BACKGROUND: Non-small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma 
kinase gene (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib, 
but resistance invariably develops. Ceritinib (LDK378) is a new ALK inhibitor 
that has shown greater antitumor potency than crizotinib in preclinical studies.
METHODS: In this phase 1 study, we administered oral ceritinib in doses of 50 to 
750 mg once daily to patients with advanced cancers harboring genetic 
alterations in ALK. In an expansion phase of the study, patients received the 
maximum tolerated dose. Patients were assessed to determine the safety, 
pharmacokinetic properties, and antitumor activity of ceritinib. Tumor biopsies 
were performed before ceritinib treatment to identify resistance mutations in 
ALK in a group of patients with NSCLC who had had disease progression during 
treatment with crizotinib.
RESULTS: A total of 59 patients were enrolled in the dose-escalation phase. The 
maximum tolerated dose of ceritinib was 750 mg once daily; dose-limiting toxic 
events included diarrhea, vomiting, dehydration, elevated aminotransferase 
levels, and hypophosphatemia. This phase was followed by an expansion phase, in 
which an additional 71 patients were treated, for a total of 130 patients 
overall. Among 114 patients with NSCLC who received at least 400 mg of ceritinib 
per day, the overall response rate was 58% (95% confidence interval [CI], 48 to 
67). Among 80 patients who had received crizotinib previously, the response rate 
was 56% (95% CI, 45 to 67). Responses were observed in patients with various 
resistance mutations in ALK and in patients without detectable mutations. Among 
patients with NSCLC who received at least 400 mg of ceritinib per day, the 
median progression-free survival was 7.0 months (95% CI, 5.6 to 9.5).
CONCLUSIONS: Ceritinib was highly active in patients with advanced, 
ALK-rearranged NSCLC, including those who had had disease progression during 
crizotinib treatment, regardless of the presence of resistance mutations in ALK. 
(Funded by Novartis Pharmaceuticals and others; ClinicalTrials.gov number, 
NCT01283516.).