New Treatment Options for ALK-Rearranged Non-Small Cell Lung Cancer.

ALK rearrangements are present in 3-5% of patients with non-small cell lung cancer (NSCLC) and after epidermal growth factor receptor (EGFR) mutations represent the second molecular target in NSCLC to be validated through phase III clinical trials. The PROFILE 1014 international multicentre phase III trial demonstrated the superiority of crizotinib over standard chemotherapy, establishing crizotinib as standard first-line therapy for patients with advanced ALK-positive NSCLC and indicating the requirement for ALK testing to guide selection of optimal first-line therapy for non-squamous NSCLC. Despite impressive and durable responses, progression on treatment reflecting the development of acquired resistance is inevitable. There are several mechanisms of resistance including ALK kinase mutation or copy number gain, activation of bypass pathways and potentially pharmacokinetic failure of therapy (most commonly in CNS). A broad array of newer generation ALK inhibitors are in development that appear effective in the crizotinib-resistant setting including in patients with intracranial progression. These agents, including ceritinib and alectinib, have a higher potency against ALK kinase than crizotinib, activity against mutations that confer resistance to crizotinib and potentially improved CNS penetration. While in selected patients, continued therapy with crizotinib after local ablative treatments of oligo-progressive systemic or CNS disease may be an option, for many patients use of a newer generation compound will be effective. First-line treatment with newer generation ALK inhibitors may have potential advantages over sequential treatment after crizotinib; however, the optimal sequence of therapy with ALK inhibitors has not been determined and is being explored in ongoing phase III studies.