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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Systemic therapies for melanoma brain metastases: which drug for whom and when?
TL;DR: This review will examine the evidence for systemic therapies in patients with active melanoma brain metastasis (untreated or treated and progressed) and highlight active and evolving clinical trials in this challenging field.
Journal ArticleDOI
Genomic classification of the RAS network identifies a personalized treatment strategy for lung cancer.
Nader N. El-Chaar,Stephen R. Piccolo,Stephen R. Piccolo,Kenneth M. Boucher,Adam L. Cohen,Jeffrey T. Chang,Philip J. Moos,Andrea H. Bild +7 more
TL;DR: A gene‐expression‐based biomarker for RAS network activity in non‐small cell lung cancer (NSCLC) cells was used and screened for drugs whose efficacy was significantly highly correlated to Ras network activity, and EGFR and MEK co‐inhibition was identified as the most effective treatment for Ras‐active NSCLC.
Journal ArticleDOI
Genetic profiling of melanoma in routine diagnostics: assay performance and molecular characteristics in a consecutive series of 274 cases.
Jonas Leichsenring,Fabian Stögbauer,Anna-Lena Volckmar,Ivo Buchhalter,Cristiano Oliveira,Martina Kirchner,Stefan Fröhling,Jessica C. Hassel,Alexander Enk,Peter Schirmacher,Volker Endris,Roland Penzel,Albrecht Stenzinger,Albrecht Stenzinger +13 more
TL;DR: Fast, quality-controlled high-throughput genetic profiling of FFPE melanoma samples is feasible and provides a landscape of genetic aberrations in melanoma that is currently relevant in clinical practice and approximates TCGA subtypes.
Journal ArticleDOI
Loss of 1p36.33 Frequent in Low-Grade Serous Ovarian Cancer.
Els Van Nieuwenhuysen,Pieter Busschaert,Annouschka Laenen,Philippe Moerman,Sileny Han,Patrick Neven,Diether Lambrechts,Ignace Vergote +7 more
TL;DR: Activating RAS mutations were dominant in this series, with supplementary detection of two PIK3CA mutations which may lead to therapeutic options, and 1p36.33 deletions in half of the cases, indicating a role in tumorigenesis, and these deletions may serve as a prognostic marker.
Journal ArticleDOI
Immunohistochemical Detection of NRASQ61R Mutation in Diverse Tumor Types.
TL;DR: The authors' studies confirmed that immunohistochemistry provides excellent sensitivity and specificity for detecting the NRASQ61R mutation in a variety of tumor types in a clinical setting.
References
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Improved Survival with Ipilimumab in Patients with Metastatic Melanoma.
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Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation
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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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