The Current Landscape of Anaplastic Lymphoma Kinase (ALK) in Non-Small Cell Lung Cancer: Emerging Treatment Paradigms and Future Directions

Abstract

Tumorigenic rearrangements in anaplastic lymphoma kinase (ALK) account for 3–7% of all non-small cell lung cancers (NSCLC). Treatment with targeted tyrosine kinase inhibitors (TKIs) has shown impressive clinical responses. Crizotinib was the first agent approved for front-line therapy of ALK-rearranged NSCLC after it demonstrated superiority to chemotherapy in response rate, duration of response, and progression-free survival. However, eventually all patients progress on crizotinib therapy, with the central nervous system (CNS) being the most common site, which served as the impetus for the development of more potent next-generation ALK inhibitors. Currently, ceritinib, alectinib, and brigatinib are all approved for second-line therapy after progression on or intolerance to crizotinib. Investigations into whether the initiation of a second-generation ALK inhibitor as first-line therapy is the superior treatment paradigm has resulted in the approval of ceritinib as initial therapy. Alectinib has also shown impressive results as front-line therapy, as recently reported in two large randomized studies that compared it to crizotinib. There is a significant need to better understand the drivers of and mechanisms underlying resistance to ALK inhibitors. While specific mutations have been identified, there is currently only limited evidence that the identification of specific mutations should impact selection of the next ALK inhibitor. The best treatment option for patients who become TKI refractory is also unclear, though there is some evidence to suggests that these patients are not responsive to checkpoint inhibitors and may respond better to chemotherapy. Combination therapy with other classes of agents may help to overcome resistance mechanisms and should be investigated further.

Ensartinib (X-396) Effectively Modulates Pharmacokinetic Resistance Mediated by ABCB1 and ABCG2 Drug Efflux Transporters and CYP3A4 Biotransformation Enzyme

“…At present, the most clinically successful group of targeted drugs are tyrosine kinase inhibitors (TKIs) and therapeutic antibodies. Ensartinib (X-396) is a third-generation TKI (Figure 1) that is a potent inhibitor of mutated anaplastic lymphoma kinase (ALK); deregulation of this enzyme has been found to be a meaningful target in 3-7% of all NSCLC cases [3]. Ensartinib is currently undergoing phase II and III clinical trials for the treatment of NSCLC [4]; preclinical investigations have shown that it is more active than the approved ALK inhibitors crizotinib, alectinib, and ceritinib and that it retains activity even in models with ALK mutations that confer resistance to these agents [5].…”

Gastrointestinal tissue‐based molecular biomarkers: a practical categorisation based on the 2019 World Health Organization classification of epithelial digestive tumours

“…21 At the protein level, examples are mesenchymal-epithelial transition factor (c-MET) in CRC and anaplastic lymphoma kinase fusion in NSCLC; both can be detected by immunohistochemistry. 22,23 To add more complexity, a biomarker can be detected at different levels with different degrees of clinical significance, independently of the system/organ where it occurs. An example of this is ERBB2 in NSCLC, in which mutation is not associated with ERBB2 amplification or ERBB2 overexpression, suggesting a distinct entity and a potential different therapeutic target.…”

A Review: Status of Genetic Modulated Nonsmall Cell Lung Cancer Targets and Treatment (Current Updates in Drugs for Non-Small Cell Lung Cancer Treatment)

“…Other ALK mutations do not been found involving EML-4, including KIF5B-ALK and TFG ALK. Regarding treatment, patients suffered from EML4-ALK fusions or ALK rearrangements not benefited from EGFR-specific tyrosine kinase inhibitor therapy in NSCLC and ovarian cancer [49][50][51][52].…”

“…Interventions for the treatment of ALK mutations ALK fusion oncogene associated with advanced NSCLC is highly sensitive to ALK tyrosine kinase (TK) inhibitors [51,53].…”