Ceritinib for the Treatment of Late-Stage (Metastatic) Non-Small Cell Lung Cancer

摘要

Abstract Over the past decade, the non-small cell lung cancer therapeutics landscape has been dominated by the increasing focus on identification and validation of molecular targets, as well as the identification of the best candidate agents to address these targets. Among the notable successes have been the approval of erlotinib, gefitinib, and afatinib for the EGFR mutation, and more recently crizotinib for anaplastic lym-phoma kinase (ALK) gene rearrangement. Despite the excellent efficacy of crizotinib, several mechanisms of resistance, including secondary mutation in the ALK gene, eventually result in disease progression, and several second-generation ALK inhibitors, notably ceritinib, have demonstrated evidence of clinical activity in this setting. This review discusses the data associated with the recent accelerated approval of ceritinib for treatment of patients with ALK-positive, metastatic lung adenocarcinoma with disease progression on or who are intolerant to crizotinib. Introduction Since the original report by Soda and colleagues that the anaplastic lymphoma kinase (ALK) gene fuses with the echi-noderm microtubule-associated protein like 4 (EML4), resulting in potent transforming activity in non-small cell lung cancer (NSCLC) limited to the adenocarcinoma histologic subtype, it is well recognized that between 3% and 7% of NSCLC is molecularly defined by the presence of an inversion or translocation of chromosome 2p involving the ALK gene, resulting in a transforming fusion gene and representing a distinct molecular subset of disease (1, 2). Generally, all the ALK rearrangements identified so far are constituted by two portions. The first is the highly conserved break point within ALK, located in the intron immediately upstream of the exons encoding the kinase domain; the second are the 5'-end partners containing a coiled-coil or leucine zipper domain responsible for oligomerization of fusion protein and ligand-independent activation of the ALK tyrosine kinase (TK) activity. Constitutive activation of downstream signaling pathways, such as the Ras/ MAPK, PI3K/AKT, and JAK/STAT, results in uncontrolled cancer cell proliferation and survival. Thirteen variants of the EML4-ALK fusion have been described, according to the break point on EML4 (from exon 2 to exon 20; ref. 3). Furthermore, in addition to EML4, the TRK-fused gene (TFG; refs. 4-6) and the kinesin family member 5B (KIF5B; refs. 4-6) have been described to be fused to ALK in rare cases (Table 1).