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ALK inhibitors: a new targeted therapy in the treatment of advanced NSCLC

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Abstract

The anaplastic lymphoma kinase (ALK) fusion gene is a key oncogenic driver in a subset of patients with advanced non-small cell lung cancer (NSCLC). Oncogenic fusion genes, including echinoderm microtubule-associated protein-like 4 (EML4) and ALK, have been detected in approximately 2–7 % of NSCLC patients. Fluorescence in situ hybridization (FISH) is the recommended method for detecting ALK gene rearrangement. EML4–ALK fusion genes define a molecular subset of NSCLC with distinct clinical characteristic (lung adenocarcinoma, never or former smoker, usually mutually exclusive with EGFR mutations). Crizotinib (PF-02341066) is an orally bioavailable, ATP-competitive, small molecule inhibitor of both the receptor tyrosine kinases ALK and c-MET (hepatocyte growth factor receptor). Crizotinib has been shown to yield important clinical benefit such as objective response rate, progression-free survival (PFS), and anticipated improvements in quality of life when used in pretreated patients with advanced NSCLC harboring EML4–ALK gene rearrangement. Preliminary phase II data suggested that crizotinib is safe and well tolerated with rapid and robust antitumor activity. A phase III randomized trial in a second-line setting showed response rate and PFS (primary study endpoint) advantage for crizotinib as compared to second-line chemotherapy. Treatment-related adverse events, predominantly restricted to the gastrointestinal and visual systems, are generally self-limiting or easily managed. Crizotinib is a new standard of care for patients with advanced, ALK-positive, NSCLC. In this review, we will discuss the discovery of ALK rearrangements, the clinical epidemiology of lung cancer driven by ALK, the clinical data for ALK-targeted therapy in NSCLC, and ongoing ALK inhibitor-based clinical trials.

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Conflict of interest

Gridelli C. received honoraria as speaker bureau member and is an ordinary board member by Roche and Eli Lilly.

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Authors and Affiliations

  1. Department of Clinical and Experimental Medicine, Second University of Naples, Naples, Italy

    Francesca Casaluce, Assunta Sgambato & Fortunato Ciardiello

  2. Division of Medical Oncology, “S.G. Moscati” Hospital, Città Ospedaliera, Contrada Amoretta, 83100, Avellino, Italy

    Paolo Maione, Antonio Rossi, Carmine Ferrara & Cesare Gridelli

  3. Hospital Pharmacy, “S.G. Moscati”, Avellino, Italy

    Alba Napolitano

  4. Division of Medical Oncology, “ULSS 15 Cittadella”, Padua, Italy

    Giovanni Palazzolo

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  1. Francesca Casaluce
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  2. Assunta Sgambato
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Casaluce, F., Sgambato, A., Maione, P. et al. ALK inhibitors: a new targeted therapy in the treatment of advanced NSCLC. Targ Oncol 8, 55–67 (2013). https://doi.org/10.1007/s11523-012-0250-9

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