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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">coBRIM: a phase 3, double-blind, placebo-controlled study of vemurafenib versus vemurafenib + cobimetinib in previously untreated <italic>BRAF</italic><sup>V600</sup> mutation–positive patients with unresectable locally advanced or metastatic melanoma (NCT01689519)</title><author><name sortKey="Ascierto, Paolo A" sort="Ascierto, Paolo A" uniqKey="Ascierto P" first="Paolo A" last="Ascierto">Paolo A. Ascierto</name><affiliation><nlm:aff id="I1">Istituto Nazionale Tumori Fondazione G. Pascale, Naples, Italy</nlm:aff></affiliation></author><author><name sortKey="Mcarthur, Grant A" sort="Mcarthur, Grant A" uniqKey="Mcarthur G" first="Grant A" last="Mcarthur">Grant A. Mcarthur</name><affiliation><nlm:aff id="I2">Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia</nlm:aff></affiliation></author><author><name sortKey="Dreno, Brigitte" sort="Dreno, Brigitte" uniqKey="Dreno B" first="Brigitte" last="Dréno">Brigitte Dréno</name><affiliation><nlm:aff id="I3">Hôtel Dieu Place Alexis Ricordeau, Nantes, France</nlm:aff></affiliation></author><author><name sortKey="Larkin, James" sort="Larkin, James" uniqKey="Larkin J" first="James" last="Larkin">James Larkin</name><affiliation><nlm:aff id="I4">The Royal Marsden Hospital, London, UK</nlm:aff></affiliation></author><author><name sortKey="Liszkay, Gabriella" sort="Liszkay, Gabriella" uniqKey="Liszkay G" first="Gabriella" last="Liszkay">Gabriella Liszkay</name><affiliation><nlm:aff id="I5">National Institute of Oncology, Budapest, Hungary</nlm:aff></affiliation></author><author><name sortKey="Maio, Michele" sort="Maio, Michele" uniqKey="Maio M" first="Michele" last="Maio">Michele Maio</name><affiliation><nlm:aff id="I6">Azienda Ospedaliera Universitaria Senese, Siena, Italy</nlm:aff></affiliation></author><author><name sortKey="Mandala, Mario" sort="Mandala, Mario" uniqKey="Mandala M" first="Mario" last="Mandala">Mario Mandala</name><affiliation><nlm:aff id="I7">Papa Giovanni XXIII Hospital, Bergamo, Italy</nlm:aff></affiliation></author><author><name sortKey="Demidov, Lev" sort="Demidov, Lev" uniqKey="Demidov L" first="Lev" last="Demidov">Lev Demidov</name><affiliation><nlm:aff id="I8">N.N. Blokhin Russian Cancer Research Center, Moscow, Russia</nlm:aff></affiliation></author><author><name sortKey="Stroyakovskiy, Daniil" sort="Stroyakovskiy, Daniil" uniqKey="Stroyakovskiy D" first="Daniil" last="Stroyakovskiy">Daniil Stroyakovskiy</name><affiliation><nlm:aff id="I9">Moscow City Oncology Hospital 62, Krasnogorsk, Russia</nlm:aff></affiliation></author><author><name sortKey="Thomas, Luc" sort="Thomas, Luc" uniqKey="Thomas L" first="Luc" last="Thomas">Luc Thomas</name><affiliation><nlm:aff id="I10">Centre Hospitalier Lyon Sud, Pierre-Bénite, France</nlm:aff></affiliation></author><author><name sortKey="De La Cruz Merino, Luis" sort="De La Cruz Merino, Luis" uniqKey="De La Cruz Merino L" first="Luis" last="De La Cruz-Merino">Luis De La Cruz-Merino</name><affiliation><nlm:aff id="I11">Hospital Universitario Virgen Macarena, Seville, Spain</nlm:aff></affiliation></author><author><name sortKey="Atkinson, Victoria" sort="Atkinson, Victoria" uniqKey="Atkinson V" first="Victoria" last="Atkinson">Victoria Atkinson</name><affiliation><nlm:aff id="I12">Princess Alexandra Hospital, Woolloongabba, QLD, Australia</nlm:aff></affiliation></author><author><name sortKey="Dutriaux, Caroline" sort="Dutriaux, Caroline" uniqKey="Dutriaux C" first="Caroline" last="Dutriaux">Caroline Dutriaux</name><affiliation><nlm:aff id="I13">Hopital Saint André, Bordeaux, France</nlm:aff></affiliation></author><author><name sortKey="Garbe, Claus" sort="Garbe, Claus" uniqKey="Garbe C" first="Claus" last="Garbe">Claus Garbe</name><affiliation><nlm:aff id="I14">University of Tübingen, Tübingen, Germany</nlm:aff></affiliation></author><author><name sortKey="Chang, Ilsung" sort="Chang, Ilsung" uniqKey="Chang I" first="Ilsung" last="Chang">Ilsung Chang</name><affiliation><nlm:aff