How I treat ALK-positive non-small cell lung cancer

Abstract

Since the discovery of anaplastic lymphocyte kinase (ALK) rearrangement in non-small cell lung cancer (NSCLC) and subsequent development of increasingly effective and central nervous system (CNS)-penetrant first-generation, second-generation and third-generation ALK tyrosine kinase inhibitors (TKIs), the landscape of resistance mechanisms and treatment decisions has become increasingly complex. Tissue and/or plasma-based molecular tests can identify not only the rearrangement proper but also common resistance mechanisms to guide decision-making for further lines of treatment. However, frequently encountered questions exist regarding how to diagnosis ALK rearrangement, how to select a first-line ALK TKI, how to diagnose and manage ALK TKI resistance, how to control CNS disease and how to handle failure of ALK inhibition. Herein, we attempt to answer these questions through the evidence-based interpretation of studies on ALK-rearranged NSCLC combined with experience gained from our institution. The authors also propose a therapeutic algorithm for the management of this complex and highly treatable disease to assist clinicians globally in the treatment of patients with ALK-positive NSCLC.

Keywords: ALK; NSCLC; acquired resistance; alectinib; ceritinib; crizotinib; lorlatinib.

Figure 1

Proposed therapeutic algorithm in ALK-positive NSCLC. ALK, anaplastic lymphoma kinase; cfDNA, cell-free DNA; NSCLC, non-small cell lung cancer; I.O. immunotherapy.