Research in context
Evidence before this study
We searched PubMed, ClinicalTrials.gov, and conference abstracts for reports published in English with terms related to ALK and NSCLC, with no data limits. These searches, which were done before finalisation of the protocol (August, 2010), indicated that the standard of care for most patients with advanced non-small-cell lung cancer (NSCLC) is cytotoxic chemotherapy. However, the identification of oncogenic drivers has led to the development of targeted therapeutics that have become the first-line treatment in suitable patients. The success of this targeted approach has highlighted the need to identify genotype-specific subsets of patients who might benefit from targeted therapies. ALK rearrangement occurs in 2–7% of patients with NSCLC, in which it acts as a potent oncogenic driver. ALK is one of the newer molecular targets, and at the time of study design (2010) no ALK-targeted therapeutic was available for patients with ALK-rearranged NSCLC. The first-in-class ALK-targeted therapeutic, crizotinib, which was originally synthesised as an inhibitor of cMET, was in the early stages of efficacy assessment in this patient population. More recent searches using terms related to crizotinib, resistance, and brain metastases, which were done throughout the study duration and, most recently, before submission of the manuscript (October, 2015), have indicated that crizotinib is more effective than chemotherapy in patients with ALK-rearranged NSCLC in both first-line and second-line settings. However, patients invariably develop resistance within a year, with frequent disease progression in the brain. Consequently, this population of patients is in need of effective alternative therapeutics.
Added value of this study
This updated analysis of the ASCEND-1 phase 1 study builds upon early reports of 130 patients who received the second-generation ALK inhibitor, ceritinib, at 50–750 mg/day. Here, notable antitumour activity and a high proportion of durable responses are reported in 246 patients with advanced metastatic ALK-rearranged NSCLC who received ceritinib at the recommended dose of 750 mg/day. Tumour responses were noted in patients who were ALK-inhibitor naive and in patients who had previously received ALK inhibitors. Moreover, durable whole-body responses were reported for patients with brain metastases at study entry. A retrospective analysis by independent neuroradiologists of intracranial responses in these patients with brain metastases at baseline and at least one post-baseline tumour assessment found a high proportion of patients with intracranial disease control.
Implications of all the available evidence
Clinical activity of ceritinib was noted in patients with ALK-rearranged NSCLC who had progressed on previous treatment with crizotinib, providing a therapeutic option for patients who might otherwise have limited choices. Moreover, in patients with brain metastases at study entry, both whole-body and intracranial responses were reported, suggesting the potential for ceritinib to effectively treat this patient population and the possibility that ceritinib could be an alternative therapeutic approach to local ablative therapy in patients with ALK-rearranged NSCLC and brain metastases. Our results raise the possibility that ceritinib might also have a role as an alternative to crizotinib in patients with ALK-rearranged NSCLC.