id="I15">Genentech, Inc, South San Francisco, CA, USA</nlm:aff></affiliation></author><author><name sortKey="Hack, Stephen P" sort="Hack, Stephen P" uniqKey="Hack S" first="Stephen P" last="Hack">Stephen P Hack</name><affiliation><nlm:aff id="I15">Genentech, Inc, South San Francisco, CA, USA</nlm:aff></affiliation></author><author><name sortKey="Ribas, Antoni" sort="Ribas, Antoni" uniqKey="Ribas A" first="Antoni" last="Ribas">Antoni Ribas</name><affiliation><nlm:aff id="I16">Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, Los Angeles, CA, USA</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmc">4315268</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4315268</idno><idno type="RBID">PMC:4315268</idno><idno type="doi">10.1186/1479-5876-13-S1-O4</idno><idno type="pmid">NONE</idno><date when="2015">2015</date><idno type="wicri:Area/Pmc/Corpus">001162</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001162</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">coBRIM: a phase 3, double-blind, placebo-controlled study of vemurafenib versus vemurafenib + cobimetinib in previously untreated <italic>BRAF</italic><sup>V600</sup> mutation–positive patients with unresectable locally advanced or metastatic melanoma (NCT01689519)</title><author><name sortKey="Ascierto, Paolo A" sort="Ascierto, Paolo A" uniqKey="Ascierto P" first="Paolo A" last="Ascierto">Paolo A. Ascierto</name><affiliation><nlm:aff id="I1">Istituto Nazionale Tumori Fondazione G. Pascale, Naples, Italy</nlm:aff></affiliation></author><author><name sortKey="Mcarthur, Grant A" sort="Mcarthur, Grant A" uniqKey="Mcarthur G" first="Grant A" last="Mcarthur">Grant A. Mcarthur</name><affiliation><nlm:aff id="I2">Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia</nlm:aff></affiliation></author><author><name sortKey="Dreno, Brigitte" sort="Dreno, Brigitte" uniqKey="Dreno B" first="Brigitte" last="Dréno">Brigitte Dréno</name><affiliation><nlm:aff id="I3">Hôtel Dieu Place Alexis Ricordeau, Nantes, France</nlm:aff></affiliation></author><author><name sortKey="Larkin, James" sort="Larkin, James" uniqKey="Larkin J" first="James" last="Larkin">James Larkin</name><affiliation><nlm:aff id="I4">The Royal Marsden Hospital, London, UK</nlm:aff></affiliation></author><author><name sortKey="Liszkay, Gabriella" sort="Liszkay, Gabriella" uniqKey="Liszkay G" first="Gabriella" last="Liszkay">Gabriella Liszkay</name><affiliation><nlm:aff id="I5">National Institute of Oncology, Budapest, Hungary</nlm:aff></affiliation></author><author><name sortKey="Maio, Michele" sort="Maio, Michele" uniqKey="Maio M" first="Michele" last="Maio">Michele Maio</name><affiliation><nlm:aff id="I6">Azienda Ospedaliera Universitaria Senese, Siena, Italy</nlm:aff></affiliation></author><author><name sortKey="Mandala, Mario" sort="Mandala, Mario" uniqKey="Mandala M" first="Mario" last="Mandala">Mario Mandala</name><affiliation><nlm:aff id="I7">Papa Giovanni XXIII Hospital, Bergamo, Italy</nlm:aff></affiliation></author><author><name sortKey="Demidov, Lev" sort="Demidov, Lev" uniqKey="Demidov L" first="Lev" last="Demidov">Lev Demidov</name><affiliation><nlm:aff id="I8">N.N. Blokhin Russian Cancer Research Center, Moscow, Russia</nlm:aff></affiliation></author><author><name sortKey="Stroyakovskiy, Daniil" sort="Stroyakovskiy, Daniil" uniqKey="Stroyakovskiy D" first="Daniil" last="Stroyakovskiy">Daniil Stroyakovskiy</name><affiliation><nlm:aff id="I9">Moscow City Oncology Hospital 62, Krasnogorsk, Russia</nlm:aff></affiliation></author><author><name sortKey="Thomas, Luc" sort="Thomas, Luc" uniqKey="Thomas L" first="Luc" last="Thomas">Luc Thomas</name><affiliation><nlm:aff id="I10">Centre Hospitalier Lyon Sud, Pierre-Bénite, France</nlm:aff></affiliation></author><author><name sortKey="De La Cruz Merino, Luis" sort="De La Cruz Merino, Luis" uniqKey="De La Cruz Merino L" first="Luis" last="De La Cruz-Merino">Luis De La Cruz-Merino</name><affiliation><nlm:aff id="I11">Hospital Universitario Virgen Macarena, Seville, Spain</nlm:aff></affiliation></author><author><name