Oncogenic mutations in non-small cell lung cancer: from molecular mechanisms to clinical practice

Targeted therapy has revolutionized the treatment of non-small cell lung cancer (NSCLC) patients harboring oncogenic alterations, and next-generation tyrosine kinase inhibitors (TKIs) significantly increase blood-brain barrier (BBB) penetration, leading to improved disease control and survival benefits. However, several issues remain to be addressed, including the selection of more appropriate and individualized agents, the emergence of TKI resistance, and the challenging management of central nervous system (CNS) progression. In this review, we comprehensively summarize the efficacy and safety of TKIs and targeted specific antibodies in advanced or metastatic patients with common or rare mutations, providing guidance in selecting the optimal agent. We further explore the mechanisms underlying drug resistance and regimens aimed at overcoming resistance. In nonmetastatic resectable or unresectable NSCLC, we discuss the therapeutic potential of targeted agents and current issues requiring further research. In addition, we distinguish current and potential therapeutic strategies for patients with baseline brain metastasis (BM) and those without baseline BM who subsequently develop brain progression, leading to more effective and personalized treatment. Finally, we provide perspectives on challenges and future directions in the identification and treatment of oncogenic alterations, particularly in the context of co-mutations and the heterogeneous nature of metastases, and emphasize the clinical importance of artificial intelligence (AI)-assisted genetic testing and biomarker development.