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Clinical Activity of Crizotinib in Patients with Advanced Non-Small Cell Lung Cancer (NSCLC) Harboring Ros1 Gene Rearrangement

2012; Elsevier BV; Volume: 23; Linguagem: Inglês

10.1093/annonc/mds408

1569-8041

S. Ou, D. Ross Camidge, J. A. Engelman, J. Clark, L. Tye, K. Wilner, Patricia Stephenson, Marileila Varella‐Garcia, A. John Iafrate, Alice T. Shaw, Pierre Hainaut, Xiaoyu Ma, Benjamin Lacas, May Tsao, Jean‐Yves Douillard, Vanessa Rousseau, A. Dunant, Lesley Seymour, Martin Filipits, Stephen L. Graziano, Jing He, Huan Yang, Qiuhua Deng, Ping He, Jing Jiang, Meiling Zhao, Xiaowei Gu, Li-Mou Zheng, Hui Pang, Jeff X. Zhou, Niels Reinmuth, Stefan Scherer, Roland Penzel, P. Schnabel, Michael Meister, Joachim Kiemle-Kallee, Alexander Reuß, Jürgen R. Fischer, M. Wolf, Michael J. Thomas, Maximilian von Laffert, Erika Gebel Berg, Dido Lenze, Philipp Lohneis, Michael Hummel, Manfred Dietel, Xiaohong Han, Li Ma, Yu Liu, N.N. Zhang, Dong Li, Yafei Shi, Koh Furugaki, Toshiki Iwai, Yoshitomo Moriya, Kaori Fujimoto-Ouchi, Tony Mok, K. Park, S.L. Geater, Shefali Agarwal, Min Han, Marc Credi, K. McKee, Naohisa Kuriyama, W. Slichenmyer, Ee Hong Tan, L. Greillier, Isabelle Martel‐Lafay, D. Arpin, N. Pourel, S. Chabaud, R. Lamy, A. Madroszyk, P. Fournel, Hans H. Strøm, Stein Sundstrøm, Nina Helbekkmo, R. M. Bremnes, Ulf Aasebø, Wouter van Elmpt, Michel Öllers, Anne‐Marie C. Dingemans, Ph. Lambin, Dave De ruysscher, Erkan Topkan, Cem Parlak, Savaş Topuk, Özgür Özyılkan, Wilma Uyterlinde, Andrew Vincent, J. Belderbos, Tiny Korse, Peter C. Baas, M. van den Heuvel, Miyako Satouchi, Yasutaka Chiba, N. Yamamoto, Yoshiko Nishimura, K. Tsujino, Yasuhito Fujisaka, Satoshi Kudoh, Tomoyuki Hida, Shinji Atagi, Kazuhiko Nakagawa, N. Ianotti, S. Thongprasert, A. Spira, D. Smith, Victor Lee, W.-T. Lim, P. Gopalakrishna, C. Reynolds, N. Nogami, R. Sekiguchi, Sotaro Enatsu, T. Tamura, İlknur Alsan Çetin, Ziya Çetinkaya, Perran Fulden Yumuk, Faysal Dane, G. Karaüç, N. Sunnetci, N. S. Turhal, Beste M. Atasoy, Peter Schirmacher, Hans Kreipe, Reinhard Büttner, Iver Petersen, Wolfram Jochum, S. Wang, J. Li, X. Hu, Xuezhu Wang, Lin Gui, Lulu Zhao, Yi Sun, C. Butts, R. Nevin Murray, Colum J Smith, Peter Ellis, Kevin Jasas, Andrew W. Maksymiuk, Glenwood D. Goss, Martin Falk, A. H. Loos, Denis Soulières, M. Chabowski, Rodryg Ramlau, Wojciech Dyszkiewicz, Nadia Chouaki, Victoria Soldatenkova, R. Varea, Susana Barriga, Carla Visseren‐Grul, Tadeusz Orłowski, J. Casal Rubio, B. Taboada, M. Lázaro, Silvia Vázquez, X.L. Firvida, María Vieito, Eduardo J Hernández, J.E. Castro, F.J. Barón, C. Peña, Rinus Wanders, Angela van Baardwijk, Bart Reymen, Gerben Bootsma, Jan‐Jakob Sonke, Miklos Pless, Daniel Betticher, C. Droege, Marc Salzberg, Roger von Moos, S. Niho, Hiroshi Nokihara, Keiji Nihei, Tetsuo Akimoto, Minako Sumi, Y. Ito, Ikuo Sekine, Kei Kubota, Y. Ohe, Hoda Sharifi, R. Vandendries, Mayukh Das, Georgi Nalbantov, M. Oellers, BL Ramaekers, MA Joore, B. Lueza, Jean-François Bonastre, Audrey Mauguen, Jean‐Pierre Pignon, C. Le Péchoux, Janneke P.C. Grutters, Katsuyuki Hotta, Katsuyuki Kiura, Hirohisa Yoshizawa, I. Borget, M. Pérol, David Pérol, A. Lavolé, R. Gervais, Gérard Zalcman, A. Vergnenègre, C. Chouaid, Weixiao Qi, Yi Yao, Zan Shen, Aina He, Fengyuan Lin, I. Abdel Halim, Mohamed A. Elashry, W. El-Sadda, S. Temraz, Alexandru Grigorescu, I. Turtoi, S.E. Boeru, М. В. Копп, Irina Koroleva, Sergey V. Kozlov, Л. В. Шаплыгин, Marija Popova, J.G. Kutyreva,

