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

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.

Fluorescence in situ hybridization (FISH): an increasingly demanded tool for biomarker research and personalized medicine

“…With the discovery of numerous disease-related genes in recent years, the applications of FISH broadened to include more genetic diseases, hematologic malignancies, and solid tumors. For example, FISH detection of BCR/ABL1 translocation, HER2 amplification, and ALK rearrangement is critical for guiding targeted therapy in chronic myeloid leukemia [5], breast cancer [6,7] and lung adenocarcinoma, respectively [8,9]. Hence, FISH tests have been recognized as vital components of personalized medicine.…”

“…Fusion of ALK kinase with EML4 or other fusion partners, such as TFG or KIF5B, leads to constitutive activation of ALK kinase [39,42]. Patients with EML4-ALK fusion-positive NSCLC, who were treated with the small-molecule kinase inhibitor Crizotinib, showed a response rate of 50-60% [8]. 2011 was the first time that the US FDA simultaneously approved a novel anti-cancer drug (Crizotinib, Pfizer) and its companion FISH detection kit (ALK FISH probe kit, Abbott Molecular), which highlighted the critical role of the FISH assay in guiding ALK-targeted therapy [8,9].…”

“…Patients with EML4-ALK fusion-positive NSCLC, who were treated with the small-molecule kinase inhibitor Crizotinib, showed a response rate of 50-60% [8]. 2011 was the first time that the US FDA simultaneously approved a novel anti-cancer drug (Crizotinib, Pfizer) and its companion FISH detection kit (ALK FISH probe kit, Abbott Molecular), which highlighted the critical role of the FISH assay in guiding ALK-targeted therapy [8,9]. Because ALK rearrangements are reportedly mutually exclusive with EGFR/KRAS mutations [43], ALK FISH testing is generally recommended for patients with wild-type EGFR/KRAS non-squamous NSCLC.…”

Translational Pharmacokinetic-Pharmacodynamic Modeling for an Orally Available Novel Inhibitor of Anaplastic Lymphoma Kinase and c-Ros Oncogene 1

“…As an example of personalized cancer medicine, the labeling language states that "Xalkori is a kinase inhibitor indicated for the treatment of patients with locally advanced or metastatic NSCLC that is ALK-positive as detected by an FDA-approved test" (http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/ 202570s000lbl.pdf). Unfortunately, as seen with other target therapies, such as the first-generation EGFR inhibitors, resistance to crizotinib attributable to EML4-ALK mutations has been reported even before its approval, leading to the rapid development of second-generation ALK inhibitors for crizotinibresistant NSCLC patients (Choi et al, 2010;Casaluce et al, 2013;Gridelli et al, 2014).…”

Mechanistic Understanding of Translational Pharmacokinetic-Pharmacodynamic Relationships in Nonclinical Tumor Models: A Case Study of Orally Available Novel Inhibitors of Anaplastic Lymphoma Kinase

“…Unfortunately, clinical responses to crizotinib have not been durable in some NSCLC patients, as tumor cells readily acquire drug resistance through multiple mechanisms, leading to the rapid development of second-generation ALK inhibitors for crizotinib-resistant cancer patients (Choi et al, 2010;Casaluce et al, 2013;Gridelli et al, 2014). A macrocyclic small molecule, PF06463922 [(10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo [4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile] (Fig.…”