The treatment approach to advanced anaplastic lymphoma kinase fusion-positive (ALK-positive) non-small cell lung cancer (NSCLC) serves as a paradigm for precision oncology. To date, five ALK-tyrosine kinase inhibitors (TKIs)—crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib—have been approved by the US Food and Drug Administration [1,2]. Although each TKI has significant efficacy in ALK-positive NSCLC, the duration of benefit is invariably limited by the development of acquired resistance... Finally, although not addressed in this study, ALK-independent mechanisms of resistance such as bypass signaling or lineage changes remain a major therapeutic hurdle in ALK-positive NSCLC. In an analysis of 20 lorlatinib-resistant tumour biopsies, 65% did not harbour compound ALK resistance mutations [8], implicating ALK-independent resistance. The prevalence of ALK-independent resistance mechanisms will likely rise as strategies to overcome ALK mutations continue to improve. Thus, eff..... READ ARTICLE
eBioMedicine
DOI:10.1016/j.ebiom.2019.01.059
Authors: Jessica J. Lin and Alice T. Shaw