and exon 20 insertions. Particularly, BLU-451 demonstrated robust antitumor activity in EGFR exon 20 insertion cell-derived and patient-derived xenograft models and was well tolerated in animal studies. Pharmacokinetic and pharmacodynamics analyses showed that BLU-451 suppressed exon 20 insertion phosphorylated EGFR expression levels within tumor tissues but not in skin and intestinal tissues, potentially indicative of lower toxicity associated with wild-type EGFR. In intracranial tumor models with imaging-based analyses, BLU-451 showed CNS antitumor efficacy. Early clinical data from patients enrolled in the phase 1 portion of the phase 1/2 CONCERTO trial (NCT05241873) demonstrated the overall clinical potential of BLU-451, including its CNS antitumor activity in patients with EGFR exon 20 insertions and atypical mutations. Initial data suggest that BLU-451 is an active molecule. Further evaluation of the safety profile and pharmacokinetic properties of BLU-451 is needed.