The changing treatment landscape of EGFR-mutant non-small-cell lung cancer

The discovery of the association between EGFR mutations and the efficacy of EGFR tyrosine-kinase inhibitors (TKIs) has revolutionized the treatment paradigm for patients with non-small-cell lung cancer (NSCLC). Currently, third-generation EGFR TKIs, which are often characterized by potent central nervous system penetrance, are the standard-of-care first-line treatment for advanced-stage EGFR-mutant NSCLC. Rational combinations of third-generation EGFR TKIs with anti-angiogenic drugs, chemotherapy, the EGFR–MET bispecific antibody amivantamab or local tumour ablation are being investigated as strategies to delay drug resistance and increase clinical benefit. Furthermore, EGFR TKIs are being evaluated in patients with early stage or locally advanced EGFR-mutant NSCLC, with the ambitious aim of achieving cancer cure. Despite the inevitable challenge of acquired resistance, emerging treatments such as new TKIs, antibody–drug conjugates, new immunotherapeutic approaches and targeted protein degraders have shown considerable promise in patients with progression of EGFR-mutant NSCLC on or after treatment with EGFR TKIs. In this Review, we describe the current first-line treatment options for EGFR-mutant NSCLC, provide an overview of the mechanisms of acquired resistance to third-generation EGFR TKIs and explore novel promising treatment strategies. We also highlight potential avenues for future research that are aimed at improving the survival outcomes of patients with this disease.