Crizotinib and Testing for ALK

Abstract

Crizotinib was recently approved by the US FDA for the treatment of advanced non-small cell lung cancer (NSCLC) harboring the ALK (anaplastic lymphoma kinase) gene rearrangement. To ensure identification of patients most likely to benefit, the FDA approved crizotinib concurrently with a companion diagnostic test-the Vysis ALK Break Apart FISH Probe Kit. This kit was used in 1 of the 2 pivotal trials leading to the FDA approval of crizotinib and has become the gold standard for detecting ALK rearrangement in NSCLC. Although ALK FISH is clinically validated, the assay can be technically challenging and costly. Therefore, other diagnostic modalities are being explored, including immunohistochemistry (IHC) and reverse transcriptase-polymerase chain reaction. This article provides an overview of the diagnostic assays available for detecting ALK rearrangement. Each assay, including ALK FISH, has its strengths and weaknesses. Recent work with commercially available ALK antibodies suggests that IHC-based tests may represent a reliable and cost-effective screening strategy; however, large multicenter studies comparing IHC with FISH are needed to validate ALK IHC. While ALK FISH remains the current standard for diagnosing ALK positivity, large-scale screening of patients with newly diagnosed advanced NSCLC, as recommended by NCCN, may require development and validation of alternative screening strategies, such as combination IHC and FISH.

Molecular characterization of pulmonary sarcomatoid carcinoma: analysis of 33 cases

“…[11][12][13][14] Currently, tumors with ALK rearrangement and EGFR mutations have molecular targeted therapies approved by the US Food and Drug Administration. Crizotinib and ceritinib are approved for use in ALK rearranged tumors, [15][16][17] while erlotinib, gefitinib, and afatinib are approved for tumors with EGFR mutations. [18][19][20][21] In the US population, these therapies are applicable to a minority of patients with lung carcinoma, as ALK rearrangement is present in o 5% of lung adenocarcinomas and EGFR mutations are present in 15-25% of lung adenocarcinomas.…”

Data Set for Reporting of Lung Carcinomas: Recommendations From International Collaboration on Cancer Reporting

“…The preferred and only US Food and Drug Administrationapproved method for EML4-ALK translocation testing is a fluorescence in situ hybridization assay that uses a breakapart probe. 57 Studies of other detection techniques, such as using an immunohistochemical marker that is specific for EML4-ALK, are ongoing. 58 …”

Translational Pharmacokinetic-Pharmacodynamic Modeling from Nonclinical to Clinical Development: A Case Study of Anticancer Drug, Crizotinib

“…Crizotinib has recently been approved by the Food and Drug Administration (FDA) for the treatment of patients with locally advanced or metastatic NSCLC that is ALK-positive as detected by an FDA-approved test. The companion diagnostic test kit to detect ALK rearrangements (i.e., a breakapart fluorescence in situ hybridization assay) has also been developed in parallel with clinical trials of crizotinib (25,29). Investigations into the clinical responses derived from crizotinib-mediated MET inhibition are still ongoing with case reports describing clinical activity in some patients with MET-amplified NSCLC, gastroesophageal carcinoma and glioblastoma (25).…”