sortKey="Atkinson, Victoria" sort="Atkinson, Victoria" uniqKey="Atkinson V" first="Victoria" last="Atkinson">Victoria Atkinson</name><affiliation><nlm:aff id="I12">Princess Alexandra Hospital, Woolloongabba, QLD, Australia</nlm:aff></affiliation></author><author><name sortKey="Dutriaux, Caroline" sort="Dutriaux, Caroline" uniqKey="Dutriaux C" first="Caroline" last="Dutriaux">Caroline Dutriaux</name><affiliation><nlm:aff id="I13">Hopital Saint André, Bordeaux, France</nlm:aff></affiliation></author><author><name sortKey="Garbe, Claus" sort="Garbe, Claus" uniqKey="Garbe C" first="Claus" last="Garbe">Claus Garbe</name><affiliation><nlm:aff id="I14">University of Tübingen, Tübingen, Germany</nlm:aff></affiliation></author><author><name sortKey="Chang, Ilsung" sort="Chang, Ilsung" uniqKey="Chang I" first="Ilsung" last="Chang">Ilsung Chang</name><affiliation><nlm:aff id="I15">Genentech, Inc, South San Francisco, CA, USA</nlm:aff></affiliation></author><author><name sortKey="Hack, Stephen P" sort="Hack, Stephen P" uniqKey="Hack S" first="Stephen P" last="Hack">Stephen P Hack</name><affiliation><nlm:aff id="I15">Genentech, Inc, South San Francisco, CA, USA</nlm:aff></affiliation></author><author><name sortKey="Ribas, Antoni" sort="Ribas, Antoni" uniqKey="Ribas A" first="Antoni" last="Ribas">Antoni Ribas</name><affiliation><nlm:aff id="I16">Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, Los Angeles, CA, USA</nlm:aff></affiliation></author></analytic><series><title level="j">Journal of Translational Medicine</title><idno type="eISSN">1479-5876</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader></TEI><pmc article-type="abstract" xml:lang="en"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">J Transl Med</journal-id><journal-id journal-id-type="iso-abbrev">J Transl Med</journal-id><journal-title-group><journal-title>Journal of Translational Medicine</journal-title></journal-title-group><issn pub-type="epub">1479-5876</issn><publisher><publisher-name>BioMed Central</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmc">4315268</article-id><article-id pub-id-type="publisher-id">1479-5876-13-S1-O4</article-id><article-id pub-id-type="doi">10.1186/1479-5876-13-S1-O4</article-id><article-categories><subj-group subj-group-type="heading"><subject>Oral Presentation</subject></subj-group></article-categories><title-group><article-title>coBRIM: a phase 3, double-blind, placebo-controlled study of vemurafenib versus vemurafenib + cobimetinib in previously untreated <italic>BRAF</italic><sup>V600</sup> mutation–positive patients with unresectable locally advanced or metastatic melanoma (NCT01689519)</article-title></title-group><contrib-group><contrib contrib-type="author" corresp="yes" id="A1"><name><surname>Ascierto</surname><given-names>Paolo A</given-names></name><xref ref-type="aff" rid="I1">1</xref></contrib><contrib contrib-type="author" id="A2"><name><surname>McArthur</surname><given-names>Grant A</given-names></name><xref ref-type="aff" rid="I2">2</xref></contrib><contrib contrib-type="author" id="A3"><name><surname>Dréno</surname><given-names>Brigitte</given-names></name><xref ref-type="aff" rid="I3">3</xref></contrib><contrib contrib-type="author" id="A4"><name><surname>Larkin</surname><given-names>James</given-names></name><xref ref-type="aff" rid="I4">4</xref></contrib><contrib contrib-type="author" id="A5"><name><surname>Liszkay</surname><given-names>Gabriella</given-names></name><xref ref-type="aff" rid="I5">5</xref></contrib><contrib contrib-type="author" id="A6"><name><surname>Maio</surname><given-names>Michele</given-names></name><xref ref-type="aff" rid="I6">6</xref></contrib><contrib contrib-type="author" id="A7"><name><surname>Mandala</surname><given-names>Mario</given-names></name><xref ref-type="aff" rid="I7">7</xref></contrib><contrib contrib-type="author" id="A8"><name><surname>Demidov</surname><given-names>Lev</given-names></name><xref ref-type="aff" rid="I8">8</xref></contrib><contrib contrib-type="author" id="A9"><name><surname>Stroyakovskiy</surname><given-names>Daniil</given-names></name><xref