title: ALK inhibitors and advanced non-small cell lung cancer (review).
abstract: Treatment of unselected patients with advanced non-small cell lung cancer (NSCLC) receiving third-generation platinum-based chemotherapy has reached a plateau of effectiveness. Histology and molecular analyses are the cornerstone in the initial diagnosis of NSCLC and are key determinants to address the appropriate strategy of treatment. In non-squamous histology the combination of cisplatin plus pemetrexed or carboplatin plus paclitaxel plus bevacizumab are considered today the best regimens yielding better activity and efficacy. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib, erlotinib or afatinib are the standard-of-care for patients with advanced NSCLC harbouring activating EGFR mutations. The identification of anaplastic lymphoma kinase (ALK) rearrangements in 2-5% of NSCLC patients led to the rapid clinical development of its oral TKI, crizotinib, also targeting the proto-oncogene MET and ROS1. The results reported from the first phase III trial showed superiority of crizotinib compared with standard chemotherapy in second-line treatment of ALK-positive NSCLC, which was recently approved in several countries in this setting. Unfortunately, after initial activity of crizotinib, patients will ultimately develop acquired resistances within 1 or 2 years of therapy. A second generation of ALK inhibitors, such as LDK378, alectinib and AP26113 may represent a promising treatment approach: they are under investigation with very promising early results. This review discusses ALK rearrangements, the clinical development and use of crizotinib, and other ALK-TKIs in advanced NSCLC.
authors.affiliation: Division of Medical Oncology, 'S.G. Moscati' Hospital, Avellino, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Rossi
authors.affiliation: Division of Medical Oncology, 'S.G. Moscati' Hospital, Avellino, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Maione
authors.affiliation: Division of Medical Oncology, 'S.G. Moscati' Hospital, Avellino, Italy.
authors.forename: Paola Claudia
authors.initials: PC
authors.lastname: Sacco
authors.affiliation: Department of Clinical and Experimental Medicine, Second University of Naples, Naples, Italy.
authors.forename: Assunta
authors.initials: A
authors.lastname: Sgambato
authors.affiliation: Department of Clinical and Experimental Medicine, Second University of Naples, Naples, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Casaluce
authors.affiliation: Department of Clinical and Experimental Medicine, Second University of Naples, Naples, Italy.
authors.forename: Marianna Luciana
authors.initials: ML
authors.lastname: Ferrara
authors.affiliation: Division of Medical Oncology, 'ULSS 15 Cittadella', Padova, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Palazzolo
authors.affiliation: Department of Clinical and Experimental Medicine, Second University of Naples, Naples, Italy.
authors.forename: Fortunato
authors.initials: F
authors.lastname: Ciardiello
authors.affiliation: Division of Medical Oncology, 'S.G. Moscati' Hospital, Avellino, Italy.
authors.forename: Cesare
authors.initials: C
authors.lastname: Gridelli
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D000090063:Proto-Oncogene Mas; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; C000715470:MAS1 protein, human; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases