Profile of ceritinib in the treatment of ALK+ metastatic non-small-cell lung cancer

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Approximately 3% to 7% of patients with non-small cell lung cancer (NSCLC) possess a gene rearrangement in anaplastic lymphoma kinase (ALK). Although crizotinib is approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with ALK-positive metastatic NSCLC, many patients treated with crizotinib develop resistance to the drug due to various genetic mutations. However, ceritinib was shown to provide clinical benefit in those whose disease progressed on crizotinib, leading to the FDA approval of ceritinib for the treatment of patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib.

The phase I ASCEND-1 trial demonstrated ceritinib 750 mg/day has potent antitumor activity in ALK-positive NSCLC regardless of previous treatment status. Furthermore, unlike crizotinib, ceritinib has shown efficacy in untreated central nervous system (CNS) metastases in both patients with crizotinib-naïve and crizotinib-resistant ALK-positive NSCLC.

In regard to safety, the most common grade 3/4 adverse events associated with ceritinib use are increased ALT/AST, hyperglycemia, decreased phosphate, diarrhea, anemia, and fatigue.

Of the 230,000 new cases of lung cancer diagnosed in the United States each, approximately 80% are NSCLC, and bbout 160,000 deaths from lung cancer occur in the United States each year, making it the leading cause of cancer-related death in both men and women. 

Profile of ceritinib in the treatment of ALK+ metastatic non-small-cell lung cancer
Profile of ceritinib in the treatment of ALK+ metastatic non-small-cell lung cancer

Abstract: Lung cancer has become one of the leading causes of death in both men and women in the United States, with approximately 230,000 new cases and 160,000 deaths each year. Approximately 80% of lung cancer patients are diagnosed with non-small-cell lung cancer (NSCLC), a subset of epithelial lung cancers that are generally insensitive to chemotherapy. An estimated 3%–7% of NSCLC patients harbor tumors containing anaplastic lymphoma kinase (ALK) gene rearrangement as an oncogenic driver. Subsequent development of the first-generation tyrosine kinase inhibitor crizotinib demonstrated substantial initial ALK+-tumor regression, yet ultimately displayed resistance in treated patients. The recently approved tyrosine kinase inhibitor ceritinib has been shown to be an effective antitumor agent against crizotinib-naïve and -resistant ALK+-NSCLC patients. In this review, we will provide an overview of biology and management of ALK+-NSCLC with a special focus on clinical development of ceritinib.

Keywords: ceritinib, anaplastic lymphoma kinase, non-small-cell lung cancer

Anaplastic lymphoma kinase and its role in non-small-cell lung cancer

The anaplastic lymphoma kinase (ALK) is a type-I transmembrane tyrosine kinase belonging to the insulin receptor superfamily and is hypothesized to be active in the early development and maintenance of the central and peripheral nervous systems.1 This 729 kbp gene is located on the p-arm of human chromosome 2 and encodes a functioning 220 kDa transmembrane receptor, containing an extracellular ligand-binding domain, a single-pass membrane spanning domain, and a catalytic intracellular kinase domain.2 A significant degree of ALK mRNA expression throughout developing nervous tissues of both embryonic mice and humans has led to the hypothesis that theALK gene product is involved in the maturation and maintenance of early nervous tissues.3 It has been generally understood that, under normal psychological conditions, binding of a currently unknown mammalian ligand to the extracellular domain induces dimerization of ALK, allowing autophosphorylation and subsequent activation of the intracellular kinase domain.4 The kinase propagates downstream pathways required for cell growth and passage through the cell cycle. Activated ALK proteins are involved in numerous overlapping signaling pathways, specifically the PLC-γ and Ras/ERK1/2 pathways that participate in cell proliferation and the JAK/STAT and PI3K/AKT pathways that propagate cell survival.5 The intensity of ALK mRNA and protein expression subsequently diminishes in mammals after birth, reaching a minimum level approximately 3 weeks after birth and maintained at low levels throughout normal adulthood.6

Considering that normal ALK has very little (if any) activity in mature human tissues, the detection of active ALK domains in tumor samples of non-small-cell lung cancer (NSCLC) patients implicates the oncogenic nature of activated ALK pathways in this subset of metastatic cancers. Despite a vast majority of NSCLCs being associated with mutations induced through tobacco use or exposure, ALK+-NSCLC is most prevalent in nonsmokers.7 Genetic anomalies within the ALK gene through rearrangement, amplification, or mutation produce constitutively active ALK fusion protein domains responsible for the pathogenesis of ALK+-NSCLCs.8 These ALK fusion genes are currently identified in NSCLC patients through tests such as fluorescence in situ hybridization (FISH), immunohistochemistry assay, and reverse transcription-polymerase chain reaction.9 Furthermore, advancements in next-generation genomic sequencing now permit more rapid and reliable detection of ALK+ tumors.10,11  

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