Resistance Mechanisms of Alectinib in ALK-Positive Non-Small Cell Lung Cancer and Therapeutic Strategies

Anaplastic Lymphoma Kinase (ALK) -positive Non-Small Cell Lung Cancer (NSCLC) treatment has advanced dramatically since the EML4-ALK fusion gene discovery. Alectinib, a first-line ALK-Tyrosine Kinase Inhibitor (TKI) with high selectivity and blood-brain barrier penetration, markedly improves prognosis. However, approximately 50% of patients develop resistance within 2 years, with mechanisms including ALK-dependent mutations, bypass pathway activation, and histological transformation. Mechanism-driven strategies include next-generation TKIs, combination therapies, immunotherapy, and repurposed agents. Dynamic monitoring via ctDNA liquid biopsy and genomic profiling guides precision treatment. This review summarizes alectinib's value, resistance mechanisms, and tailored strategies to optimize care for ALK-positive NSCLC.