Treatment Sequencing for Anaplastic Lymphoma Kinase-Rearranged Non-Small-Cell Lung Cancer

Non-small-cell lung cancer (NSCLC) accounts for about 85% of all lung cancer cases and is the leading cause of cancer-related deaths. Most NSCLC patients are diagnosed with advanced disease and require systemic treatment. Despite emerging advances in chemotherapy and immunotherapy, the prognosis of stage IV patients remains poor. However, the discovery of oncogenic driver mutations including mutations in the epidermal growth factor receptor (EGFR), the anaplastic lymphoma kinase (ALK) and others, characterize a subset of patients with the opportunity of targeted therapies. Fusions between the ALK and echinoderm microtubule-associated protein-like 4 (EML4) are present in ∼ 3-5% of patients with NSCLC. Several first-, second-, and third-generation ALK tyrosine kinase inhibitors (TKIs) have been developed in the last decade and have tremendously changed treatment options and outcomes of ALK-positive NSCLC patients. With increasing treatment options, treatment sequence decisions have become more and more complex. ALK-mutations, fusion variants, or activation of by-pass pathways result in treatment resistance during the course of treatment in nearly all patients. Mutation-guided treatment sequencing can lead to better outcomes, and re-biopsy or liquid-biopsy should be performed whenever possible in case of disease progression in ALK-rearranged patients. In the future, combinational treatment of ALK TKIs with other pathway-inhibitors might further improve patients' treatment options and outcomes. Here, we review the data for currently available ALK TKIs, discuss approaches of treatment sequencing, and give an outlook on emerging developments.