Enozertinib Is a Selective, Brain-Penetrant EGFR Inhibitor for Treating Non-Small Cell Lung Cancers with EGFR Exon 20 and Atypical Mutations.

EGFR mutations are common oncogenic drivers in non-small cell lung cancer (NSCLC), and approximately half of patients develop brain metastases over the course of their disease. Patients with nonclassic EGFR mutations, such as insertions in exon 20, are a high unmet need with a worse prognosis compared with patients with classic EGFR mutations. Here, we describe the discovery and development of enozertinib (formerly ORIC-114), a highly brain-penetrant, orally bioavailable, irreversible inhibitor that targets EGFR exon 20 mutations with unparalleled kinome selectivity. Preclinical studies revealed strong potency and tumor regressions driven by enozertinib across a broad range of atypical EGFR-mutant models. In a phase I clinical trial of enozertinib in patients with advanced NSCLC bearing atypical mutations in EGFR, a patient harboring an EGFR exon 20 insertion experienced sustained complete response of all systemic and brain metastases. Together, these findings identify enozertinib as a promising investigational inhibitor to address the unmet need for brain-penetrant therapies in NSCLC with EGFR exon 20 insertions or other atypical mutations. SIGNIFICANCE: Preclinical and initial phase I clinical data demonstrate the potency, kinome selectivity, efficacy, and brain penetration of enozertinib in NSCLC with EGFR exon 20 insertions and atypical mutations, warranting further clinical development.