Current and Emerging Treatment Landscape of Common EGFR-Mutated Advanced Non-small Cell Lung Cancer

Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has been standard of care as monotherapy for EGFR-mutated advanced non-small cell lung cancer since reporting of the FLAURA phase III clinical trial, which demonstrated superiority over first-generation EGFR tyrosine kinase inhibitors. Efforts to improve efficacy have led to combination therapies with chemotherapy or co-inhibition of EGFR and MET, which have become additional standards. Choosing between these strategies requires careful understanding of disease biology and disease burden, and joint decision making with patients. Despite increasing understanding of acquired resistance mechanisms in later-line therapies, advances in the first-line options have made second-line treatment decision making increasingly nuanced. Physicians require an in-depth understanding of the genomics of the disease, and ideally an ability to reassess the tumour genomic/expression profile to guide next-line therapy at each timepoint of progression. Targeting on-target resistance (e.g. C797X mutations) with fourth-generation EGFR tyrosine kinase inhibitors has been disappointing, and in addition to biological challenges, there are regulatory challenges with approaches combining tyrosine kinase inhibitors targeting EGFR and off-target oncogenic resistance kinases. There are multiple broader approaches to improve second^-line outcomes in development, such as antibody drug conjugates, vascular endothelial growth factor (VEGF) inhibition and immunotherapeutic approaches, which further complicate treatment selection in the second- and later-line settings. Optimal therapy selection and treatment sequencing provides a great challenge moving into the future. Here, we provide an overview of current and possible future pharmacotherapeutic strategies in the first- and later-line settings for EGFR-mutated non-small cell lung cancer in the context of new first-line strategies and seek to explore the nuances that may guide treatment selection based on current understanding of this disease.