Anaplastic lymphoma kinase inhibition in metastatic non-small cell lung cancer: clinical impact of alectinib
Ittai B Muller, Adrianus J de Langen, Elisa Giovannetti, Godefridus J Peters, Ittai B Muller, Adrianus J de Langen, Elisa Giovannetti, Godefridus J Peters
Abstract
A subset of non-small cell lung cancer (NSCLC) tumors (5%) harbors an anaplastic lymphoma kinase (ALK) translocation that drives tumorigenesis. The clinically approved first-line treatment crizotinib specifically inhibits ALK and improves progression-free survival (PFS) in treated and untreated patients by 4 months compared to standard chemotherapy. While some patients relapse after crizotinib treatment due to resistance mutations in ALK, second-generation ALK inhibitors effectively induce tumor response and prolong PFS. Alectinib, a second-generation ALK inhibitor, has recently been approved for ALK-rearranged NSCLC after patients progressed on crizotinib. Alectinib is able to inhibit several crizotinib- and ceritinib-resistant ALK mutations in vitro. Furthermore, alectinib is a more potent tyrosine kinase inhibitor (TKI), with favorable safety profile, and has increased penetration into the central nervous system, inhibiting crizotinib-resistant brain metastases. The discovery of effective personalized therapies to combat ALK-rearranged NSCLC such as alectinib is an example of the importance of genomic profiling of NSCLC and provides an excellent template for future discoveries in managing these tumors.
Keywords: acquired resistance; alectinib; anaplastic lymphoma kinase; crizotinib; non-small cell lung cancer; tyrosine kinase inhibitors.
Conflict of interest statement
Disclosure The authors report no conflicts of interest in this work.
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References
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