Targeting common EGFR mutations in NSCLC—review of global phase III trials of third-generation inhibitors

Abstract Mutations of the epidermal growth factor receptor (EGFR) are frequent oncogenic drivers in non-small cell lung cancer (NSCLC). Third-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs), which target common EGFR mutations and the acquired T790M resistance mutation, offer improved inhibitory potency and selectivity. Our review critically assesses the evolving role of these agents for management of NSCLC harboring common EGFR mutations. Multiple global phase III trials have recently evaluated third-generation EGFR-TKIs in NSCLC patients with common EGFR mutations. The addition of osimertinib to curative-intent strategies have demonstrated improvements in disease-free survival and overall survival (OS) as adjuvant therapy in resected stage IB-IIIa patients, major pathological responses compared to chemotherapy when used as neoadjuvant therapy, and progression-free survival (PFS) compared to placebo when used as consolidation therapy in unresectable stage III patients. Furthermore, third-generation EGFR-TKI monotherapy improved PFS compared to first-generation EGFR-TKIs in the first-line treatment of advanced disease. Intensification strategies, such as the addition of chemotherapy or a bi-specific antibody have further enhanced both PFS and OS outcomes. Several new therapeutic options are emerging for patients previously treated with third-generation EGFR-TKIs. Currently, subsequent treatment recommendations include chemotherapy or datopotamab deruxtecan following progression on a third-generation EGFR-TKI combination and amivantamab plus platinum-based chemotherapy following progression on monotherapy. The treatment landscape for NSCLC with common EGFR mutations is rapidly evolving and third-generation EGFR-TKIs play an integral role in both the curative-intent and palliative settings.