ref-type="aff" rid="I9">9</xref></contrib><contrib contrib-type="author" id="A10"><name><surname>Thomas</surname><given-names>Luc</given-names></name><xref ref-type="aff" rid="I10">10</xref></contrib><contrib contrib-type="author" id="A11"><name><surname>de la Cruz-Merino</surname><given-names>Luis</given-names></name><xref ref-type="aff" rid="I11">11</xref></contrib><contrib contrib-type="author" id="A12"><name><surname>Atkinson</surname><given-names>Victoria</given-names></name><xref ref-type="aff" rid="I12">12</xref></contrib><contrib contrib-type="author" id="A13"><name><surname>Dutriaux</surname><given-names>Caroline</given-names></name><xref ref-type="aff" rid="I13">13</xref></contrib><contrib contrib-type="author" id="A14"><name><surname>Garbe</surname><given-names>Claus</given-names></name><xref ref-type="aff" rid="I14">14</xref></contrib><contrib contrib-type="author" id="A15"><name><surname>Chang</surname><given-names>Ilsung</given-names></name><xref ref-type="aff" rid="I15">15</xref></contrib><contrib contrib-type="author" id="A16"><name><surname>Hack</surname><given-names>Stephen P </given-names></name><xref ref-type="aff" rid="I15">15</xref></contrib><contrib contrib-type="author" id="A17"><name><surname>Ribas</surname><given-names>Antoni</given-names></name><xref ref-type="aff" rid="I16">16</xref></contrib></contrib-group><aff id="I1"><label>1</label>Istituto Nazionale Tumori Fondazione G. Pascale, Naples, Italy</aff><aff id="I2"><label>2</label>Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia</aff><aff id="I3"><label>3</label>Hôtel Dieu Place Alexis Ricordeau, Nantes, France</aff><aff id="I4"><label>4</label>The Royal Marsden Hospital, London, UK</aff><aff id="I5"><label>5</label>National Institute of Oncology, Budapest, Hungary</aff><aff id="I6"><label>6</label>Azienda Ospedaliera Universitaria Senese, Siena, Italy</aff><aff id="I7"><label>7</label>Papa Giovanni XXIII Hospital, Bergamo, Italy</aff><aff id="I8"><label>8</label>N.N. Blokhin Russian Cancer Research Center, Moscow, Russia</aff><aff id="I9"><label>9</label>Moscow City Oncology Hospital 62, Krasnogorsk, Russia</aff><aff id="I10"><label>10</label>Centre Hospitalier Lyon Sud, Pierre-Bénite, France</aff><aff id="I11"><label>11</label>Hospital Universitario Virgen Macarena, Seville, Spain</aff><aff id="I12"><label>12</label>Princess Alexandra Hospital, Woolloongabba, QLD, Australia</aff><aff id="I13"><label>13</label>Hopital Saint André, Bordeaux, France</aff><aff id="I14"><label>14</label>University of Tübingen, Tübingen, Germany</aff><aff id="I15"><label>15</label>Genentech, Inc, South San Francisco, CA, USA</aff><aff id="I16"><label>16</label>Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, Los Angeles, CA, USA</aff><pub-date pub-type="collection"><year>2015</year></pub-date><pub-date pub-type="epub"><day>15</day><month>1</month><year>2015</year></pub-date><volume>13</volume><issue>Suppl 1</issue><supplement><named-content content-type="supplement-title">Melanoma Bridge 2014: meeting abstracts</named-content><named-content content-type="supplement-editor">Paolo A Ascierto, Gennaro Ciliberto, John M Kirkwood, Francesco M Marincola, Giuseppe Masucci, Ignacio Melero, Nicola Mozzillo, Giuseppe Palmieri and Magdalena Thurin.</named-content><named-content content-type="supplement-sponsor">The publication charges for this supplement were funded by 3P solutions. Abstracts were evaluated by the Supplement Editors. Supplement Editor declarations: John Kirkwood reports grants from Prometheus and personal fees from BMS, Merck, GSK, Celgene, Vica and Ziopharm Oncology. Malero has received Consulting honoraria from Bristol Myers Squibb, Roche Genentech and Astra Zeneca. All other Supplement Editors declare that they have no competing interests.</named-content></supplement><fpage>O4</fpage><lpage>O4</lpage><permissions><copyright-statement>Copyright © 2015 Ascierto et al; licensee BioMed Central Ltd.</copyright-statement><copyright-year>2015</copyright-year><copyright-holder>Ascierto et al; licensee BioMed Central Ltd.