Biology and impact of lineage plasticity in ALK-positive NSCLC: a narrative review

BACKGROUND AND OBJECTIVE: Lineage transformation is a known mechanism of acquired resistance to targeted therapies in non-small cell lung cancer (NSCLC). Transformation to small cell and squamous carcinoma and epithelial-to-mesenchymal transition (EMT) have all been identified as recurrent but rare events in ALK-positive NSCLC. However, centralized data informing our understanding of the biology and clinical implications of lineage transformation in ALK-positive NSCLC are lacking. METHODS: We performed a narrative review by searching the PubMed and clinicaltrials.gov databases for articles published in English from August, 2007 until October, 2022 and reviewing the bibliographies of key references to identify important literature related to lineage transformation in ALK-positive NSCLC. KEY CONTENT AND FINDINGS: In this review, we aimed to synthesize the published literature describing the incidence, mechanism(s), and clinical outcomes of lineage transformation in ALK-positive NSCLC. Lineage transformation as a mechanism of resistance to ALK TKIs in ALK-positive NSCLC is reported at a frequency of <5%. Available data across molecular subtypes of NSCLC suggest that the process of lineage transformation is likely to be driven by transcriptional reprogramming rather than acquired genomic mutations. Retrospective cohorts including tissue-based translational studies together with clinical outcomes make up the highest level of evidence that exists to inform treatment approach for patients with transfomed ALK-positive NSCLC. CONCLUSIONS: The clinicopathologic features of transformed ALK-positive NSCLC as well as the biologic mechanisms underling lineage transformation remain incompletely understood. Prospective data are needed to develop improved diagnostic and treatment algorithms for patients with ALK-positive NSCLC that undergo lineage transformation.