Crizotinib for the treatment of ALK-rearranged non-small cell lung cancer: a success story to usher in the second decade of molecular targeted therapy in oncology

Abstract

Crizotinib, an ALK/MET/ROS1 inhibitor, was approved by the U.S. Food and Drug Administration for the treatment of anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) in August 2011, merely 4 years after the first publication of ALK-rearranged NSCLC. The crizotinib approval was accompanied by the simultaneous approval of an ALK companion diagnostic fluorescent in situ hybridization assay for the detection of ALK-rearranged NSCLC. Crizotinib continued to be developed as an ALK and MET inhibitor in other tumor types driven by alteration in ALK and MET. Crizotinib has recently been shown to be an effective ROS1 inhibitor in ROS1-rearranged NSCLC, with potential future clinical applications in ROS1-rearranged tumors. Here we summarize the heterogeneity within the ALK- and ROS1-rearranged molecular subtypes of NSCLC. We review the past and future clinical development of crizotinib for ALK-rearranged NSCLC and the diagnostic assays to detect ALK-rearranged NSCLC. We highlight how the success of crizotinib has changed the paradigm of future drug development for targeted therapies by targeting a molecular-defined subtype of NSCLC despite its rarity and affected the practice of personalized medicine in oncology, emphasizing close collaboration between clinical oncologists, pathologists, and translational scientists.

Figure 1.

Signaling pathways transduced by EML4–ALK. Abbreviations: ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor.

Figure 2.

List of ALK fusion variants in NSCLC and proportion of various of EML4-ALK fusion variants. (A): Schematic of various forms of ALK fusions in ALK-rearranged NSCLC [, , , , , , –78, 75a]. Adapted from Sasaki T, Rodig SJ, Chirieac LR et al. The biology and treatment of EML4-ALK non-small cell lung cancer. Eur J Cancer 2010;46:1773–1780, with permission. (B): Pie chart of distribution of EML4–ALK various fusions [, , , , , , , –, , , , –94].

Figure 3.

Synthesis of crizotinib. (A): Design and synthesis of crizotinib. Figure 3A provided by Jean Cui. Please refer to reference 107 for detailed synthesis of crizotinib. (B): Crystallography of crizotinib in unphosphorylated MET and ALK [108, 109]. PDB ID 2wgj for PF-02341066/c-MET complex; PDB ID 2xp2 for PF-02341066/ALK complex. Figure 3B provided Jean Cui. Abbreviation: MW, molecular weight.

Figure 4.

Steady-state crizotinib levels in Asians and non-Asians receiving repeated doses of crizotinib 250 mg twice daily [115].

Figure 5.

ALK breakapart FISH assay. (A): Greater than 2 signal diameter separation as a criterion for anaplastic lymphoma kinase (ALK) break-apart fluorescense in situ hybridization (FISH) positivity. (B): 5′3′ break-apart ALK FISH. Figure provided by John Iafrate. (C): Isolated 3′ break-apart ALK FISH. (D): Using the 15% criterion for ALK break-apart, FISH resulted in a clear separation of two groups of NSCLC patients. Adapted and modified from figure 2 of reference [130], with permission.

Figure 6.

Comparison of immunohistochemistry (IHC) using anaplastic lymphoma kinase (ALK) 1 and 5A4 in anaplastic large cell lymphoma and ALK-rearranged non-small cell lung cancer. Both 5A4 IHCs were detected with Leica automation. Magnification: ×200. Figure provided by Marie Mino-Kenudson. Abbreviations: ALCL, anaplastic large cell lymphoma; NSCLC, non-small cell lung cancer.