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 ALKrearranged 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 moleculardefined 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. The Oncologist 2012; 17:1351-1375

Clinical Experience With Crizotinib in Patients With Advanced ALK-Rearranged Non–Small-Cell Lung Cancer and Brain Metastases

“…4,5 Inversions in the short arm of chromosome 2 that juxtapose echinoderm microtubuleassociated protein-like 4 (EML4) with ALK and produce EML4-ALK-fusion tyrosine kinases 4,6 are the most common changes noted. The reported prevalence of ALK rearrangements in unselected NSCLC is approximately 5%.…”

“…Crizotinib-a multitargeted TKI with activity against MET, ALK, [13][14][15] and ROS1 16,17 -was approved by the US Food and Drug Administration in August 2011 for advanced NSCLC positive for ALK rearrangements. 5,[18][19][20] More recently, the randomized phase III PROFILE 1007 trial showed that for previously treated patients with ALK-rearranged NSCLC, crizotinib led to improved outcomes (progression-free survival [PFS; primary outcome], objective response rate [ORR], and quality-of-life measurements) when compared with docetaxel or pemetrexed. 21 The median overall survival (OS) of patients with ALK-rearranged NSCLC from the phase I and II trials (PROFILE 1001 and 1005, respectively) was reported as an unprecedented 29.6 months for 120 patients who continued crizotinib even beyond disease progression (PD).…”

Hapten Improved Overall Survival Benefit in Late Stages of Non-Small Cell Lung Cancer (NSCLC) by Ultra-Minimum Incision Personalized Intratumoral Chemo Immunotherapy (UMIPIC) Therapy With and without Radiation Therapy

“…The five-year survival rate for all stages combined, however, is only 16% [1]. Currently, as a first-line treatment of chemotherapy, several agents clinically approved in targeted therapies for lung cancer have ongoing developments such as bevacizumab (Avastin) [3] and erlotinib (Tarceva), as well as the second generation drugs afatinib (BIBW2992) [4][5] and crizotinib (Xalkori) [6]. However, they still exhibit toxicities and limitations due to the differences in molecular and histological profiles of lung cancers [7].…”

Activation of Nrf2 Pathways Correlates with Resistance of NSCLC Cell Lines to CBP501In Vitro

“…During the last decade, several anticancer drugs were developed on the basis of known oncogenic mutations, and the presence of the mutation by itself has been found to be a useful biomarker for these drugs. Examples include some tyrosine kinase inhibitors, including gefitinib and erlotinib, that target epidermal growth factor receptor (EGFR) in NSCLC and for which efficacy depends on the presence of particular EGFR mutations (1,2); crizotinib, which is highly effective when NSCLC cells harbor the EML4-ALK fusion gene (3); and the BRAF inhibitor vemurafenib, which is highly effective when melanoma cells carry the V600E mutation of BRAF (4).…”