Journal ArticleDOI
CH5424802 (RO5424802) for patients with ALK-rearranged advanced non-small-cell lung cancer (AF-001JP study): a single-arm, open-label, phase 1–2 study
Takashi Seto,Katsuyuki Kiura,Makoto Nishio,Kazuhiko Nakagawa,Makoto Maemondo,Akira Inoue,Toyoaki Hida,Nobuyuki Yamamoto,Hiroshige Yoshioka,Masao Harada,Yuichiro Ohe,Naoyuki Nogami,Kengo Takeuchi,Tadashi Shimada,Tomohiro Tanaka,Tomohide Tamura +15 more
TLDR
CH5424802 is well tolerated and highly active in patients with advanced ALK-rearranged NSCLC, and the study is still ongoing, since 40 of the 46 patients in the phase 2 portion remain on treatment.Abstract:
Summary Background Currently, crizotinib is the only drug that has been approved for treatment of ALK -rearranged non-small-cell lung cancer (NSCLC). We aimed to study the activity and safety of CH5424802, a potent, selective, and orally available ALK inhibitor. Methods In this multicentre, single-arm, open-label, phase 1–2 study of CH5424802, we recruited ALK inhibitor-naive patients with ALK -rearranged advanced NSCLC from 13 hospitals in Japan. In the phase 1 portion of the study, patients received CH5424802 orally twice daily by dose escalation. The primary endpoints of the phase 1 were dose limiting toxicity (DLT), maximum tolerated dose (MTD), and pharmacokinetic parameters. In the phase 2 portion of the study, patients received CH5424802 at the recommended dose identified in the phase 1 portion of the study orally twice a day. The primary endpoint of the phase 2 was the proportion of patients who had an objective response. Treatment was continued in 21-day cycles until disease progression, intolerable adverse events, or withdrawal of consent. The analysis was done by intent to treat. This study is registered with the Japan Pharmaceutical Information Center, number JapicCTI-101264. Findings Patients were enrolled between Sept 10, 2010, and April 18, 2012. The data cutoff date was July 31, 2012. In the phase 1 portion, 24 patients were treated at doses of 20–300 mg twice daily. No DLTs or adverse events of grade 4 were noted up to the highest dose; thus 300 mg twice daily was the recommended phase 2 dose. In the phase 2 portion of the study, 46 patients were treated with the recommended dose, of whom 43 achieved an objective response (93·5%, 95% CI 82·1–98·6) including two complete responses (4·3%, 0·5–14·8) and 41 partial responses (89·1%, 76·4–96·4). Treatment-related adverse events of grade 3 were recorded in 12 (26%) of 46 patients, including two patients each experiencing decreased neutrophil count and increased blood creatine phosphokinase. Serious adverse events occurred in five patients (11%). No grade 4 adverse events or deaths were reported. The study is still ongoing, since 40 of the 46 patients in the phase 2 portion remain on treatment. Interpretation CH5424802 is well tolerated and highly active in patients with advanced ALK -rearranged NSCLC. Funding Chugai Pharmaceutical Co, Ltd.read more
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Lung cancer: current therapies and new targeted treatments
Fred R. Hirsch,Giorgio V. Scagliotti,James L. Mulshine,Regina Kwon,Walter J. Curran,Yi-Long Wu,Luis Paz-Ares +6 more
TL;DR: Prevention and early detection of lung cancer with an emphasis on lung cancer screening is discussed, and the importance of smoking prevention and cessation is acknowledged.
Journal ArticleDOI
Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial
Toyoaki Hida,Hiroshi Nokihara,Masashi Kondo,Young Hak Kim,Koichi Azuma,Takashi Seto,Yuichi Takiguchi,Makoto Nishio,Hiroshige Yoshioka,Fumio Imamura,Katsuyuki Hotta,Satoshi Watanabe,Koichi Goto,Miyako Satouchi,Toshiyuki Kozuki,Takehito Shukuya,Kazuhiko Nakagawa,Tetsuya Mitsudomi,Nobuyuki Yamamoto,Takashi Asakawa,Ryoichi Asabe,Tomohiro Tanaka,Tomohide Tamura +22 more
TL;DR: These results provide the first head-to-head comparison of alectinib and crizotinib and have the potential to change the standard of care for the first-line treatment of ALK-positive non-small-cell lung cancer.
