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
Reads0
Chats0
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
Citations
More filters
Journal ArticleDOI
Somatic driver mutations in melanoma.
TL;DR: The authors review the current literature on important somatic driver mutations in melanoma, along with the implications for treatment.
Journal ArticleDOI
MEK Inhibitors in the Treatment of Metastatic Melanoma and Solid Tumors.
Antonio M. Grimaldi,Ester Simeone,Lucia Festino,Vito Vanella,Martina Strudel,Paolo A. Ascierto +5 more
TL;DR: Future possibilities for MEK inhibitors in advanced melanoma, as well as other solid tumors, include their use in combination with other targeted therapies (e.g. anti-CDK4/6 inhibitors) and/or various immune-modulating antibodies.
Journal ArticleDOI
Sequential Treatment with Ipilimumab and BRAF Inhibitors in Patients With Metastatic Melanoma: Data From the Italian Cohort of the Ipilimumab Expanded Access Program
Paolo A. Ascierto,Ester Simeone,Vanna Chiarion Sileni,Michele Del Vecchio,Paolo Marchetti,Gian Carlo Antonini Cappellini,Ruggero Ridolfi,Francesco De Rosa,Francesco Cognetti,Virginia Ferraresi,Alessandro Testori,Paola Queirolo,Maria Grazia Bernengo,Michele Guida,Luca Galli,Mario Mandalà,Carolina Cimminiello,Gaetana Rinaldi,Fabrizio Carnevale-Schianca,Michele Maio +19 more
TL;DR: Prospective, randomized studies are required to determine the optimal sequencing of ipilimumab and BRAF inhibitors in patients with BRAF-mutated metastatic melanoma.
Journal ArticleDOI
MEK1/2 inhibitors in the treatment of gynecologic malignancies
TL;DR: The translational evidence in favor of MEK inhibitors in cancer, their role in gynecologic malignancies, and details regarding the status of the fourteen MEK inhibitor currently being clinically tested are reviewed.
Journal ArticleDOI
Integrated genomic and transcriptomic analysis of human brain metastases identifies alterations of potential clinical significance.
Jodi M. Saunus,Jodi M. Saunus,Michael C.J. Quinn,Michael C.J. Quinn,Ann-Marie Patch,Ann-Marie Patch,John V. Pearson,John V. Pearson,Peter Bailey,Peter Bailey,Katia Nones,Katia Nones,Amy E. McCart Reed,Amy E. McCart Reed,David Miller,David Miller,Peter Wilson,Fares Al-Ejeh,Mythily Mariasegaram,Mythily Mariasegaram,Queenie Lau,Teresa K. Withers,Rosalind L. Jeffree,Lynne Reid,Lynne Reid,Leonard Da Silva,Admire Matsika,Admire Matsika,Colleen Niland,Colleen Niland,Margaret C. Cummings,Margaret C. Cummings,Timothy J. C. Bruxner,Angelika N. Christ,Ivon Harliwong,Senel Idrisoglu,Suzanne Manning,Craig Nourse,Craig Nourse,Ehsan Nourbakhsh,Shivangi Wani,Shivangi Wani,Matthew J. Anderson,J. Lynn Fink,Oliver Holmes,Oliver Holmes,Stephen H. Kazakoff,Stephen H. Kazakoff,Conrad Leonard,Conrad Leonard,Felicity Newell,Darrin Taylor,Nick Waddell,Scott Wood,Scott Wood,Qinying Xu,Qinying Xu,Karin S. Kassahn,Karin S. Kassahn,Karin S. Kassahn,Vairavan Narayanan,Nur Aishah Taib,Soo Hwang Teo,Yock Ping Chow,kConFab,Parmjit S. Jat,Sebastian Brandner,Adrienne M. Flanagan,Adrienne M. Flanagan,Kum Kum Khanna,Georgia Chenevix-Trench,Sean M. Grimmond,Sean M. Grimmond,Peter T. Simpson,Peter T. Simpson,Nicola Waddell,Nicola Waddell,Sunil R. Lakhani,Sunil R. Lakhani +78 more
TL;DR: In this article, the authors investigated the genomic and transcriptomic landscapes of 36 brain metastases from breast, lung, melanoma and oesophageal cancers, using DNA copy-number analysis and exome-and RNA-sequencing.
References
More filters
Journal ArticleDOI
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.
Journal ArticleDOI
Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation
Paul B. Chapman,Axel Hauschild,Caroline Robert,John B. A. G. Haanen,Paolo A. Ascierto,James Larkin,Reinhard Dummer,Claus Garbe,Alessandro Testori,Michele Maio,David W. Hogg,Paul Lorigan,Céleste Lebbé,Thomas Jouary,Dirk Schadendorf,Antoni Ribas,Jeffrey A. Sosman,John M. Kirkwood,Brigitte Dréno,K. B. Nolop,Jiang Li,B. Nelson,Jeannie Hou,Richard J. Lee,Keith T. Flaherty,Grant A. McArthur +25 more
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.
Journal ArticleDOI
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.
Journal ArticleDOI
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.
Related Papers (5)
Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation
Paul B. Chapman,Axel Hauschild,Caroline Robert,John B. A. G. Haanen,Paolo A. Ascierto,James Larkin,Reinhard Dummer,Claus Garbe,Alessandro Testori,Michele Maio,David W. Hogg,Paul Lorigan,Céleste Lebbé,Thomas Jouary,Dirk Schadendorf,Antoni Ribas,Jeffrey A. Sosman,John M. Kirkwood,Brigitte Dréno,K. B. Nolop,Jiang Li,B. Nelson,Jeannie Hou,Richard J. Lee,Keith T. Flaherty,Grant A. McArthur +25 more
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
Mutations of the BRAF gene in human cancer
Helen Davies,Graham R. Bignell,Charles Cox,Philip J. Stephens,Sarah Edkins,S. M. Clegg,Jon W. Teague,Hayley Woffendin,Mathew J. Garnett,William Bottomley,Neil Davis,Ed Dicks,Rebecca Ewing,Yvonne Floyd,Kristian Gray,S. Hall,Rachel Hawes,Jaime Hughes,Vivian Kosmidou,Andrew Menzies,Catherine Mould,Adrian Parker,Claire Stevens,Stephen Watt,Steven Hooper,Rebecca Wilson,Hiran Jayatilake,Barry A. Gusterson,Colin Cooper,Janet Shipley,Darren Hargrave,Kathy Pritchard-Jones,Norman J. Maitland,Georgia Chenevix-Trench,Gregory J. Riggins,Darell D. Bigner,Giuseppe Palmieri,Antonio Cossu,Adrienne M. Flanagan,Andrew G. Nicholson,Judy W. C. Ho,Suet Yi Leung,Siu Tsan Yuen,Barbara L. Weber,Hilliard F. Seigler,Timothy L. Darrow,Hugh Paterson,Richard Marais,Christopher J. Marshall,Richard Wooster,Michael R. Stratton,P. Andrew Futreal +51 more
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
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