Alice T Shaw1, Dong-Wan Kim, Ranee Mehra, Daniel S W Tan, Enriqueta Felip, Laura Q M Chow, D Ross Camidge, Johan Vansteenkiste, Sunil Sharma, Tommaso De Pas, Gregory J Riely, Benjamin J Solomon, Juergen Wolf, Michael Thomas, Martin Schuler, Geoffrey Liu, Armando Santoro, Yvonne Y Lau, Meredith Goldwasser, Anthony L Boral, Jeffrey A Engelman. 1. 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.).
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.).
Authors: Susumu Kobayashi; Titus J Boggon; Tajhal Dayaram; Pasi A Jänne; Olivier Kocher; Matthew Meyerson; Bruce E Johnson; Michael J Eck; Daniel G Tenen; Balázs Halmos Journal: N Engl J Med Date: 2005-02-24 Impact factor: 91.245
Authors: Thomas H Marsilje; Wei Pei; Bei Chen; Wenshuo Lu; Tetsuo Uno; Yunho Jin; Tao Jiang; Sungjoon Kim; Nanxin Li; Markus Warmuth; Yelena Sarkisova; Frank Sun; Auzon Steffy; AnneMarie C Pferdekamper; Allen G Li; Sean B Joseph; Young Kim; Bo Liu; Tove Tuntland; Xiaoming Cui; Nathanael S Gray; Ruo Steensma; Yongqin Wan; Jiqing Jiang; Greg Chopiuk; Jie Li; W Perry Gordon; Wendy Richmond; Kevin Johnson; Jonathan Chang; Todd Groessl; You-Qun He; Andrew Phimister; Alex Aycinena; Christian C Lee; Badry Bursulaya; Donald S Karanewsky; H Martin Seidel; Jennifer L Harris; Pierre-Yves Michellys Journal: J Med Chem Date: 2013-06-26 Impact factor: 7.446
Authors: Maria Paola Martelli; Gabriella Sozzi; Luis Hernandez; Valentina Pettirossi; Alba Navarro; Davide Conte; Patrizia Gasparini; Federica Perrone; Piergiorgio Modena; Ugo Pastorino; Antonino Carbone; Alessandra Fabbri; Angelo Sidoni; Shigeo Nakamura; Marcello Gambacorta; Pedro Luis Fernández; Jose Ramirez; John K C Chan; Walter Franco Grigioni; Elias Campo; Stefano A Pileri; Brunangelo Falini Journal: Am J Pathol Date: 2009-01-15 Impact factor: 4.307
Authors: Sergei Roumiantsev; Neil P Shah; Mercedes E Gorre; John Nicoll; Bradley B Brasher; Charles L Sawyers; Richard A Van Etten Journal: Proc Natl Acad Sci U S A Date: 2002-07-29 Impact factor: 11.205
Authors: D Ross Camidge; Yung-Jue Bang; Eunice L Kwak; A John Iafrate; Marileila Varella-Garcia; Stephen B Fox; Gregory J Riely; Benjamin Solomon; Sai-Hong I Ou; Dong-Wan Kim; Ravi Salgia; Panagiotis Fidias; Jeffrey A Engelman; Leena Gandhi; Pasi A Jänne; Daniel B Costa; Geoffrey I Shapiro; Patricia Lorusso; Katherine Ruffner; Patricia Stephenson; Yiyun Tang; Keith Wilner; Jeffrey W Clark; Alice T Shaw Journal: Lancet Oncol Date: 2012-09-04 Impact factor: 41.316
Authors: William Pao; Vincent A Miller; Katerina A Politi; Gregory J Riely; Romel Somwar; Maureen F Zakowski; Mark G Kris; Harold Varmus Journal: PLoS Med Date: 2005-02-22 Impact factor: 11.069
Authors: Adam S Crystal; Alice T Shaw; Lecia V Sequist; Luc Friboulet; Matthew J Niederst; Elizabeth L Lockerman; Rosa L Frias; Justin F Gainor; Arnaud Amzallag; Patricia Greninger; Dana Lee; Anuj Kalsy; Maria Gomez-Caraballo; Leila Elamine; Emily Howe; Wooyoung Hur; Eugene Lifshits; Hayley E Robinson; Ryohei Katayama; Anthony C Faber; Mark M Awad; Sridhar Ramaswamy; Mari Mino-Kenudson; A John Iafrate; Cyril H Benes; Jeffrey A Engelman Journal: Science Date: 2014-11-13 Impact factor: 47.728
Authors: Heike Richly; Tae Min Kim; Martin Schuler; Dong-Wan Kim; Simon J Harrison; Alice T Shaw; Anthony L Boral; Alejandro Yovine; Benjamin Solomon Journal: Blood Date: 2015-09-03 Impact factor: 22.113
Authors: Justin F Gainor; Leila Dardaei; Satoshi Yoda; Luc Friboulet; Ignaty Leshchiner; Ryohei Katayama; Ibiayi Dagogo-Jack; Shirish Gadgeel; Katherine Schultz; Manrose Singh; Emily Chin; Melissa Parks; Dana Lee; Richard H DiCecca; Elizabeth Lockerman; Tiffany Huynh; Jennifer Logan; Lauren L Ritterhouse; Long P Le; Ashok Muniappan; Subba Digumarthy; Colleen Channick; Colleen Keyes; Gad Getz; Dora Dias-Santagata; Rebecca S Heist; Jochen Lennerz; Lecia V Sequist; Cyril H Benes; A John Iafrate; Mari Mino-Kenudson; Jeffrey A Engelman; Alice T Shaw Journal: Cancer Discov Date: 2016-07-18 Impact factor: 39.397
Authors: Hengyu Lu; Nicole Villafane; Turgut Dogruluk; Caitlin L Grzeskowiak; Kathleen Kong; Yiu Huen Tsang; Oksana Zagorodna; Angeliki Pantazi; Lixing Yang; Nicholas J Neill; Young Won Kim; Chad J Creighton; Roel G Verhaak; Gordon B Mills; Peter J Park; Raju Kucherlapati; Kenneth L Scott Journal: Cancer Res Date: 2017-05-16 Impact factor: 12.701