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

Alectinib

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

References

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2. 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.
3. 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.
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8. 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.
9. 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.
10. Xalkori [package insert]. New York, NY: Pfizer Inc; 2015.
11. 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.
12. 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.
13. 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.