Journal ArticleDOI
MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study
Paolo A. Ascierto,Dirk Schadendorf,Carola Berking,Sanjiv S. Agarwala,Carla M.L. van Herpen,Paola Queirolo,Christian U. Blank,Axel Hauschild,J. Thaddeus Beck,Annie St-Pierre,Faiz Niazi,Simon Wandel,Malte Peters,Angela Zubel,Reinhard Dummer +14 more
TLDR
MEK162 is the first targeted therapy to show activity in patients with NRAS -mutated melanoma and might offer a new option for a cancer with few effective treatments.Abstract:
Summary Background Patients with melanoma harbouring Val600 BRAF mutations benefit from treatment with BRAF inhibitors. However, no targeted treatments exist for patients with BRAF wild-type tumours, including those with NRAS mutations. We aimed to assess the use of MEK162, a small-molecule MEK1/2 inhibitor, in patients with NRAS -mutated or Val600 BRAF -mutated advanced melanoma. Methods In our open-label, non-randomised, phase 2 study, we assigned patients with NRAS -mutated or BRAF -mutated advanced melanoma to one of three treatment arms on the basis of mutation status. Patients were enrolled at university hospitals or private cancer centres in Europe and the USA. The three arms were: twice-daily MEK162 45 mg for NRAS -mutated melanoma, twice-daily MEK162 45 mg for BRAF -mutated melanoma, and twice-daily MEK162 60 mg for BRAF -mutated melanoma. Previous treatment with BRAF inhibitors was permitted, but previous MEK inhibitor therapy was not allowed. The primary endpoint was the proportion of patients who had an objective response (ie, a complete response or confirmed partial response). We report data for the 45 mg groups. We assessed clinical activity in all patients who received at least one dose of MEK162 and in patients assessable for response (with two available CT scans). This study is registered with ClinicalTrials.gov, number NCT01320085, and is currently recruiting additional patients with NRAS mutations (based on a protocol amendment). Findings Between March 31, 2011, and Jan 17, 2012, we enrolled 71 patients who received at least one dose of MEK162 45 mg. By Feb 29, 2012 (data cutoff), median follow-up was 3·3 months (range 0·6–8·7; IQR 2·2–5·0). No patients had a complete response. Six (20%) of 30 patients with NRAS -mutated melanoma had a partial response (three confirmed) as did eight (20%) of 41 patients with BRAF -mutated melanoma (two confirmed). The most frequent adverse events were acneiform dermatitis (18 [60%] patients with NRAS -mutated melanoma and 15 [37%] patients with the BRAF -mutated melanoma), rash (six [20%] and 16 [39%]), peripheral oedema (ten [33%] and 14 [34%]), facial oedema (nine [30%] and seven [17%]), diarrhoea (eight [27%] and 15 [37%]), and creatine phosphokinase increases (11 [37%] and nine [22%]). Increased creatine phosphokinase was the most common grade 3–4 adverse event (seven [23%] and seven [17%]). Four patients had serious adverse events (two per arm), which included diarrhoea, dehydration, acneiform dermatitis, general physical deterioration, irregular heart rate, malaise, and small intestinal perforation. No deaths occurred from treatment-related causes. Interpretation To our knowledge, MEK162 is the first targeted therapy to show activity in patients with NRAS -mutated melanoma and might offer a new option for a cancer with few effective treatments. Funding Novartis Pharmaceuticals.read more
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CRISPR-Cas9 Knockdown and Induced Expression of CD133 Reveal Essential Roles in Melanoma Invasion and Metastasis.
Cynthia M. Simbulan-Rosenthal,Ryan Dougherty,Sahar Vakili,Alexandra M Ferraro,Li-Wei Kuo,Ryyan Alobaidi,Leala Aljehane,Anirudh Gaur,Peter Sykora,Eric Glasgow,Seema Agarwal,Dean S. Rosenthal +11 more
TL;DR: It is shown that CD133(+) ‘melanoma-initiating cells’ are associated with chemoresistance, contributing to poor patient outcome, and CD133 may play an essential role in invasion and metastasis via upregulation of MMP2/MMP9, leading to tumor progression, and represents an attractive target for intervention in melanoma.
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A phase I study of binimetinib (MEK162) in Japanese patients with advanced solid tumors
Koichiro Watanabe,Satoshi Otsu,Yoshinori Hirashima,Ryotaro Morinaga,K. Nishikawa,Yasushi Hisamatsu,Tomoya Shimokata,Megumi Inada-Inoue,Takashi Shibata,Hiromi Takeuchi,T. Watanabe,Kota Tokushige,Heiko Maacke,K. Shiaro,Y. Ando +14 more
TL;DR: Binimetinib demonstrated efficacy and acceptable safety in Japanese patients with solid tumors, supporting the 45 mg BID dose of binimet inib as the RP2D.
