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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Safety and efficacy of vemurafenib in <italic>BRAF</italic><sup>V600E</sup> and <italic>BRAF</italic><sup>V600K</sup> mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study</title><author><name sortKey="Mcarthur, Grant A" sort="Mcarthur, Grant A" uniqKey="Mcarthur G" first="Grant A" last="Mcarthur">Grant A. Mcarthur</name></author><author><name sortKey="Chapman, Paul B" sort="Chapman, Paul B" uniqKey="Chapman P" first="Paul B" last="Chapman">Paul B. Chapman</name></author><author><name sortKey="Robert, Caroline" sort="Robert, Caroline" uniqKey="Robert C" first="Caroline" last="Robert">Caroline Robert</name></author><author><name sortKey="Larkin, James" sort="Larkin, James" uniqKey="Larkin J" first="James" last="Larkin">James Larkin</name></author><author><name sortKey="Haanen, John B" sort="Haanen, John B" uniqKey="Haanen J" first="John B" last="Haanen">John B. Haanen</name></author><author><name sortKey="Dummer, Reinhard" sort="Dummer, Reinhard" uniqKey="Dummer R" first="Reinhard" last="Dummer">Reinhard Dummer</name></author><author><name sortKey="Ribas, Antoni" sort="Ribas, Antoni" uniqKey="Ribas A" first="Antoni" last="Ribas">Antoni Ribas</name></author><author><name sortKey="Hogg, David" sort="Hogg, David" uniqKey="Hogg D" first="David" last="Hogg">David Hogg</name></author><author><name sortKey="Hamid, Omid" sort="Hamid, Omid" uniqKey="Hamid O" first="Omid" last="Hamid">Omid Hamid</name></author><author><name sortKey="Ascierto, Paolo A" sort="Ascierto, Paolo A" uniqKey="Ascierto P" first="Paolo A" last="Ascierto">Paolo A. Ascierto</name></author><author><name sortKey="Garbe, Claus" sort="Garbe, Claus" uniqKey="Garbe C" first="Claus" last="Garbe">Claus Garbe</name></author><author><name sortKey="Testori, Alessandro" sort="Testori, Alessandro" uniqKey="Testori A" first="Alessandro" last="Testori">Alessandro Testori</name></author><author><name sortKey="Maio, Michele" sort="Maio, Michele" uniqKey="Maio M" first="Michele" last="Maio">Michele Maio</name></author><author><name sortKey="Lorigan, Paul" sort="Lorigan, Paul" uniqKey="Lorigan P" first="Paul" last="Lorigan">Paul Lorigan</name></author><author><name sortKey="Lebbe, Celeste" sort="Lebbe, Celeste" uniqKey="Lebbe C" first="Celeste" last="Lebbé">Celeste Lebbé</name></author><author><name sortKey="Jouary, Thomas" sort="Jouary, Thomas" uniqKey="Jouary T" first="Thomas" last="Jouary">Thomas Jouary</name></author><author><name sortKey="Schadendorf, Dirk" sort="Schadendorf, Dirk" uniqKey="Schadendorf D" first="Dirk" last="Schadendorf">Dirk Schadendorf</name></author><author><name sortKey="O Ay, Stephen J" sort="O Ay, Stephen J" uniqKey="O Ay S" first="Stephen J" last="O Ay">Stephen J. O Ay</name></author><author><name sortKey="Kirkwood, John M" sort="Kirkwood, John M" uniqKey="Kirkwood J" first="John M." last="Kirkwood">John M. Kirkwood</name></author><author><name sortKey="Eggermont, Alexander M" sort="Eggermont, Alexander M" uniqKey="Eggermont A" first="Alexander M" last="Eggermont">Alexander M. Eggermont</name></author><author><name sortKey="Dreno, Brigitte" sort="Dreno, Brigitte" uniqKey="Dreno B" first="Brigitte" last="Dréno">Brigitte Dréno</name></author><author><name sortKey="Sosman, Jeffrey A" sort="Sosman, Jeffrey A" uniqKey="Sosman J" first="Jeffrey A" last="Sosman">Jeffrey A. Sosman</name></author><author><name sortKey="Flaherty, Keith