</copyright-holder><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/4.0"><license-p>This is an Open Access article distributed under the terms of the Creative Commons Attribution License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0">http://creativecommons.org/licenses/by/4.0</ext-link>), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/publicdomain/zero/1.0/">http://creativecommons.org/publicdomain/zero/1.0/</ext-link>) applies to the data made available in this article, unless otherwise stated.</license-p></license></permissions><self-uri xlink:href="http://www.translational-medicine.com/content/13/S1/O4"></self-uri><conference><conf-date>3-6 December 2014</conf-date><conf-name>Melanoma Bridge Meeting 2014</conf-name><conf-loc>Naples, Italy</conf-loc></conference></article-meta></front><body><sec><title>Background</title><p>Combined inhibition of BRAF and MEK is hypothesized to improve clinical outcomes by preventing or delaying onset of resistance observed with BRAF inhibitors alone. This randomized phase 3 study evaluated the combination of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib.</p></sec><sec sec-type="materials|methods"><title>Materials and methods</title><p>495 patients were randomly assigned to receive vemurafenib + cobimetinib (60 mg QD, 21 days on/7 days off) or vemurafenib (960 mg BID) + placebo. Eligibility included treatment-naive <italic>BRAF</italic><sup>V600</sup> mutation–positive patients with unresectable locally advanced or metastatic melanoma and adequate performance status and organ function. The primary end point was investigator-assessed progression-free survival (PFS). Safety monitoring included serial cardiac and ophthalmic evaluation and measurement of creatine phosphokinase.</p></sec><sec sec-type="results"><title>Results</title><p>Median PFS was 9.9 months with the combination compared with 6.2 months with the control (HR, 0.51; 95% CI, 0.39-0.68; <italic>P</italic><0.0001). Objective response rate (ORR) was 68% in the combination and 45% in the control arm (<italic>P</italic><0.0001), including complete response in 10% in the combination and 4% of patients in the control group. Subgroup analyses of PFS based on key demographic and tumor characteristics were consistent with PFS in the intent-to-treat population, including those with normal or elevated baseline lactate dehydrogenase (LDH). PFS assessed by independent review was comparable with investigator-assessed PFS. Interim overall survival (OS) data showed an HR of 0.65 (95% CI, 0.42-1.00) but did not cross the prespecified stopping boundary. Compared with vemurafenib alone, the combination was associated with a higher incidence of grade 3 or 4 adverse events (65% vs 59%), with no difference in the rate of adverse events leading to study drug discontinuation (13% vs 12%). Most grade ≥3 events occurred in the first 28 days and resolved quickly. Known MEK inhibitor–related toxicities such as diarrhea, serous retinopathy, elevated creatine phosphokinase, and increased liver transaminase levels were more commonly observed with the combination. The majority was grade 1 or 2, occurred between 1 and 4 months in the treatment course, and resolved quickly. The occurrence of secondary cutaneous neoplasms decreased with the combination (4% vs 18%). Photosensitivity was more common in patients treated with the combination (all grades 32% vs 18%).</p></sec><sec sec-type="conclusions"><title>Conclusion</title><p>Cobimetinib + vemurafenib significantly improved PFS and response rate among patients with <italic>BRAF</italic><sup>V600</sup>-mutant metastatic melanoma, with promising preliminary OS analysis. Most combination-related toxicities are mild or moderate, occur early in treatment, and are manageable by dose modification and supportive care; treatment discontinuation is uncommon.</p></sec><sec><title>Clinical trial registration number</title><p>NCT01689519</p></sec></body></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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