Anaplastic lymphoma kinase inhibition in metastatic non-small cell lung cancer: clinical impact of alectinib

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.

Figure 1

EML4–ALK pathways and the mechanism of resistance to crizotinib. Notes: (A) Crizotinib binds to the ALK-TKI domain of the EML4–ALK fusion protein and inhibits downstream signaling of canonical oncogenic pathways such as the PI3K pathway and RAS pathway. (B) Acquired resistance to crizotinib occurs after crizotinib treatment due to mutations in ALK. In addition, amplification of C-KIT and/or increased EGFR signaling can cause progression, independent of EML4–ALK. Cells remain ALK driven, and alectinib successfully improves PFS by inhibiting several ALK mutations that cause crizotinib resistance. Abbreviations: EML4–ALK, echinoderm microtubule-associated protein-like–anaplastic lymphoma kinase; ALK, anaplastic lymphoma kinase; TKI, tyrosine kinase inhibitor; PI3K, phosphoinositide 3-kinase; RAS, rat sarcoma protein; C-KIT, proto-oncogene C-KIT; EGFR, epidermal growth factor receptor; PFS, progression-free survival; mTOR, mechanistic target of rapamycin; Mek, mitogen-activated protein kinase; Erk, extracellular signal-regulated kinase.