T" sort="Flaherty, Keith T" uniqKey="Flaherty K" first="Keith T" last="Flaherty">Keith T. Flaherty</name></author><author><name sortKey="Yin, Ming" sort="Yin, Ming" uniqKey="Yin M" first="Ming" last="Yin">Ming Yin</name></author><author><name sortKey="Caro, Ivor" sort="Caro, Ivor" uniqKey="Caro I" first="Ivor" last="Caro">Ivor Caro</name></author><author><name sortKey="Cheng, Suzanne" sort="Cheng, Suzanne" uniqKey="Cheng S" first="Suzanne" last="Cheng">Suzanne Cheng</name></author><author><name sortKey="Trunzer, Kerstin" sort="Trunzer, Kerstin" uniqKey="Trunzer K" first="Kerstin" last="Trunzer">Kerstin Trunzer</name></author><author><name sortKey="Hauschild, Axel" sort="Hauschild, Axel" uniqKey="Hauschild A" first="Axel" last="Hauschild">Axel Hauschild</name></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">24508103</idno><idno type="pmc">4382632</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382632</idno><idno type="RBID">PMC:4382632</idno><idno type="doi">10.1016/S1470-2045(14)70012-9</idno><date when="2014">2014</date><idno type="wicri:Area/Pmc/Corpus">001D81</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001D81</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Safety and efficacy of vemurafenib in <italic>BRAF</italic><sup>V600E</sup> and <italic>BRAF</italic><sup>V600K</sup> mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study</title><author><name sortKey="Mcarthur, Grant A" sort="Mcarthur, Grant A" uniqKey="Mcarthur G" first="Grant A" last="Mcarthur">Grant A. Mcarthur</name></author><author><name sortKey="Chapman, Paul B" sort="Chapman, Paul B" uniqKey="Chapman P" first="Paul B" last="Chapman">Paul B. Chapman</name></author><author><name sortKey="Robert, Caroline" sort="Robert, Caroline" uniqKey="Robert C" first="Caroline" last="Robert">Caroline Robert</name></author><author><name sortKey="Larkin, James" sort="Larkin, James" uniqKey="Larkin J" first="James" last="Larkin">James Larkin</name></author><author><name sortKey="Haanen, John B" sort="Haanen, John B" uniqKey="Haanen J" first="John B" last="Haanen">John B. Haanen</name></author><author><name sortKey="Dummer, Reinhard" sort="Dummer, Reinhard" uniqKey="Dummer R" first="Reinhard" last="Dummer">Reinhard Dummer</name></author><author><name sortKey="Ribas, Antoni" sort="Ribas, Antoni" uniqKey="Ribas A" first="Antoni" last="Ribas">Antoni Ribas</name></author><author><name sortKey="Hogg, David" sort="Hogg, David" uniqKey="Hogg D" first="David" last="Hogg">David Hogg</name></author><author><name sortKey="Hamid, Omid" sort="Hamid, Omid" uniqKey="Hamid O" first="Omid" last="Hamid">Omid Hamid</name></author><author><name sortKey="Ascierto, Paolo A" sort="Ascierto, Paolo A" uniqKey="Ascierto P" first="Paolo A" last="Ascierto">Paolo A. Ascierto</name></author><author><name sortKey="Garbe, Claus" sort="Garbe, Claus" uniqKey="Garbe C" first="Claus" last="Garbe">Claus Garbe</name></author><author><name sortKey="Testori, Alessandro" sort="Testori, Alessandro" uniqKey="Testori A" first="Alessandro" last="Testori">Alessandro Testori</name></author><author><name sortKey="Maio, Michele" sort="Maio, Michele" uniqKey="Maio M" first="Michele" last="Maio">Michele Maio</name></author><author><name sortKey="Lorigan, Paul" sort="Lorigan, Paul" uniqKey="Lorigan P" first="Paul" last="Lorigan">Paul Lorigan</name></author><author><name sortKey="Lebbe, Celeste" sort="Lebbe, Celeste" uniqKey="Lebbe C" first="Celeste" last="Lebbé">Celeste