Clinical Information

Lung cancer is the leading cause of cancer death in the United States. Non-small cell lung carcinoma (NSCLC) accounts for 75% to 80% of all lung cancers with an overall 5-year survival rate of 10% to 15%. Standard chemotherapy regimens have had marginal success in improving clinical outcomes. Epidermal growth factor receptor (EGFR) is activated by the binding of specific ligands, resulting in activation of the RAS/MAPK pathway. EGFR-targeted therapies (eg, gefitinib and erlotinib) have been approved by the FDA for use in treating patients with NSCLC who previously failed to respond to traditional chemotherapy. EGFR tyrosine kinase inhibitors have also been shown to increase progression-free and overall survival in patients who receive these therapies as a first-line therapy for the treatment of NSCLC. Agents such as gefitinib and erlotinib, which prevent ATP binding to EGFR kinase, do not appear to have any meaningful inhibitor activity on tumors that lack an activating EGFR mutation or in tumors that demonstrate the presence of drug-resistant EGFR mutations (eg, exon 20 insertions and T790M). Therefore, current data suggest that the efficacy of EGFR-targeted therapies in NSCLC is confined to patients with tumors demonstrating the presence of EGFR-activating mutations such as L858R, L861Q, G719A/S/C, S768I, or small deletions within exon 19 and the absence of drug-resistant mutations. As a result, the mutation status of EGFR is a critical marker for selecting patients for EGFR-targeted therapy.

Rearrangements of the anaplastic lymphoma kinase (ALK) locus are found in a subset of lung carcinomas (generally EGFR wild-type tumors) and their identification by FISH may guide important therapeutic decisions for the management of these tumors. The fusion of the EML4 (echinoderm microtubule-associated protein-like 4) gene with the ALK (anaplastic large cell lymphoma kinase) gene results from an inversion of chromosome band 2p23. The ALK-EML4 rearrangement has been identified in 3% to 5% of NSCLC with the majority occurring in adenocarcinoma and younger male patients who were light or nonsmokers. Recent studies have demonstrated that lung cancers harboring ALK rearrangements are resistant to epidermal growth factor receptor tyrosine kinase inhibitors, but may be highly sensitive to ALK inhibitors, like crizotinib (Xalkori).The drug crizotinib works by blocking certain kinases, including those produced by the abnormal ALK gene. Clinical studies have demonstrated that crizotinib treatment of patients with tumors exhibiting ALK rearrangements can halt tumor progression or result in tumor regression. The ALK/EML4 FISH assay is an FDA-approved companion diagnostic test for crizotinib, which was recently approved by the FDA to treat certain patients with late-stage (locally advanced or metastatic), non-small cell lung cancers that harbor ALK gene rearrangements. It is useful for the identification of lung cancer patients who will benefit from crizotinib therapy.