Pancreatic and Hepatic Oncology Research

ABSTRACT Background Chromosomal rearrangements in the receptor tyrosine kinase (RTK) ROS1 define a new molecular subset of NSCLC. ALK inhibitors can inhibit ROS1 kinase activity in cell lines. We examined the efficacy and safety of crizotinib, a small molecule inhibitor of two other RTKs, MET and ALK, in patients with advanced, ROS1-rearranged NSCLC. Methods Patients with advanced NSCLC harboring ROS1 rearrangement, as determined using a break-apart FISH assay, were recruited into an expansion cohort of the original phase 1 study of crizotinib. Patients were treated with crizotinib at the standard oral dose of 250 mg BID. The objective response rate (ORR) was determined based on RECIST v1.0. The disease control rate (DCR; stable disease [SD] + partial response [PR] + complete response [CR]) was evaluated at weeks 8 and 16. Results At the time of data cut-off on April 19, 2012, 15 patients with ROS1 NSCLC had received crizotinib and 14 were evaluable for response. The median age was 54 years (range 31–72). Fourteen patients were never-smokers and all had adenocarcinoma histology. All patients were confirmed negative for ALK rearrangement. The median number of prior treatments was 1 (range 0–6). The first ROS1 patient received crizotinib on October 19, 2010. To date, the ORR is 57% (8/14; 95% CI 28.9–82.3), with 7 PR and 1 CR. There were 4 SD, one of which was unconfirmed as PR at the time of data cut-off. The DCR at 8 weeks was 79% (11/14). Median duration of treatment was 25.7 weeks (range 0.1 + to 65.3 + ), and 12 patients continue on study. The pharmacokinetics, antitumor activity and safety profile of crizotinib in this group of patients were similar to those observed in patients with ALK-positive NSCLC. Conclusions Crizotinib is associated with clinically significant antitumor activity in patients with ROS1 NSCLC. Similar to ALK, ROS1 rearrangement defines another unique molecular subset of NSCLC patients for whom crizotinib therapy may be highly effective. Importantly, this study represents the first clinical investigation of ROS1 as a driver mutation and therapeutic target in cancer. Disclosure S.I. Ou: Advisory role: Pfizer, Genentech. Compensated Honoraria: Pfizer, Genentech, Lilly. Myself Research funding: Pfizer. Myself (institution). D.R. Camidge: Advisory role: Pfizer. Myself. Honoraria: Pfizer. Myself. L. Tye: Employment: Pfizer. Clinician. Myself. Stock Ownership; Pfizer. Myself. K. Wilner: Emplyement: Pfizer. Senior Director. Myself. Compensated. Stock ownership: Pfizer. Myself. M. Varella-Garcia: Honoraria: Abbott Molecular. Myself. funding for the trial provided by NIH - yes. A.T. Shaw: Advisory role: Pfizer, Ariad, Chugai, Novartis, Daiichi-sankyo. Myself. Compensated Research funding: Astra Zeneca, Novartis. Myself. All other authors have declared no conflicts of interest.