Lebbé</name></author><author><name sortKey="Jouary, Thomas" sort="Jouary, Thomas" uniqKey="Jouary T" first="Thomas" last="Jouary">Thomas Jouary</name></author><author><name sortKey="Schadendorf, Dirk" sort="Schadendorf, Dirk" uniqKey="Schadendorf D" first="Dirk" last="Schadendorf">Dirk Schadendorf</name></author><author><name sortKey="O Ay, Stephen J" sort="O Ay, Stephen J" uniqKey="O Ay S" first="Stephen J" last="O Ay">Stephen J. O Ay</name></author><author><name sortKey="Kirkwood, John M" sort="Kirkwood, John M" uniqKey="Kirkwood J" first="John M." last="Kirkwood">John M. Kirkwood</name></author><author><name sortKey="Eggermont, Alexander M" sort="Eggermont, Alexander M" uniqKey="Eggermont A" first="Alexander M" last="Eggermont">Alexander M. Eggermont</name></author><author><name sortKey="Dreno, Brigitte" sort="Dreno, Brigitte" uniqKey="Dreno B" first="Brigitte" last="Dréno">Brigitte Dréno</name></author><author><name sortKey="Sosman, Jeffrey A" sort="Sosman, Jeffrey A" uniqKey="Sosman J" first="Jeffrey A" last="Sosman">Jeffrey A. Sosman</name></author><author><name sortKey="Flaherty, Keith T" sort="Flaherty, Keith T" uniqKey="Flaherty K" first="Keith T" last="Flaherty">Keith T. Flaherty</name></author><author><name sortKey="Yin, Ming" sort="Yin, Ming" uniqKey="Yin M" first="Ming" last="Yin">Ming Yin</name></author><author><name sortKey="Caro, Ivor" sort="Caro, Ivor" uniqKey="Caro I" first="Ivor" last="Caro">Ivor Caro</name></author><author><name sortKey="Cheng, Suzanne" sort="Cheng, Suzanne" uniqKey="Cheng S" first="Suzanne" last="Cheng">Suzanne Cheng</name></author><author><name sortKey="Trunzer, Kerstin" sort="Trunzer, Kerstin" uniqKey="Trunzer K" first="Kerstin" last="Trunzer">Kerstin Trunzer</name></author><author><name sortKey="Hauschild, Axel" sort="Hauschild, Axel" uniqKey="Hauschild A" first="Axel" last="Hauschild">Axel Hauschild</name></author></analytic><series><title level="j">The Lancet. Oncology</title><idno type="ISSN">1470-2045</idno><idno type="eISSN">1474-5488</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>Summary</title><sec id="S1"><title>Background</title><p id="P1">In the BRIM-3 trial, vemurafenib was associated with risk reduction versus dacarbazine of both death and progression in patients with advanced <italic>BRAF</italic><sup>V600</sup> mutation-positive melanoma. We present an extended follow-up analysis of the total population and in the <italic>BRAF</italic><sup>V600E</sup> and <italic>BRAF</italic><sup>V600K</sup> mutation subgroups.</p></sec><sec id="S2"><title>Methods</title><p id="P2">Patients older than 18 years, with treatment-naive metastatic melanoma and whose tumour tissue was positive for <italic>BRAF</italic><sup>V600</sup> mutations were eligible. Patients also had to have a life expectancy of at least 3 months, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate haematological, hepatic, and renal function. Patients were randomly assigned by interactive voice recognition system to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg/m<sup>2</sup> of body surface area intravenously every 3 weeks). Coprimary endpoints were overall survival and progression-free survival, analysed in the intention-to-treat population (n=675), with data censored at crossover. A sensitivity analysis was done. This trial is registered with ClinicalTrials.gov, NCT01006980.</p></sec><sec id="S3"><title>Findings</title><p id="P3">675 eligible patients were enrolled from 104 centres in 12 countries between Jan 4, 2010, and Dec 16, 2010. 