The next-generation ALK inhibitor ceritinib was safe and active in patients with ALK-rearranged NSCLC.

  • Major finding: The next-generation ALK inhibitor ceritinib was safe and active in patients with ALK-rearranged NSCLC.

  • Concept: Significant, prolonged responses to ceritinib were observed in patients with resistance to crizotinib.

  • Impact: More potent and specific ALK inhibition may be effective in both crizotinib-sensitive and resistant tumors.

The chromosomal rearrangements in anaplastic lymphoma kinase (ALK) observed in approximately 5% of non–small-cell lung cancers (NSCLC) lead to aberrant ALK activation and dependence on ALK for tumor growth and survival. The ALK inhibitor crizotinib has significant activity in patients with ALK-rearranged NSCLC, but most patients ultimately relapse, often due to secondary mutation or amplification of ALK. In preclinical studies, ceritinib, an oral second-generation ALK inhibitor with greater potency and selectivity than crizotinib, showed antitumor activity against both crizotinib-sensitive and crizotinib-resistant ALK-rearranged NSCLC. Shaw and colleagues performed a phase I study of ceritinib in patients with advanced ALK-rearranged NSCLC or other cancers with ALK alterations to determine the maximum-tolerated dose (MTD), safety, pharmacokinetics, and antitumor activity. Ceritinib primarily caused grade 1 or 2 gastrointestinal adverse events and had favorable pharmacokinetic properties. Among 114 patients with NSCLC who received at least 400 mg of ceritinib each day, 1% had a complete response, 57% had a partial response, and 22% experienced disease stabilization. Among 8 patients with other cancers, one patient with anaplastic large-cell lymphoma and one patient with inflammatory myofibroblastic tumor had partial responses. Among responders with NSCLC, 64% had responses lasting 6 or more months, with a median duration of response of 8.2 months. Overall, the median progression-free survival was 7.0 months. Notably, among the 83 patients with NSCLC who had previously been treated with crizotinib, the overall response rate was 56%, and tumor regression was observed in all 19 patients for whom post-crizotinib ALK status was known, suggesting that ceritinib may be active in patients with acquired crizotinib resistance regardless of the underlying mechanism. These observations raise the possibility that a more potent inhibitor of ALK may overcome crizotinib resistance arising due to subtherapeutic ALK inhibition, and provide strong support for further clinical evaluation of ceritinib in ALK-rearranged NSCLC.

Shaw AT, Kim DW, Mehra R, Tan DS, Felip E, Chow LQ, et al. Ceritinib in ALK-rearranged non–small-cell lung cancer. N Engl J Med 2014;370:1189–97.

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