Mechanism of Action Magnifier – 2016 Desk Reference
Alectinib: an Anaplastic Lymphoma Kinase (ALK) Inhibitor
ALK Rearrangements in Lung Adenocarcinoma
ALK has been found to fuse with other partners, leading to potent malignant transformation.1,2 The most common among ALK fusion genes in lung cancer, specifically non–small cell lung cancer (NSCLC), is the EML4 ALK translocation fusion gene (EML4-ALK).1,3-5
The relative prevalence of ALK translocation mutations among lung adenocarcinoma patients is rather low in comparison with EGFR and KRAS mutations; the chromosomal translocation EML4-ALK may be present in approximately 3% to 6% of patients.6-8 However, the ALK rearrangement is frequently observed in relatively younger patients, nonsmokers or light smokers, and those whose histology is without other genetic disorders, such as mutations of the EGFR gene.1,9
Crizotinib, approved by the FDA in 2011, was the first clinically available ALK tyrosine kinase inhibitor, showing remarkable activity against ALK-rearranged NSCLC.1,10 However, resistance to crizotinib inevitably develops, with the brain being a common site of relapse.1,11,12
Alectinib is a highly selective, next-generation ALK inhibitor with potent inhibitory activity, including against ALK mutations conferring resistance to crizotinib.11 In a phase 1/2 study from Japan, alectinib was found to be highly active and safe in crizotinib-naive, ALK-rearranged NSCLC patients. Alectinib also demonstrated promising antitumor activity in crizotinib-resistant patients, including those with central nervous system metastases. Based on these data, the drug received breakthrough therapy designation by the FDA in 2013 for patients with ALK-positive NSCLC whose disease progressed on crizotinib.13 An ongoing, global, randomized phase 3 study is comparing alectinib to crizotinib as first-line treatment in patients with advanced NSCLC whose tumors were characterized as ALK-positive by a companion immunohistochemistry test.13
- Toyokawa G, Seto T. Anaplastic lymphoma kinase rearrangement in lung cancer: its biological and clinical significance. Respir Investig. 2014;52:330-338.
- Revannasiddaiah S, Thakur P, Bhardwaj B, et al. Pulmonary adenocarcinoma: implications of the recent advances in molecular biology, treatment and the IASLC/ATS/ERS classification. J Thorac Dis. 2014;6(suppl 5):S502-S525.
- Inamura K, Takeuchi K, Togashi Y, et al. EML4-ALK fusion is linked to histological characteristics in a subset of lung cancers. J Thorac Oncol. 2008;3:13-17.
- Rikova K, Guo A, Zeng Q, et al. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell. 2007;131:1190-1203.
- Katayama R, Shaw AT, Khan TM, et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers. Sci Transl Med. 2012;4:120ra17.
- Bulman W, Saqi A, Powell CA. Acquisition and processing of endobronchial ultrasound-guided transbronchial needle aspiration specimens in the era of targeted lung cancer chemotherapy. Am J Respir Crit Care Med. 2012;185:606-611.
- Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448:561-566.
- Yung RC, Otell S, Illei P, et al. Improvement of cellularity on cell block preparations using the so-called tissue coagulum clot method during endobronchial ultrasound-guided transbronchial fine-needle aspiration. Cancer Cytopathol. 2012;120:185-195.
- Kim HR, Shim HS, Chung JH, et al. Distinct clinical features and outcomes in never-smokers with nonsmall cell lung cancer who harbor EGFR or KRAS mutations or ALK rearrangement. Cancer. 2012;118:729-739.
- Xalkori [package insert]. New York, NY: Pfizer Inc; 2015.
- Santarpia M, Altavilla G, Rosell R. Alectinib: a selective, next-generation ALK inhibitor for treatment of ALK-rearranged non-small-cell lung cancer. Expert Rev Respir Med. 2015;9:255-268.
- Perez CA, Velez M, Raez LE, et al. Overcoming the resistance to crizotinib in patients with non-small cell lung cancer harboring EML4/ALK translocation. Lung Cancer. 2014;84:110-115.
- Genentech. FDA grants Genentech’s alectinib priority review for specific type of ALK-positive lung cancer [press release]. September 8, 2015. www.gene.com/media/press-releases/14605/2015-09-08/fda-grants-genentechs-alectinib-priority. Accessed November 23, 2015.
The application of molecularly targeted cancer therapies has rapidly expanded in the past 2 decades. The identification of genetic mutations in tumors has led to a growing list of therapies developed to specifically target those alterations. Indeed, molecularly targeted therapies—along with predictive biomarker testing and site-specific chemotherapy—have significantly improved the [ Read More ]
Mechanism of Pathway: Considerations of Cytogenetic and Molecular Mutation Status for Patients with Acute Myeloid Leukemia: A Deeper Look at the Role of Diagnostic and Ongoing Testing Across the Care Continuum
Acute myeloid leukemia (AML) is a heterogeneous disease that is characterized by uncontrolled proliferation of undifferentiated myeloid progenitors. While these leukemic blasts accumulate in the bone marrow and peripheral blood, impairment of normal hematopoiesis may lead to a reduction in the number of differentiated myeloid cells (granulocytes, neutrophils, monocytes, erythrocytes, megakaryocytes). Associated symptoms and consequences include anemia, bleeding, and an increased risk for infection.