337 patients were randomly assigned to receive vemurafenib and 338 to receive dacarbazine. Median follow-up was 12·5 months (IQR 7·7–16·0) on vemurafenib and 9·5 months (3·1–14·7) on dacarbazine. 83 (25%) of the 338 patients initially randomly assigned to dacarbazine crossed over from dacarbazine to vemurafenib. Median overall survival was significantly longer in the vemurafenib group than in the dacarbazine group (13·6 months [95% CI 12·0–15·2] <italic>vs</italic> 9·7 months [7·9–12·8]; hazard ratio [HR] 0·70 [95% CI 0·57–0·87]; p=0·0008), as was median progression-free survival (6·9 months [95% CI 6·1–7·0] <italic>vs</italic> 1·6 months [1·6–2·1]; HR 0·38 [95% CI 0·32–0·46]; p<0·0001). For the 598 (91%) patients with <italic>BRAF</italic><sup>V600E</sup> disease, median overall survival in the vemurafenib group was 13·3 months (95% CI 11·9–14·9) compared with 10·0 months (8·0–14·0) in the dacarbazine group (HR 0·75 [95% CI 0·60–0·93]; p=0·0085); median progression-free survival was 6·9 months (95% CI 6·2–7·0) and 1·6 months (1·6–2·1), respectively (HR 0·39 [95% CI 0·33–0·47]; p<0·0001). For the 57 (9%) patients with <italic>BRAF</italic><sup>V600K</sup> disease, median overall survival in the vemurafenib group was 14·5 months (95% CI 11·2–not estimable) compared with 7·6 months (6·1–16·6) in the dacarbazine group (HR 0·43 [95% CI 0·21–0·90]; p=0·024); median progression-free survival was 5·9 months (95% CI 4·4–9·0) and 1·7 months (1·4–2·9), respectively (HR 0·30 [95% CI 0·16–0·56]; p<0·0001). The most frequent grade 3–4 events were cutaneous squamous-cell carcinoma (65 [19%] of 337 patients) and keratoacanthomas (34 [10%]), rash (30 [9%]), and abnormal liver function tests (38 [11%]) in the vemurafenib group and neutropenia (26 [9%] of 287 patients) in the dacarbazine group. Eight (2%) patients in the vemurafenib group and seven (2%) in the dacarbazine group had grade 5 events.</p></sec><sec id="S4"><title>Interpretation</title><p id="P4">Inhibition of BRAF with vemurafenib improves survival in patients with the most common <italic>BRAF</italic><sup>V600E</sup> mutation and in patients with the less common <italic>BRAF</italic><sup>V600K</sup> mutation.</p></sec><sec id="S5"><title>Funding</title><p id="P5">F Hoffmann-La Roche-Genentech.</p></sec></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">100957246</journal-id><journal-id journal-id-type="pubmed-jr-id">27004</journal-id><journal-id journal-id-type="nlm-ta">Lancet Oncol</journal-id><journal-id journal-id-type="iso-abbrev">Lancet Oncol.</journal-id><journal-title-group><journal-title>The Lancet. Oncology</journal-title></journal-title-group><issn pub-type="ppub">1470-2045</issn><issn pub-type="epub">1474-5488</issn></journal-meta><article-meta><article-id pub-id-type="pmid">24508103</article-id><article-id pub-id-type="pmc">4382632</article-id><article-id pub-id-type="doi">10.1016/S1470-2045(14)70012-9</article-id><article-id pub-id-type="manuscript">NIHMS673519</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Safety and efficacy of vemurafenib in <italic>BRAF</italic><sup>V600E</sup> and <italic>BRAF</italic><sup>V600K</sup> mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>McArthur</surname><given-names>Grant A</given-names><prefix>Prof.</prefix></name><degrees>MB BS</degrees><aff id="A1">Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia</aff></contrib><contrib contrib-type="author"><name><surname>Chapman</surname><given-names>Paul B</given-names><prefix>Prof.