ALK Rearrangements as a Therapeutic Target in Advanced Non-Small Cell Lung Cancer

D. Ross Camidge, MD, PhD
Published: Thursday, Jun 14, 2012
Dr. D. Ross Camidge Corresponding Author:

D. Ross Camidge, MD, PhD

University of Colorado
Comprehensive Cancer Center,
Anschutz Medical Campus,
Aurora, CO;


Frequency of ALK positivity in non-small cell lung cancer (NSCLC) varies depending on the presence or absence of several key clinical and pathologic factors; groups with a true 0% chance of positivity are hard to define. Only a small proportion of ALK-positive (ALK+) cases manifest intrinsic resistance to crizotinib, a small-molecule inhibitor of ALK recently licensed for treatment of ALK+ NSCLC by the FDA. The majority demonstrate rapid and dramatic responses to this therapy. Although in general crizotinib is well tolerated, several common mild side effects and a few rare severe side effects require specific management. Despite its remarkable clinical activity, acquired resistance to crizotinib is predicted to develop in all ALK+ cases, just as epidermal growth factor receptor (EGFR)-mutant NSCLC develops resistance to treatment with EGFR tyrosine kinase inhibitors. Multiple mechanisms of intrinsic and acquired resistance to crizotinib in ALK+ NSCLC have been described, and treatment options in this setting are discussed.

The anaplastic lymphoma kinase (ALK) gene encodes a transmembrane tyrosine kinase receptor involved in a number of developmental processes.1 Oncogenic ALK gene rearrangements are characterized by chromosomal translocations that place one of a series of different 5’ fusion partners and their associated promoter upstream of the 3’ kinase domain of the ALK gene. These rearrangements were originally described in a subset of non-Hodgkin lymphoma2; hence, the new gene was named anaplastic lymphoma kinase. In 2007, an ALK gene rearrangement involving EML4 as the 5’ partner was discovered by looking for cDNAs with the potential to transform cells isolated from a lung adenocarcinoma occurring in a Japanese male smoker.3 Although other 5’ partners for ALK in non-small cell lung cancer (NSCLC), notably KIF5B and TFG, have since been described, EML4-ALK is by far the most common ALK rearrangement seen in NSCLC.4,5 In series dominated by adenocarcinomas, ALK positivity has been reported to occur in approximately 4% of NSCLC.6

Finding ALK-Positive Lung Cancer

Patients in all of the initial crizotinib studies were proven to be ALK-positive (ALK+) using the Vysis Break-Apart fluorescence in situ hybridization (FISH) Probe Kit.7,8 With this assay, the FISH probes flank the common breakpoint in ALK and separate when a rearrangement occurs (Figure 1).9 Immunohistochemistry and reverse transcriptase-polymerase chain reaction are also being explored as alternative diagnostic techniques.10,11 Whether insurers will mandate one test over another to cover access to crizotinib is unclear. When considering different testing methodologies, false-positive results will reduce the benefit from the drug. However, the greater fear is of false-negative results that would deny patients with a high chance of benefit from getting access to the drug. Studies directly comparing techniques and the benefit from crizotinib in patients who are ALK+ according to different criteria are planned.

Figure 1. Break-Apart FISH Probe Kit Used to Detect ALK Positivity

Detection of ALK Positivity

Red and green FISH probes flank the common breakpoint in the native ALK gene. When no rearrangement is present, the probes appear fused together (yellow arrows in panel A). When an ALK rearrangement occurs, the probes separate, either appearing as a classic "split" pattern (red and green arrows in panel B) or a "single red" pattern where red signals outnumber green signals, suggesting that both a rearrangement and loss of the 5' probe (non-kinase encoding) binding site has occurred (red arrows in panel C). Increases in both rearranged (double red and green arrows in panel D) and native ALK copy number can occur. Copy number gain (CNG) of rearranged signals has been associated with acquired resistance to crizotinib, but CNG of the native gene is not currently considered of any clinical significance.

ALK=anaplastic lymphoma kinase; FISH=fluorescence in situ hybridization.

Adapted with permission from Camidge DR, Kono SA, Flacco A, et al. Clin Cancer Res. 2010;16(22):5581-5590.

In addition to the issue of how to test, the issue of who should be tested is also under discussion. Recognizing that ALK positivity in NSCLC is associated with adenocarcinoma histology, never-smoking status, and absence of other common molecular drivers such as epidermal growth factor receptor (EGFR) and K-ras mutations, clinical enrichment using some or all of these factors has clearly been shown to increase the positivity rate from screening.9 However, no groups with a 0% chance of positivity stand out. Therefore, a policy of only screening an enriched population has to weigh both (1) the cost savings in terms of reducing the absolute numbers of patients screened and the reduced cost per positive found within an enriched population and (2) the number of true positives missed by any preselection approach.12

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