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Trametinib in the treatment of melanoma
TL;DR: The underlying biology of MEK inhibition and its rationale in melanoma treatment is discussed with special emphasis on the clinical development of trametinib, from initial Phase I studies to randomized Phase II and III studies, both as monotherapy and in combination with other therapeutics.
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The role of systemic therapies in the management of melanoma brain metastases.
Megan Lyle,Georgina V. Long +1 more
TL;DR: More research is required in patients with active brain metastases to improve patient outcomes, including studies early in the development of novel therapies, and studies to determine the safe and effective combination or sequencing of local and systemic therapies.
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Isothermal Point Mutation Detection: Toward a First-Pass Screening Strategy for Multidrug-Resistant Tuberculosis.
Benjamin Y. C. Ng,Eugene J. H. Wee,Kyra Woods,Will Anderson,Fiach Antaw,Hennes Tsang,Nicholas P. West,Matt Trau +7 more
TL;DR: This work describes a novel strategy that enabled exquisite point mutation discrimination with isothermal DNA amplification, using mismatched primers in conjunction with a two-round enrichment process, which shows potential in a broad range of healthcare screening processes for detecting and categorizing disease phenotypes at the point of care.
References
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Improved Survival with Ipilimumab in Patients with Metastatic Melanoma.
F. Stephen Hodi,Steven J. O'Day,David F. McDermott,R. W. Weber,Jeffrey A. Sosman,John B. A. G. Haanen,Rene Gonzalez,Caroline Robert,Dirk Schadendorf,Jessica C. Hassel,Wallace Akerley,Alfons J.M. van den Eertwegh,Jose Lutzky,Paul Lorigan,Julia Vaubel,Gerald P. Linette,David W. Hogg,Christian H. Ottensmeier,Céleste Lebbé,Christian Peschel,Ian Quirt,Joseph I. Clark,Jedd D. Wolchok,Jeffrey S. Weber,Jason Tian,Michael Yellin,Geoffrey M. Nichol,Axel Hoos,Walter J. Urba +28 more
TL;DR: Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma.
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Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation
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TL;DR: Vemurafenib produced improved rates of overall and progression-free survival in patients with previously untreated melanoma with the BRAF V600E mutation in a phase 3 randomized clinical trial.
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Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial
Axel Hauschild,Jean-Jacques Grob,Lev V. Demidov,Thomas Jouary,Ralf Gutzmer,Michael Millward,Piotr Rutkowski,Christian U. Blank,Wilson H. Miller,Eckhart Kaempgen,Salvador Martín-Algarra,Boguslawa Karaszewska,Cornelia Mauch,Vanna Chiarion-Sileni,Anne-Marie Martin,Suzanne Swann,Patricia Haney,Beloo Mirakhur,Mary E. Guckert,Vicki L. Goodman,Paul B. Chapman +20 more
TL;DR: Dabrafenib significantly improved progression-free survival compared with dacarbazine, and skin-related toxic effects, fever, fatigue, arthralgia, and headache were uncommon in both groups.
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Combined BRAF and MEK Inhibition in Melanoma with BRAF V600 Mutations
Keith T. Flaherty,J. R. Infante,Adil Daud,Rene Gonzalez,Richard F. Kefford,Jeffrey A. Sosman,Omid Hamid,Lynn M. Schuchter,Jonathan Cebon,Nageatte Ibrahim,Ragini Kudchadkar,Howard A. Burris,Gerald S. Falchook,Alain Algazi,Karl D. Lewis,Georgina V. Long,Igor Puzanov,Peter F. Lebowitz,Ajay Singh,Shonda M Little,Peng Sun,Alicia Allred,Daniele Ouellet,Kevin B. Kim,Kiran Patel,Jeffrey S. Weber +25 more
TL;DR: Dabrafenib and trametinib were safely combined at full monotherapy doses, and the rate of pyrexia was increased with combination therapy, whereas the rates of proliferative skin lesions was nonsignificantly reduced.
Journal ArticleDOI
Distinct Sets of Genetic Alterations in Melanoma
John A. Curtin,Jane Fridlyand,Toshiro Kageshita,Hetal N. Patel,Klaus J. Busam,Heinz Kutzner,Kwang Hyun Cho,Setsuya Aiba,Eva B. Bröcker,Philip E. LeBoit,Daniel Pinkel,Boris C. Bastian +11 more
TL;DR: The genetic alterations identified in melanoma at different sites and with different levels of sun exposure indicate that there are distinct genetic pathways in the development of melanoma and implicate CDK4 and CCND1 as independent oncogenes in melanomas without mutations in BRAF or N-RAS.
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