</prefix></name><degrees>MD</degrees><aff id="A2">Memorial Sloan Kettering Cancer Center, New York, NY, USA</aff></contrib><contrib contrib-type="author"><name><surname>Robert</surname><given-names>Caroline</given-names></name><degrees>MD</degrees><aff id="A3">Institut Gustave Roussy, Paris, France</aff></contrib><contrib contrib-type="author"><name><surname>Larkin</surname><given-names>James</given-names></name><degrees>MD</degrees><aff id="A4">Royal Marsden Hospital, London, UK</aff></contrib><contrib contrib-type="author"><name><surname>Haanen</surname><given-names>John B</given-names></name><degrees>MD</degrees><aff id="A5">The Netherlands Cancer Institute, Amsterdam, Netherlands</aff></contrib><contrib contrib-type="author"><name><surname>Dummer</surname><given-names>Reinhard</given-names><prefix>Prof.</prefix></name><degrees>MD</degrees><aff id="A6">University of Zurich, Zurich, Switzerland</aff></contrib><contrib contrib-type="author"><name><surname>Ribas</surname><given-names>Antoni</given-names><prefix>Prof.</prefix></name><degrees>MD</degrees><aff id="A7">Jonsson Comprehensive Cancer Center at University of California, Los Angeles, CA, USA</aff></contrib><contrib contrib-type="author"><name><surname>Hogg</surname><given-names>David</given-names><prefix>Prof.</prefix></name><degrees>MD</degrees><aff id="A8">Princess Margaret Hospital and University Health Network, Toronto, ON, Canada</aff></contrib><contrib contrib-type="author"><name><surname>Hamid</surname><given-names>Omid</given-names></name><degrees>MD</degrees><aff id="A9">The Angeles Clinic and Research Institute, Los Angeles, CA, USA</aff></contrib><contrib contrib-type="author"><name><surname>Ascierto</surname><given-names>Paolo A</given-names></name><degrees>MD</degrees><aff id="A10">Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy</aff></contrib><contrib contrib-type="author"><name><surname>Garbe</surname><given-names>Claus</given-names><prefix>Prof.</prefix></name><degrees>MD</degrees><aff id="A11">The University of Tübingen, Tübingen, Germany</aff></contrib><contrib contrib-type="author"><name><surname>Testori</surname><given-names>Alessandro</given-names></name><degrees>MD</degrees><aff id="A12">Istituto Europeo di Oncologia, Milan, Italy</aff></contrib><contrib contrib-type="author"><name><surname>Maio</surname><given-names>Michele</given-names></name><degrees>MD</degrees><aff id="A13">University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy</aff></contrib><contrib contrib-type="author"><name><surname>Lorigan</surname><given-names>Paul</given-names></name><degrees>MD</degrees><aff id="A14">University of Manchester, Manchester, UK</aff></contrib><contrib contrib-type="author"><name><surname>Lebbé</surname><given-names>Celeste</given-names><prefix>Prof.</prefix></name><degrees>MD</degrees><aff id="A15">APHP Oncodermatology, Hôpital Saint Louis University, Paris, France</aff></contrib><contrib contrib-type="author"><name><surname>Jouary</surname><given-names>Thomas</given-names></name><degrees>MD</degrees><aff id="A16">Saint André Hospital, Bordeaux, France</aff></contrib><contrib contrib-type="author"><name><surname>Schadendorf</surname><given-names>Dirk</given-names><prefix>Prof.