Anaplastic lymphoma kinase (ALK) was first identified as a potential drug target in non–small cell lung cancer (NSCLC) 4 years ago when it was discovered as a fusion kinase in a small percentage of Japanese patients with NSCLC.1 This discovery fueled the development of a diagnostic assay for ALK rearrangement,2 which in turn enabled the identification and recruitment of patients with ALK-positive NSCLC into a phase I clinical trial of crizotinib, a dual MET/ALK tyrosine kinase inhibitor.3 In this and a subsequent phase II trial, crizotinib was shown to be highly active, with an objective response rate of approximately 50% to 60%.4,5 Based on its efficacy and safety, crizotinib was recently granted accelerated approval by the FDA for the treatment of patients with advanced ALK-positive NSCLC. As with the BRAF inhibitor vemurafenib for BRAF mutant melanoma,6 crizotinib was approved with a companion diagnostic test. This test—the Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular)—was used to identify patients with ALK-positive disease in the phase II study of crizotinib, and is now required by the FDA to offer patients treatment with crizotinib.
Rearrangements of the ALK gene are relatively uncommon events in NSCLC, but they have profound therapeutic implications for patients identified as ALK-positive. The diagnostic test for ALK rearrangement must therefore be accurate, accessible, and affordable. The FDA label for crizotinib has firmly established fluorescence in situ hybridization (FISH) as the current gold standard for detecting ALK rearrangements in the United States. However, several other methods for establishing ALK positivity have been studied, including immunohistochemistry (IHC) using different ALK-specific antibodies and reverse transcriptase–polymerase chain reaction (RT-PCR). This review discusses each of the available methods, with a focus on the potential utility of non-FISH methods in selecting patients for treatment with crizotinib. How current methods for detecting ALK could impact screening algorithms for NSCLC patients is also discussed.
We thank John Iafrate for helpful discussion and review of the manuscript.
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