Adverse Event Management in Anaplastic Lymphoma Kinase-positive Non-small Cell Lung Cancer

The development of targeted therapies has resulted in a new paradigm in the treatment of anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC), and ALK tyrosine kinase inhibitors (TKIs) are the standard of care in ALK-positive NSCLC. However, ALK inhibitors also present new challenges. As a result of improved outcomes, patients will be receiving these agents for long periods of time. Furthermore, these drugs often target multiple pathways and may cause a range of toxicities. Since ALK inhibitors will be used by a multidisciplinary team in a specific subgroup of patients, physicians are likely to have limited experience in their use.1 It is therefore essential that physicians and caregivers are aware of treatment-related adverse events (AEs) in order to optimise their management and thus enhance the patient’s quality of life. This article will focus on the management of AEs in ALK-positive NSCLC receiving targeted therapy.

The Role of ALK Signalling in NSCLC and the Use of Tyrosine Kinase Inhibitors

NSCLC is characterised by extensive genomic instability, which results in dramatic functional changes and is the molecular basis of lung carcinogenesis.^2,3 Among the most frequently encountered targetable genetic alterations are chromosomal rearrangements of the ALK gene, which encodes a receptor tyrosine kinase. The ALK association with NSCLC was reported in 2007, following the discovery of a small inversion within chromosome 2p that juxtaposes the 5′ end of the echinoderm microtubule-associated protein-like 4 (EML4) gene with the 3′ end of the ALK gene, resulting in the novel fusion oncogene EML4-ALK in NSCLC cells.4 ALK-rearranged tumours depend on ALK for growth and survival and are therefore sensitive to ALK inhibitors.^4,5 ALK-positive NSCLC accounts for 4–5 % of adenocarcinomas of the lung,⁶ and is more common in males than in females.⁷ The majority of cases of ALK rearrangement arise in patients with no smoking history or light smokers.^8,9

ALK inhibitors have shown dramatic and sustained responses in clinical studies. The first-in-class crizotinib (Xalkori®, Pfizer) is an oral, small-molecule TKI that targets ALK, MET and ROS1,¹⁰ and received accelerated approval from the US Food and Drug Administration (FDA) in 2011.¹¹ Since its launch, crizotinib has become the standard of care in ALK-positive NSCLC. However, disease typically relapses