</prefix></name><degrees>MD</degrees><aff id="A17">University Hospital Essen, Essen, Germany</aff></contrib><contrib contrib-type="author"><name><surname>O’Day</surname><given-names>Stephen J</given-names></name><degrees>MD</degrees><aff id="A18">Beverly Hills Cancer Center, Beverly Hills, CA, USA</aff></contrib><contrib contrib-type="author"><name><surname>Kirkwood</surname><given-names>John M.</given-names><prefix>Prof.</prefix></name><degrees>MD</degrees><aff id="A19">University of Pittsburgh School of Medicine, Pittsburgh, PA, USA</aff></contrib><contrib contrib-type="author"><name><surname>Eggermont</surname><given-names>Alexander M</given-names><prefix>Prof.</prefix></name><degrees>MD</degrees><aff id="A20">Gustave-Roussy Cancer Center and University Paris-Sud, Villejuif/Paris Sud, France</aff></contrib><contrib contrib-type="author"><name><surname>Dréno</surname><given-names>Brigitte</given-names><prefix>Prof.</prefix></name><degrees>MD</degrees><aff id="A21">Nantes University Hospital, Nantes, France</aff></contrib><contrib contrib-type="author"><name><surname>Sosman</surname><given-names>Jeffrey A</given-names><prefix>Prof.</prefix></name><degrees>MD</degrees><aff id="A22">Vanderbilt University School of Medicine, Nashville, TN, USA</aff></contrib><contrib contrib-type="author"><name><surname>Flaherty</surname><given-names>Keith T</given-names></name><degrees>MD</degrees><aff id="A23">Massachusetts General Hospital, Boston, MA, USA</aff></contrib><contrib contrib-type="author"><name><surname>Yin</surname><given-names>Ming</given-names></name><degrees>MD</degrees><aff id="A24">Genentech Inc, San Francisco, CA, USA</aff></contrib><contrib contrib-type="author"><name><surname>Caro</surname><given-names>Ivor</given-names></name><degrees>MD</degrees><aff id="A25">Genentech Inc, San Francisco, CA, USA</aff></contrib><contrib contrib-type="author"><name><surname>Cheng</surname><given-names>Suzanne</given-names></name><degrees>PhD</degrees><aff id="A26">Roche Molecular Systems Inc, Pleasanton, CA, USA</aff></contrib><contrib contrib-type="author"><name><surname>Trunzer</surname><given-names>Kerstin</given-names></name><degrees>PhD</degrees><aff id="A27">F Hoffmann-La Roche, Basel, Switzerland</aff></contrib><contrib contrib-type="author"><name><surname>Hauschild</surname><given-names>Axel</given-names><prefix>Prof.</prefix></name><degrees>MD</degrees><aff id="A28">University of Kiel, Kiel, Germany</aff></contrib></contrib-group><author-notes><corresp id="FN1">Correspondence to: Prof Grant A McArthur, Division of Cancer Medicine and Research, Peter MacCallum Cancer Centre, East Melbourne, VIC 8006, Australia, <email>grant.mcarthur@petermac.org</email></corresp></author-notes><pub-date pub-type="nihms-submitted"><day>21</day><month>3</month><year>2015</year></pub-date><pub-date pub-type="epub"><day>07</day><month>2</month><year>2014</year></pub-date><pub-date pub-type="ppub"><month>3</month><year>2014</year></pub-date><pub-date pub-type="pmc-release"><day>02</day><month>4</month><year>2015</year></pub-date><volume>15</volume><issue>3</issue><fpage>323</fpage><lpage>332</lpage><pmc-comment>elocation-id from pubmed: 10.1016/S1470-2045(14)70012-9</pmc-comment>
