Journal ArticleDOI
Ceritinib versus chemotherapy in patients with ALK-rearranged non-small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): a randomised, controlled, open-label, phase 3 trial
Alice T. Shaw,Tae Min Kim,Lucio Crinò,Cesare Gridelli,Katsuyuki Kiura,Geoffrey Liu,Silvia Novello,Alessandra Bearz,Oliver Gautschi,Tony Mok,Makoto Nishio,Giorgio V. Scagliotti,David R. Spigel,S. Deudon,Cheng Zheng,Serafino Pantano,Patrick Urban,Cristian Massacesi,Kalyanee Viraswami-Appanna,Enriqueta Felip +19 more
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TLDR
Ceritinib showed a significant improvement in median progression-free survival compared with chemotherapy and was compared with single-agent chemotherapy in patients with advanced ALK-rearranged non-small-cell lung cancer who had previously progressed following crizotinib and platinum-based doublet chemotherapy.Abstract:
Summary Background Ceritinib is a next-generation anaplastic lymphoma kinase (ALK) inhibitor, which has shown robust anti-tumour efficacy, along with intracranial activity, in patients with ALK -rearranged non-small-cell lung cancer. In phase 1 and 2 studies, ceritinib has been shown to be highly active in both ALK inhibitor-naive and ALK inhibitor-pretreated patients who had progressed after chemotherapy (mostly multiple lines). In this study, we compared the efficacy and safety of ceritinib versus single-agent chemotherapy in patients with advanced ALK -rearranged non-small-cell lung cancer who had previously progressed following crizotinib and platinum-based doublet chemotherapy. Methods In this randomised, controlled, open-label, phase 3 trial, we recruited patients aged at least 18 years with ALK -rearranged stage IIIB or IV non-small-cell lung cancer (with at least one measurable lesion) who had received previous chemotherapy (one or two lines, including a platinum doublet) and crizotinib and had subsequent disease progression, from 99 centres across 20 countries. Other inclusion criteria were a WHO performance status of 0–2, adequate organ function and laboratory test results, a life expectancy of at least 12 weeks, and having recovered from previous anticancer treatment-related toxicities. We randomly allocated patients (1:1; with blocking [block size of four]; stratified by WHO performance status [0 vs 1–2] and presence or absence of brain metastases) to oral ceritinib 750 mg per day fasted (in 21 day treatment cycles) or chemotherapy (intravenous pemetrexed 500 mg/m 2 or docetaxel 75 mg/m 2 [investigator choice], every 21 days). Patients who discontinued chemotherapy because of progressive disease could cross over to the ceritinib group. The primary endpoint was progression-free survival, assessed by a masked independent review committee using Response Evaluation Criteria in Solid Tumors 1.1 in the intention-to-treat population, assessed every 6 weeks until month 18 and every 9 weeks thereafter. This trial is registered with ClinicalTrials.gov, number NCT01828112, and is ongoing but no longer recruiting patients. Findings Between June 28, 2013, and Nov 2, 2015, we randomly allocated 231 patients; 115 (50%) to ceritinib and 116 (50%) to chemotherapy (40 [34%] to pemetrexed, 73 [63%] to docetaxel, and three [3%] discontinued before receiving treatment). Median follow-up was 16·5 months (IQR 11·5–21·4). Ceritinib showed a significant improvement in median progression-free survival compared with chemotherapy (5·4 months [95% CI 4·1–6·9] for ceritinib vs 1·6 months [1·4–2·8] for chemotherapy; hazard ratio 0·49 [0·36–0·67]; p vs 12 [11%] in the chemotherapy group). The most frequent grade 3–4 adverse events in the ceritinib group were increased alanine aminotransferase concentration (24 [21%] of 115 vs two [2%] of 113 in the chemotherapy group), increased γ glutamyltransferase concentration (24 [21%] vs one [1%]), and increased aspartate aminotransferase concentration (16 [14%] vs one [1%] in the chemotherapy group). Six (5%) of 115 patients in the ceritinib group discontinued because of adverse events compared with eight (7%) of 116 in the chemotherapy group. 15 (13%) of 115 patients in the ceritinib group and five (4%) of 113 in the chemotherapy group died during the treatment period (from the day of the first dose of study treatment to 30 days after the final dose). 13 (87%) of the 15 patients who died in the ceritinib group died because of disease progression and two (13%) died because of an adverse event (one [7%] cerebrovascular accident and one [7%] respiratory failure); neither of these deaths were considered by the investigator to be treatment related. The five (4%) deaths in the chemotherapy group were all due to disease progression. Interpretation These findings show that patients derive significant clinical benefit from a more potent ALK inhibitor after failure of crizotinib, and establish ceritinib as a more efficacious treatment option compared with chemotherapy in this patient population. Funding Novartis Pharmaceuticals Corporation.read more
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Population-level effect of molecular testing and targeted therapy in patients with advanced pulmonary adenocarcinoma: a prospective cohort study.
Christine Schwegler,Dinu Kaufmann,David Pfeiffer,Stefan Aebi,Joachim Diebold,Oliver Gautschi +5 more
TL;DR: Rigorous testing combined with optimal access to targeted therapy in clinical trials improved the prognosis of patients with advanced pulmonary adenocarcinoma in Central Switzerland, mainly driven by therapies targeting epidermal growth factor receptor and anaplastic lymphoma kinase.
