Diagnostic and therapeutic issues for patients with advanced non-small cell lung cancer harboring anaplastic lymphoma kinase rearrangement: European vs. US perspective (Review)

Abstract

The recent availability of crizotinib in clinical practice, for the treatment of patients with advanced non-small cell lung cancer (NSCLC) selected by the presence of anaplastic lymphoma kinase (ALK) rearrangement, has relevant implications for both the diagnostic phase and the treatment choices. In the United States, crizotinib was approved by the Food and Drug Administration (FDA) in 2011 for patients with ALK positivity detected by FDA-approved companion diagnostic test. As of January, 2014, the only FDA-approved diagnostic test is Vysis ALK Break-Apart FISH Probe Kit. In Europe, European Medicines Agency (EMA) approved crizotinib for ALK-positive patients in 2012, without specifying the type of test used for determining the positivity. FISH remains the reference technique for ALK determination, but, if fully validated, immunohistochemistry could challenge the current ALK screening practice. Given the robust evidence of activity of crizotinib in ALK-positive patients both pretreated and chemotherapy-naïve, and the favourable tolerability profile of the drug, many oncologists would prefer to administer the drug as early as possible. This is technically feasible in the United States, where crizotinib was approved well before the availability of the results of the randomized phase III trial comparing the drug with standard second-line chemotherapy, and the use of crizotinib in ALK-positive patients is not restricted to a specific line of treatment. On the contrary, in Europe, differently from the FDA decision, crizotinib cannot be used in chemotherapy-naïve patients. In both realities, a deeper knowledge of mechanisms of resistance, the role of repeated biopsies, the treatment strategy for patients experiencing disease progression with crizotinib, the choice of the best chemotherapy regimen are challenging topics for the management of ALK-positive patients in clinical practice.

Assessment of ALK gene fusions in lung cancer using the differential expression and exon integrity methods

“…FISH-based methods have an advantage in that the general morphology of tumor cells and the physical integrity of chromosome 2 may be observed simultaneously. However, FISH methods are expensive, require a high degree of technological expertise and frequently produce non-interpretable results (7,8). By contrast, IHC is able to detect the levels of ALK protein, and several commercial systems with specific monoclonal antibodies against ALK protein are available (7,8).…”

“…However, FISH methods are expensive, require a high degree of technological expertise and frequently produce non-interpretable results (7,8). By contrast, IHC is able to detect the levels of ALK protein, and several commercial systems with specific monoclonal antibodies against ALK protein are available (7,8). However, the protocol for IHC is complex and time-consuming, and final results of IHC are subject to antibody quality and pathologist experience (12).…”

“…For ALK rearrangement detection, the U.S. Food and Drug Administration (FDA)-approved method for companion diagnostics is fluorescence in situ hybridization (FISH), which measures the physical integrity of the ALK gene in chromosome 2 (7). However, previous studies have identified that FISH is prone to technical difficulties, which may lead to non-interpretable results (8,9).…”

Tackling ALK in non-small cell lung cancer: the role of novel inhibitors

“…Regardless of the line of treatment crizotinib is administered, the most challenging therapeutic decisions come when progression to the compound occurs, in terms of both the correct definition of crizotinib failure and of the selection of proper treatment. When other targeted agents were not yet available, patients with disease progression on crizotinib, if eligible for further treatment, could remain on crizotinib "beyond progression", or were switched to chemotherapy (114 In patients with frank disease progression, this latter strategy was a clinically sound approach. On the other hand, for patients experiencing progression in a single site or in a few disease sites (the so called "oligo-progressive diseases"), continuation of crizotinib, alone or associated with local therapy (surgery and/or ablative treatments), has been commonly proposed as a reasonable option (103,109,115).…”

Therapeutic management of ALK+nonsmall cell lung cancer patients

“…In Europe, authorisation for second-line therapy only was obtained in 2012 [49]. Prescription is irrespective of the method of detection.…”