• Makoto Nishio, Haruyasu Murakami, Atsushi Horiike, Toshiaki Takahashi, Fumihiko Hirai, Naoko Suenaga, Takeshi Tajima, Kota Tokushige, Masami Ishii, Anthony Boral, Matthew Robson, and Takashi Seto.
• *The Cancer Institute Hospital of JFCR, Tokyo, Japan; †Shizuoka Cancer Center, Shizuoka, Japan; ‡National Kyushu Cancer Center, Fukuoka, Japan; §Novartis Pharma K.K., Tokyo, Japan; ¶Novartis Pharmaceuticals Corporation, East Hanover, New Jersey; and ‖Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
• J Thorac Oncol. 2015 Jul 1; 10 (7): 1058-66.

IntroductionAnaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) is sensitive to ALK inhibitors, but resistance develops. This study assessed the maximum-tolerated dose, safety, pharmacokinetics (PK), and antitumor activity of ceritinib, a novel ALK inhibitor (ALKi), in Japanese patients with ALK-rearranged malignancies.MethodsThis phase I, multicenter, open-label study (NCT01634763) enrolled adult patients with ALK-rearranged (by fluorescence in situ hybridization and/or immunohistochemistry) locally advanced/metastatic malignancy that had progressed despite standard therapy. The study comprised two parts: dose escalation and dose expansion. Ceritinib (single-dose) was administered orally in the 3-day PK run-in period, then once daily, in 21-day cycles. Adaptive dose escalations were guided by a Bayesian model.ResultsTwenty patients (80% with ALKi treatment history [ALKi-pretreated]; 19 NSCLC; one inflammatory myofibroblastic tumor) received ceritinib 300 to 750 mg (19 during dose escalation, one in dose expansion). Two dose-limiting toxicities occurred: grade 3 lipase increase (600 mg); grade 3 drug-induced liver injury (750 mg). The most common adverse events were gastrointestinal (nausea: 95%; diarrhea, vomiting: 75%). Ceritinib PK profile was dose proportional across 300 to 750 mg dosages; steady state was reached by day 15. Overall response rate was 55% (11 of 20 patients). Among patients with NSCLC, partial response was observed in two of four ALKi-naive patients, five of nine crizotinib-pretreated patients, two of four alectinib-pretreated patients, and one of two crizotinib and alectinib/ASP3026 pretreated patients. The ASP3026-pretreated inflammatory myofibroblastic tumor patient achieved partial response.ConclusionsCeritinib maximum-tolerated dose was 750 mg once daily in Japanese patients. Antitumor activity was observed irrespective of prior ALKi treatment history. Dose expansion, examining the activity of ceritinib in alectinib-resistant patients, is ongoing.

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