Journal ArticleDOI
Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): Results from the dose-finding portion of a phase 1/2 study
Shirish M. Gadgeel,Leena Gandhi,Gregory J. Riely,Alberto Chiappori,Howard West,Michele C. Azada,Peter N. Morcos,Ruey Min Lee,Linta Garcia,Li Yu,Frederic Boisserie,Laura Di Laurenzio,Sophie Golding,Jotaro Sato,Shumpei Yokoyama,Tomohiro Tanaka,Sai-Hong Ignatius Ou +16 more
TL;DR: Alectinib was well tolerated, with promising antitumour activity in patients with ALK-rearranged NSCLC resistant to crizotinib, including those with CNS metastases.
Journal ArticleDOI
Targeted therapy for non-small cell lung cancer: current standards and the promise of the future
Bryan A. Chan,Brett G.M. Hughes +1 more
TL;DR: The major subtypes of oncogenic drivers behind NSCLC are examined as well as the development of targeted agents available to treat them both now and in the foreseeable future.
Journal ArticleDOI
Clinical Experience With Crizotinib in Patients With Advanced ALK-Rearranged Non–Small-Cell Lung Cancer and Brain Metastases
Daniel B. Costa,Alice T. Shaw,Sai-Hong Ignatius Ou,Benjamin Solomon,Gregory J. Riely,Myung-Ju Ahn,Caicun Zhou,S. Martin Shreeve,Paulina Selaru,Anna Polli,Patrick Schnell,Keith D. Wilner,Robin Wiltshire,D. Ross Camidge,Lucio Crinò +14 more
TL;DR: Crizotinib was associated with systemic and intracranial disease control in patients with ALK-rearranged NSCLC who were ALK inhibitor naive and had brain metastases, however, progression of preexisting or development of new intrac Cranial lesions while receiving therapy was a common manifestation of acquired resistance to crizotin ib.
References
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Identification of the transforming EML4–ALK fusion gene in non-small-cell lung cancer
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Crizotinib versus Chemotherapy in Advanced ALK-Positive Lung Cancer
Alice T. Shaw,Dong Wan Kim,Kazuhiko Nakagawa,Takashi Seto,Lucio Crinò,Myung-Ju Ahn,Tommaso De Pas,Benjamin Besse,Benjamin Solomon,Fiona H Blackhall,Yi-Long Wu,Michael Thomas,Kenneth J. O'Byrne,Denis Moro-Sibilot,D. Ross Camidge,Tony Mok,Vera Hirsh,Gregory J. Riely,Shrividya Iyer,V. Tassell,Anna Polli,Keith D. Wilner,Pasi A. Jänne +22 more
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Fusion of a Kinase Gene, ALK, to a Nucleolar Protein Gene, NPM, in Non-Hodgkin's Lymphoma
Stephan W. Morris,Mark N. Kirstein,Marcus B. Valentine,KG Dittmer,KG Dittmer,David N. Shapiro,David N. Shapiro,D. L. Saltman,AT Look,AT Look +9 more
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Clinical Features and Outcome of Patients With Non–Small-Cell Lung Cancer Who Harbor EML4-ALK
Alice T. Shaw,Beow Y. Yeap,Mari Mino-Kenudson,Subba R. Digumarthy,Daniel B. Costa,Rebecca S. Heist,Benjamin Solomon,Hannah Stubbs,Sonal Admane,Ultan McDermott,Jeffrey Settleman,Susumu Kobayashi,Eugene J. Mark,Scott J. Rodig,Lucian R. Chirieac,Eunice L. Kwak,Thomas J. Lynch,A. John Iafrate +17 more
TL;DR: EML4-ALK defines a molecular subset of NSCLC with distinct clinical characteristics and patients who harbor this mutation do not benefit from EGFR TKIs and should be directed to trials of ALK-targeted agents.
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