Patent
Alk protein degradation agent and anti-tumor application thereof
Xiaobao Yang,Biao Jiang,Song Xiaoling,Lin Haifan,Sun Ning,Chen Jinju,Qiu Xing,Ren Chaowei,Kong Ying +8 more
TL;DR: In this article, a series of compounds designed and synthesized in the present invention have wide pharmacological activities, have the functions of degrading ALK proteins and inhibiting ALK activity, and may be used for related tumor treatment.
Journal ArticleDOI
Effect of ceritinib on the pharmacokinetics of coadministered CYP3A and 2C9 substrates: a phase I, multicenter, drug–drug interaction study in patients with ALK + advanced tumors
Felipe K. Hurtado,Filippo de Braud,Javier de Castro Carpeño,Maria Jose de Miguel Luken,Ding Wang,Jeffrey W. Scott,Yvonne Y. Lau,Tracey McCulloch,Morten Mau-Sørensen +8 more
TL;DR: Ceritinib is an ALK receptor tyrosine kinase inhibitor approved as first and second-line treatment in adult patients with ALK+metastatic non-small cell lung cancer (NSCLC).
Journal ArticleDOI
Beyond epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) testing in advanced non-small cell lung cancer: Is the picture as “ROS1” as it appears?
TL;DR: Since EGFR mutations and ALK rearrangements are mutually exclusive, it is expected one of every two females with advanced/ metastatic lung adenocarcinoma tested to be a candidate for targeted therapy and thus being eligible for EGFR/ALK targeted therapies.
Journal ArticleDOI
Front-line treatment of ceritinib improves efficacy over crizotinib for Asian patients with anaplastic lymphoma kinase fusion NSCLC: The role of systemic progression control.
Shih-Hao Huang,Allen Chung-Cheng Huang,Chin-Chou Wang,Wen Chen Chang,Chien-Ying Liu,Stelios Pavlidis,Ho-Wen Ko,Fu-Tsai Chung,Ping-Chih Hsu,Yike Guo,Chih-Hsi Scott Kuo,Chih-Hsi Scott Kuo,Cheng-Ta Yang +12 more
TL;DR: Crizotinib and ceritinib have demonstrated superior efficacy to platinum‐based chemotherapy as front‐line treatment for patients with ALK‐positive advanced non‐small cell lung cancer (NSCLC), however, the direct comparison between them in the front-line setting remains lacking.
References
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Journal ArticleDOI
Identification of the transforming EML4–ALK fusion gene in non-small-cell lung cancer
Manabu Soda,Young Lim Choi,Munehiro Enomoto,Shuji Takada,Yoshihiro Yamashita,Shunpei Ishikawa,Shin-ichiro Fujiwara,Hideki Watanabe,Kentaro Kurashina,Hisashi Hatanaka,Masashi Bando,Shoji Ohno,Yuichi Ishikawa,Hiroyuki Aburatani,Toshiro Niki,Yasunori Sohara,Yukihiko Sugiyama,Hiroyuki Mano +17 more
TL;DR: It is shown that a small inversion within chromosome 2p results in the formation of a fusion gene comprising portions of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene in non-small-cell lung cancer (NSCLC) cells.
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Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial
Tetsuya Mitsudomi,Satoshi Morita,Yasushi Yatabe,Shunichi Negoro,Isamu Okamoto,Junji Tsurutani,Takashi Seto,Miyako Satouchi,Hirohito Tada,Tomonori Hirashima,Kazuhiro Asami,Nobuyuki Katakami,Minoru Takada,Hiroshige Yoshioka,Kazuhiko Shibata,Shinzoh Kudoh,Eiji Shimizu,Hiroshi Saito,Shinichi Toyooka,Kazuhiko Nakagawa,Masahiro Fukuoka +20 more
TL;DR: In this article, an open label, phase 3 study (WJTOG3405) with recruitment between March 31, 2006, and June 22, 2009, at 36 centers in Japan was conducted.
Journal ArticleDOI
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
TL;DR: Crizotinib is superior to standard chemotherapy in patients with previously treated, advanced non-small-cell lung cancer with ALK rearrangement and greater improvement in global quality of life with crizotinIB than with chemotherapy.
Journal ArticleDOI
First-line crizotinib versus chemotherapy in ALK-positive lung cancer
Benjamin Solomon,Tony Mok,Dong Wan Kim,Yi-Long Wu,Kazuhiko Nakagawa,Tarek Mekhail,Enriqueta Felip,Federico Cappuzzo,Jolanda Paolini,Tiziana Usari,Shrividya Iyer,Arlene Reisman,Keith D. Wilner,Jennifer M. Tursi,Fiona H Blackhall +14 more
TL;DR: Crizotinib was superior to standard first-line pemetrexed-plus-platinum chemotherapy in patients with previously untreated advanced ALK-positive NSCLC and was associated with greater reduction in lung cancer symptoms and greater improvement in quality of life.
Journal ArticleDOI
Mechanisms of Acquired Crizotinib Resistance in ALK-Rearranged Lung Cancers
Ryohei Katayama,Alice T. Shaw,Alice T. Shaw,Tahsin M. Khan,Tahsin M. Khan,Mari Mino-Kenudson,Benjamin Solomon,Balazs Halmos,Nicholas A. Jessop,John C. Wain,Alan Tien Yeo,Cyril H. Benes,Lisa Drew,Jamal Carlos Saeh,Katherine Crosby,Lecia V. Sequist,A. John Iafrate,Jeffrey A. Engelman +17 more
TL;DR: Findings from a series of lung cancer patients with acquired resistance to the ALK TKI crizotinib reinforce the need to tailor therapeutic strategies to the specific underlying drug resistance mechanisms in the tumors to improve clinical outcomes.
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