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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Epithelial-to-Mesenchymal Transition Is a Mechanism of ALK Inhibitor Resistance in Lung Cancer Independent of ALK Mutation Status.
Koji Fukuda,Shinji Takeuchi,Sachiko Arai,Ryohei Katayama,Shigeki Nanjo,Azusa Tanimoto,Akihiro Nishiyama,Takayuki Nakagawa,Hirokazu Taniguchi,Takeshi Suzuki,Tadaaki Yamada,Hiroshi Nishihara,Hironori Ninomiya,Yuichi Ishikawa,Satoko Baba,Kengo Takeuchi,Atsushi Horiike,Noriko Yanagitani,Makoto Nishio,Seiji Yano +19 more
TL;DR: Findings indicate that HDAC inhibitor pretreatment followed by a new ALK inhibitor may be useful to circumvent resistance constituted by coexistence of resistance mutations and EMT in the heterogeneous tumor.
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Drug Discovery Targeting Anaplastic Lymphoma Kinase (ALK)
Xiaotian Kong,Xiaotian Kong,Peichen Pan,Huiyong Sun,Hongguang Xia,Xuwen Wang,Youyong Li,Tingjun Hou +7 more
TL;DR: The "proteolysis targeting chimera" (PROTAC) technique has been successfully employed in ALK drug discovery, which opened a promising new avenue for targeted ALK therapies and the mechanism of drug resistance and potential therapeutic strategies to overcome drug resistance are summarized.
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Diversity of brain metastases screening and management in non-small cell lung cancer in Europe: Results of the European Organisation for Research and Treatment of Cancer Lung Cancer Group survey.
Antonin Levy,Corinne Faivre-Finn,Baktiar Hasan,Eleonora De Maio,Anna S. Berghoff,Nicolas Girard,Laurent Greillier,Sylvie Lantuejoul,Mary O'Brien,Martin Reck,Anne-Marie C. Dingemans,Silvia Novello,Thierry Berghmans,Benjamin Besse,Lizza E.L. Hendriks +14 more
TL;DR: BM management is highly variable in Europe: screening is not uniform, prognostic classifications are not often used and MUT+ NSCLC patients generally receive more intensive local treatment.
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Infectious Complications of Biological and Small Molecule Targeted Immunomodulatory Therapies.
Joshua S. Davis,Joshua S. Davis,Joshua S. Davis,David Ferreira,Emma Paige,Craig Gedye,Craig Gedye,Michael Boyle,Michael Boyle +8 more
TL;DR: The current state of knowledge about infectious complications of biologic and small molecule immunomodulatory agents is reviewed to create a single resource relevant to a broad range of clinicians and researchers.
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Molecular Mechanisms and Targeted Therapies Including Immunotherapy for Non-Small Cell Lung Cancer
TL;DR: Immunotherapy is explored, which is a promising new NSCLC treatment approach that targets the primary escape mechanisms, immune checkpoints, and patients who respond to ICIs are reported to experience long-lasting therapeutic effects.
References
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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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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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