<abstract><title>Summary</title><sec id="S1"><title>Background</title><p id="P1">In the BRIM-3 trial, vemurafenib was associated with risk reduction versus dacarbazine of both death and progression in patients with advanced <italic>BRAF</italic><sup>V600</sup> mutation-positive melanoma. We present an extended follow-up analysis of the total population and in the <italic>BRAF</italic><sup>V600E</sup> and <italic>BRAF</italic><sup>V600K</sup> mutation subgroups.</p></sec><sec id="S2"><title>Methods</title><p id="P2">Patients older than 18 years, with treatment-naive metastatic melanoma and whose tumour tissue was positive for <italic>BRAF</italic><sup>V600</sup> mutations were eligible. Patients also had to have a life expectancy of at least 3 months, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate haematological, hepatic, and renal function. Patients were randomly assigned by interactive voice recognition system to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg/m<sup>2</sup> of body surface area intravenously every 3 weeks). Coprimary endpoints were overall survival and progression-free survival, analysed in the intention-to-treat population (n=675), with data censored at crossover. A sensitivity analysis was done. This trial is registered with ClinicalTrials.gov, NCT01006980.</p></sec><sec id="S3"><title>Findings</title><p id="P3">675 eligible patients were enrolled from 104 centres in 12 countries between Jan 4, 2010, and Dec 16, 2010. 337 patients were randomly assigned to receive vemurafenib and 338 to receive dacarbazine. Median follow-up was 12·5 months (IQR 7·7–16·0) on vemurafenib and 9·5 months (3·1–14·7) on dacarbazine. 83 (25%) of the 338 patients initially randomly assigned to dacarbazine crossed over from dacarbazine to vemurafenib. Median overall survival was significantly longer in the vemurafenib group than in the dacarbazine group (13·6 months [95% CI 12·0–15·2] <italic>vs</italic> 9·7 months [7·9–12·8]; hazard ratio [HR] 0·70 [95% CI 0·57–0·87]; p=0·0008), as was median progression-free survival (6·9 months [95% CI 6·1–7·0] <italic>vs</italic> 1·6 months [1·6–2·1]; HR 0·38 [95% CI 0·32–0·46]; p<0·0001). For the 598 (91%) patients with <italic>BRAF</italic><sup>V600E</sup> disease, median overall survival in the vemurafenib group was 13·3 months (95% CI 11·9–14·9) compared with 10·0 months (8·0–14·0) in the dacarbazine group (HR 0·75 [95% CI 0·60–0·93]; p=0·0085); median progression-free survival was 6·9 months (95% CI 6·2–7·0) and 1·6 months (1·6–2·1), respectively (HR 0·39 [95% CI 0·33–0·47]; p<0·0001). For the 57 (9%) patients with <italic>BRAF</italic><sup>V600K</sup> disease, median overall survival in the vemurafenib group was 14·5 months (95% CI 11·2–not estimable) compared with 7·6 months (6·1–16·6) in the dacarbazine group (HR 0·43 [95% CI 0·21–0·90]; p=0·024); median progression-free survival was 5·9 months (95% CI 4·4–9·0) and 1·7 months (1·4–2·9), respectively (HR 0·30 [95% CI 0·16–0·56]; p<0·0001). The most frequent grade 3–4 events were cutaneous squamous-cell carcinoma (65 [19%] of 337 patients) and keratoacanthomas (34 [10%]), rash (30 [9%]), and abnormal liver function tests (38 [11%]) in the vemurafenib group and neutropenia (26 [9%] of 287 patients) in the dacarbazine group. Eight (2%) patients in the vemurafenib group and seven (2%) in the dacarbazine group had grade 5 events.</p></sec><sec id="S4"><title>Interpretation</title><p id="P4">Inhibition of BRAF with vemurafenib improves survival in patients with the most common <italic>BRAF</italic><sup>V600E</sup> mutation and in patients with the less common <italic>BRAF</italic><sup>V600K</sup> mutation.</p></sec><sec id="S5"><title>Funding</title><p id="P5">F Hoffmann-La Roche-Genentech.</p></sec></abstract></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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