Approximately 2% to 7% of patients with non–small cell lung cancer (NSCLC) have tumors with oncogenic fusion genes consisting of portions of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene (EML4-ALK). In a study recently reported by Kwak et al in The New England Journal of Medicine, the oral ALK tyrosine kinase inhibitor crizotinib showed remarkable activity in patients who had NSCLC with these ALK gene rearrangements. Screening of nearly 1,500 NSCLC patients identified 82 patients (5.5%) with advanced ALK-positive disease, 96% of whom had received prior treatment. ALK rearrangements tended to occur in tumors of younger patients, with most having little or no exposure to tobacco (never = 76%, ≤ 10 pack-years = 18%, > 10 pack-years = 6%) and most having adenocarcinoma (96%).

After a mean treatment duration of 6.4 months at a crizotinib dose of 250 mg twice daily, confirmed response was observed in 47 (57%) of 82 patients, with partial response in 46 and complete response in 1, and stable disease was observed in 27 additional patients (33%). These outcomes compare very favorably with an estimated response rate of 10% associated with second-line chemotherapy in such patients. Estimated probability of progression-free survival at 6 months was 72%, with median survival not yet reached at the time of analysis. The most common adverse events were grade 1 or 2 gastrointestinal side effects and mild vision disturbance. Grade 3/4 ALT and AST elevations each occurred in 6% of patients.

As noted by the authors, the rate and speed of response observed with crizotinib were similar to those with EGFR (epidermal growth factor receptor) tyrosine kinase inhibitors in EGFR-mutant NSCLC, indicating that ALK-positive tumors are a second genetically defined subgroup of oncogene-driven lung cancer that is highly susceptible to targeted therapy. If it is assumed that 5% of patients with NSCLC have tumors that harbor ALK rearrangements, it can be estimated that approximately 8,800 patients per year in the United States alone would be eligible for crizotinib or other ALK kinase inhibitor therapy.

Growing List of Genetic Alterations

ALK rearrangements join a growing list of genetic abnormalities incorporated into analysis for oncogenes in NSCLC tumors. A currently available lung cancer mutation panel tests for EGFR, KRAS, and ALK mutations that predict response and lack of response to targeted therapies in NSCLC. The presence of each of these oncogenes is almost always exclusive of the presence of the other two within an individual tumor.

Activation of the EGFR tyrosine kinase (via ligand binding of EGFR) results in activation of signaling pathways for cell growth and survival. EGFR tyrosine kinase inhibitors such as erlotinib (Tarceva) and gefitinib (Iressa) block activation of the signaling pathways. EGFR mutations (eg, exon 19 deletions, L858R, L861Q, and G719A/C/S) activate the EGFR in the absence of ligand and confer greater likelihood of response to these kinase inhibitors. Other rare mutations (eg, T790M and exon 20 insertion) are associated with resistance to these agents. Activating mutations are found in approximately 40% of East Asian patients and 10% to 15% of Caucasian patients. These mutations are more common in patients with no smoking history (although they are also found in smokers), females, and adenocarcinomas (although they are also found in squamous cell tumors). Patients with these mutations have a greater than 70% likelihood of response to erlotinib or gefitinib.

Predictive/Prognostic Value

In NSCLC, EML4-ALK is an aberrant fusion gene (see Fig. 1) encoding a cytoplasmic chimeric protein with constitutive kinase activity. Several distinct EML4-ALK chimeric variants have been identified (representing breakpoints within different EML4 exons), with all of these variants found to be transforming in vitro. As noted, EML4-ALK is more common in patients with no/light smoking history and in adenocarcinomas. In the study by Kwak et al, none of the 82 patients with ALK rearrangement had activating EGFR mutations.

In addition to EML4, other fusion partners for ALK (eg, KIF5B and TFG) have been identified in NSCLC, suggesting that ALK rearrangements may constitute a molecular subgroup of tumors susceptible to ALK kinase inhibition. It should be noted that mutations in EML4-ALK that confer resistance to crizotinib (C1156Y and L1196M) have already been identified in a patient with NSCLC with a strong initial response to the agent.

Conclusions

Mutations in EGFR and EML4-ALK fusions are important determinants of response to targeted treatments in NSCLC. Genetic tests to identify the presence of all of these alterations will greatly aid in selecting appropriate therapy, avoiding unnecessary use of treatments in significant segments of the population. The use of genotyping to detect these alterations is likely to become standard practice in this setting. Work is ongoing to identify other genetic drivers of NSCLC tumorigenesis and to bring us another step closer to personalized treatment of this disease. ■

Resources

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Hallberg B, Palmer RH: Crizotinib—latest champion in the cancer wars? N Engl J Med 363:1760-1762, 2010.

Jackman DM, Miller VA, Cioffredi L-A, et al: Impact of epidermal growth factor receptor and KRAS mutations on clinical outcomes in previously untreated non-small cell lung cancer patients: Results of an online tumor registry of clinical trials. Clin Cancer Res 15:5267-5273, 2009.

Kwak EL, Bang Y-J, Camidge R, et al: Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 363:1693-1703, 2010.

Massachusetts General Hospital Cancer Center: Tumor genotyping brings personalized, targeted therapies to patients. In: Advances at the Mass General Cancer Center, Summer 2010. Available at http://www.massgeneral.org/cancer/assets/pdfs/Advances_TRL.pdf.

Massarelli E, Varella-Garcia M, Tang X, et al: KRAS mutation is an important predictor of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Clin Cancer Res 13:2890-2896, 2007.

Quest Diagnostics: Lung cancer mutation panel (EGFR, KRAS, ALK). Available at http://www.questdiagnostics.com/hcp/intguide/jsp/showintguidepage.jsp?fn=TS_LungCancerMutation_Panel.htm.

Sasaki T, Rodig SJ, Chirieac LR, et al: The biology and treatment of EML4-ALK non-small cell lung cancer. Eur J Cancer 46:1773-1780, 2010.

Shaw AT, Yeap BY, Mino-Kenudson M, et al: Clinical features and outcome of patients with non-small–cell lung cancer who harbor EML4-ALK. J Clin Oncol 27:4247-4253, 2009.