Crizotinib: a novel and first-in-class multitargeted tyrosine kinase inhibitor for the treatment of anaplastic lymphoma kinase rearranged non-small cell lung cancer and beyond

Abstract

Epidermal growth factor receptor (EGFR) tyrosine inhibitors were first approved for the treatment of non-small cell lung cancer (NSCLC) in 2003 in the US. Activating EGFR mutations were subsequently discovered in 2004, and heralded the era of molecular targeted therapy in NSCLC. The discovery of anaplastic lymphoma kinase (ALK) rearrangement in NSCLC in 2007 by two independent groups not only represents the first time ALK rearrangement has been discovered in common solid tumors but also represents another important milestone in the era of molecular targeted therapy in NSCLC. Crizotinib, a mesenchymal-epithelial transition (MET)/ALK multi-targeted receptor tyrosine kinase inhibitor went into early Phase I clinical development in 2007. Using the knowledge that NSCLC patients with activating EGFR mutations benefited from EGFR tyrosine kinase inhibitors, crizotinib was rapidly and successfully developed as an inhibitor in ALK-rearranged NSCLC, based on a break apart fluorescence in situ hybridization assay, developed by two of the crizotinib Phase I sites. It cumulated in the conditional approval of crizotinib by the US Food and Drug Administration on August 26, 2011 for the treatment of ALK-rearranged NSCLC. The conditional approval was based on response rates of 50% and 61% from 255 ALK-rearranged NSCLC patients enrolled in two single-arm trials. Common adverse events of crizotinib include mild transient visual disorders, mild gastrointestinal toxicities, fatigue, rare alanine transaminase elevations, and even rarer pneumonitis (1.6%). Confirmatory trials comparing crizotinib with standard chemotherapy are ongoing. It took an unprecedented four years from the discovery of ALK rearrangement in NSCLC to the approval of crizotinib, the first ever ALK inhibitor, for the treatment of ALK-rearranged NSCLC.

Keywords: PF-02341066; anaplastic lymphoma kinase (ALK); crizotinib; non-small cell lung cancer; rearrangement.

Figure 1

Synthesis and structure of crizotinib. The hinge binder 2 aminopyridine in crizotinib is highlighted in red. The molecular formula for crizotinib is C₂₁H₂₂Cl₂FN₅O. The molecular weight is 450.34 Da. The chemical name for crizotinib is (R)-3-[1-(2,6-Dichloro-3-fluorophenyl)-ethoxy]-5-[(1-piperidin-4-yl)-1H-pyrazol-4-yl]pyridin-2-amine. Figure provided by Dr Jean Cui.

Figure 2

Response of ALK-rearranged NSCLC after 2 months of crizotinib.

Figure 3

Dramatic response to crizotinib in a ALK-rearranged NSCLC patient.

Figure 4

Three scenarios where there is a 33% progression (as defined by Response Evaluation in Solid Tumor [RECIST]) can occur when the tumor is still significantly smaller than from baseline, especially with molecular targeted therapy.