Paper Chase is a research database designed to offer abstracts of research articles published in journals that have a highly rated impact factor as determined by ISI Impact Factor and PageRank. Abstracts are organized by date, with the most recently published papers listed first. 

Paper Chase

Ceritinib in ALK-rearranged non-small-cell lung cancer.

N. Engl. J. Med.. Mar 27, 2014;370(13):1189-97.
Shaw AT, Kim DW, Mehra R, Tan DS, Felip E, Chow LQ, Camidge DR, Vansteenkiste J, Sharma S, De Pas T, Riely GJ, Solomon BJ, Wolf J, Thomas M, Schuler M, Liu G, Santoro A, Lau YY, Goldwasser M, Boral AL, Engelman JA.

From Massachusetts General Hospital, Boston (A.T.S., J.A.E.); Seoul National University Hospital, Seoul, South Korea (D.-W.K.); Fox Chase Cancer Center, Philadelphia (R.M.); National Cancer Center and Genome Institute of Singapore, Singapore (D.S.W.T.); Vall d'Hebron University, Barcelona (E.F.); University of Washington, Seattle (L.Q.M.C.); University of Colorado, Denver (D.R.C.); University Hospital KU Leuven, Leuven, Belgium (J.V.); Huntsman Cancer Institute, Salt Lake City (S.S.); Istituto Europeo di Oncologia (T.D.P.) and Istituto di Ricovero e Cura a Carattere Scientifico Istituto Clinico Humanitas (A.S.) - both in Milan; Memorial Sloan-Kettering Cancer Center, New York (G.J.R.); Peter MacCallum Cancer Center, Melbourne, VIC, Australia (B.J.S.); Center for Integrated Oncology, University Hospital Cologne, Cologne (J.W.), Thoraxklinik, University of Heidelberg, Translational Lung Research Center Heidelberg, German Center for Lung Research (M.T.), and German Cancer Consortium (M.S.), Heidelberg, and University Duisburg-Essen, Essen (M.S.) - all in Germany; Princess Margaret Cancer Center, Toronto (G.L.); and Novartis Institutes for BioMedical Research, Cambridge, MA (Y.Y.L., M.G., A.L.B.).

Abstract:

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.).