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ALK in Non-small Cell Lung Cancer

ALK in NSCLC

Globally, lung cancer is one of the most commonly reported cancers, with approximately 2.2 million new cases worldwide each year.1 Approximately 80% of lung cancers are non-small cell lung cancer (NSCLC).1 The prognosis for patients with lung cancer is poor; the 5-year survival rate for patients with NSCLC is approximately 17%.2 Existing therapies have limited therapeutic benefit in unselected NSCLC.3-5 Therefore, there is a need for new treatments which can improve outcomes for patients with advanced NSCLC.

There are three main histological NSCLC subtypes:

Adenocarcinoma
Squamous Cell Carcinoma
NSCLC not otherwise specified

Alternatively, NSCLC can be divided into molecular subsets based on specific biomarkers or mutations. Data indicate that 56% of non-squamous cell lung tumours have a driver mutation which can be detected through molecular testing.6 Identifying the particular molecular drivers present in individual patients may allow a personalised treatment approach to be used. One of the known molecular drivers in NSCLC is an aberrant form of anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase encoded by the ALK gene.7 ALK gene rearrangements lead to expression of ALK fusion proteins which have been identified as oncogenic drivers in a subset of patients with NSCLC. 7 Inhibition of ALK has been shown to be an effective treatment approach for patients with ALK-positive NSCLC.8-10

Figure. Evolution of knowledge of NSCLC.11,12

Evolution of knowledge of NSCLC

 

Adapted from Pao W, Girard N. Lancet Oncol 2011;12:175–180 & Shaw AT, et al. N Engl J Med 2011;365:158–167. Reproduced with permission from Elsevier and Massachusetts Medical Society ©2011.

References

References

  1. Siegel RL, Miller KD, Jemal A.. Cancer statistics, 2015. CA Cancer J Clin 2011;65:5–29
  2. American Cancer Society. Cancer Facts & Figures 2015. Atlanta: American Cancer Society; 2015
  3. Scagliotti G, DeMarinis F, Rinaldi M, et al. Phase II randomized trial comparing three platinum-based doublets in advanced non-small cell lung cancer. J Clin Oncol 2002;20:4285–4291
  4. Herbst RS, Prager D, Hermann R, et al: TRIBUTE: A phase III trial of erlotinib HCl (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 2005;23:5892–5899
  5. Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small cell lung cancer. New Engl J Med2002;346:92–98
  6. Kris MG, Arcila ME, Lau C, et al. Two year results of LC-MAP: an institutional program to routinely profile tumor specimens for the presence of mutations in targeted pathways in all patients with non-small cell lung cancers. Oral presentation at World Conference on Lung Cancer, Amsterdam, The Netherlands, July 3–7, 2011 (Abstract 016.05)
  7. Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small cell lung cancer. Nature 2007;448:561–567
  8. Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013;368:2385–2394
  9. Shaw AT, Kim DW, Mehra R, et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med 2014;370:1189–1197
  10. Gadgeel SM, Gandhi L, Riely GJ, et al. Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study. Lancet Oncol 2014;15:1119–1128
  11. Pao W, Girard N. New driver mutations in non-small-cell lung cancer. Lancet Oncol 2011;12:175–180
  12. Shaw AT, Forcione DG, Digumarthy SR, Iafrate AJ. Case 21-2011: A 31-year-old man with ALK-positive adenocarcinoma of the lung. N Engl J Med 2011;365:158–167