Ceritinib Exhibits Responses in Patients with ALK-Rearranged NSCLC

Rearrangements in anaplastic lymphoma receptor tyrosine kinase (ALK) occur in approximately 2% to 7% of patients with non–small-cell lung cancer (NSCLC), and 30% to 50% of these patients develop brain metastases. Targeted therapy with the ALK inhibitor crizotinib has proven effective. However, patients eventually develop acquired resistance and experience disease progression, and alternative drugs to overcome crizotinib resistance are being investigated; these alternatives include ceritinib, which is also an ALK inhibitor and can penetrate across the blood–brain barrier. In a single-arm, open-label phase II trial (ASCEND-2), Crinò and colleagues investigated the safety and efficacy of ceritinib in 140 heavily pretreated patients with ALK-rearranged NSCLC, all of whom had progressed on crizotinib. The primary endpoint was overall response rate, and secondary end points included disease control rate, response duration, and progression-free survival. The overall response rate was 38.6%, and the disease control rate was 77.1%. Responses were durable, with a median response duration of 9.7 months. Further, intracranial responses were evaluated in 20 patients with brain metastases, and 45% showed an objective intracranial response. Adverse events resulted in treatment discontinuation in 7.9% of patients; grade 3/4 adverse events occurred in 71.4% of patients and serious adverse events occurred in 40.7% of patients. The global quality of life score did not decrease during treatment. Taken together, these findings indicate that ceritinib has an acceptable safety profile and durable antitumor activity in patients with ALK-rearranged NSCLC who progressed on chemotherapy and crizotinib, including those patients with brain metastases. In addition, these results demonstrate that treatment with alternative ALK inhibitors may be beneficial even in patients who develop resistance to crizotinib.

Crinò L, Ahn MJ, De Marinis F, Groen HJ, Wakelee H, Hida T, et al. Multicenter phase II study of whole-body and intracranial activity with ceritinib in patients with ALK-rearranged non–small-cell lung cancer previously treated with chemotherapy and crizotinib: results from ASCEND-2. J Clin Oncol 2016 Jul 18 [Epub ahead of print].

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