Efficacy of crizotinib in ALK fusion variants

In 1995, rearrangement of the anaplastic lymphoma kinase (ALK) gene was first reported as a fusion gene in anaplastic large cell non-Hodgkin lymphoma, and in 2005 it was again on focus when Soda et al. reported that echinoderm microtubule-associated protein-like4 (EML4)-ALK fusion gene is a powerful oncogene in lung cancer (1,2). EML4-ALK is a fusion of the intracellular scaffold protein EML4 and the kinase protein ALK. The EML4-ALK fusion protein constitutively activates ALK kinase by forming a coiled-coil domain in the EML4 region (2). About 3–5% of non-small cell lung cancer is positive for EML4-ALK (2). Transgenic mice expressing EML4-ALK develop non-small cell lung cancer (3). Several drugs that inhibit the activity of this fusion gene have been recently developed. Crizotinib that was initially developed as a mesenchymal-epithelial transition factor (MET) inhibitor can also inhibit multiple kinases including ALK. In 2008, crizotinib was used as an ALK tyrosine kinase inhibitor (TKI) in a phase I clinical trial in ALK-positive lung cancer patients (4). The study showed a good overall response rate (ORR; 60.8%) and progression-free survival (PFS; 9.7 months) (4). Thereafter, similar ORR and PFS results were reported in a phase II clinical trial, and the US Food and Drug Administration (FDA) approved it in 2011 (5). Crizotinib became available for clinical use in a very short time (4 years) since its initial report, and is currently the first line therapy for ALK-positive lung cancer. However, subsequent studies have shown frequent recurrence and brain metastasis of ALK-positive lung tumors that are resistant to crizotinib therapy (6-8)