Combined BRAF and MEK Inhibition versus BRAF Inhibition Alone in Melanoma
Identifieur interne : 005C59 ( PascalFrancis/Curation ); précédent : 005C58; suivant : 005C60Combined BRAF and MEK Inhibition versus BRAF Inhibition Alone in Melanoma
Auteurs : G. V. Long [Australie] ; D. Stroyakovskiy [Russie] ; H. Gogas [Grèce] ; E. Levchenko [Russie] ; F. De Braud [Italie] ; J. Larkin [Royaume-Uni] ; C. Garbe [Allemagne] ; T. Jouary [France] ; A. Hauschild [Allemagne] ; J. J. Grob [France] ; V. Chiarion Sileni [Italie] ; C. Lebbe [France] ; M. Mandala [Italie] ; M. Millward [Australie] ; A. Arance [Royaume-Uni] ; I. Bondarenko [Ukraine] ; J. B. A. G. Haanen [Pays-Bas] ; J. Hansson ; J. Utikal [Allemagne] ; V. Ferraresi [Italie] ; N. Kovalenko [Russie] ; P. Mohr [Allemagne] ; V. Probachai [Ukraine] ; D. Schadendorf [Allemagne] ; P. Nathan [Royaume-Uni] ; C. Robert [France] ; A. Ribas ; D. J. Demarini ; J. G. Irani ; M. Casey ; D. Ouellet ; A.-M. Martin ; N. Le ; K. Patel ; K. FlahertySource :
- The New England journal of medicine [ 0028-4793 ] ; 2014.
Descripteurs français
- Pascal (Inist)
- Wicri :
- topic : Médecine.
English descriptors
- KwdEn :
Abstract
BACKGROUND Combined BRAF and MEK inhibition, as compared with BRAF inhibition alone, delays the emergence of resistance and reduces toxic effects in patients who have melanoma with BRAF V600E or V600K mutations. METHODS In this phase 3 trial, we randomly assigned 423 previously untreated patients who had unresectable stage IIIC or stage IV melanoma with a BRAF V600E or V600K mutation to receive a combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily) or dabrafenib and placebo. The primary end point was progression-free survival. Secondary end points included overall survival, response rate, response duration, and safety. A preplanned interim overall survival analysis was conducted. RESULTS The median progression-free survival was 9.3 months in the dabrafenib-trametinib group and 8.8 months in the dabrafenib-only group (hazard ratio for progression or death in the dabrafenib-trametinib group, 0.75; 95% confidence interval [CI], 0.57 to 0.99; P=0.03). The overall response rate was 67% in the dabrafenib-trametinib group and 51% in the dabrafenib-only group (P=0.002). At 6 months, the interim overall survival rate was 93% with dabrafenib-trametinib and 85% with dabrafenib alone (hazard ratio for death, 0.63; 95% CI, 0.42 to 0.94; P=0.02). However, a specified efficacy-stopping boundary (two-sided P=0.00028) was not crossed. Rates of adverse events were similar in the two groups, although more dose modifications occurred in the dabrafenib-trametinib group. The rate of cutaneous squamous-cell carcinoma was lower in the dabrafenib-trametinib group than in the dabrafenib-only group (2% vs. 9%), whereas pyrexia occurred in more patients (51% vs. 28%) and was more often severe (grade 3, 6% vs. 2%) in the dabrafenib-trametinib group. CONCLUSIONS A combination of dabrafenib and trametinib, as compared with dabrafenib alone, improved the rate of progression-free survival in previously untreated patients who had metastatic melanoma with BRAF V600E or V600K mutations.
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Jouary</name><affiliation wicri:level="1"><inist:fA14 i1="18"><s1>Hopital Francois Mitterrand</s1><s2>Pau</s2><s3>FRA</s3><sZ>8 aut.</sZ></inist:fA14><country>France</country></affiliation></author><author><name sortKey="Hauschild, A" sort="Hauschild, A" uniqKey="Hauschild A" first="A." last="Hauschild">A. Hauschild</name><affiliation wicri:level="1"><inist:fA14 i1="14"><s1>University Hospital Schleswig-Holstein, Campus Kiel</s1><s2>Kiel</s2><s3>DEU</s3><sZ>9 aut.</sZ></inist:fA14><country>Allemagne</country></affiliation></author><author><name sortKey="Grob, J J" sort="Grob, J J" uniqKey="Grob J" first="J. J." last="Grob">J. J. Grob</name><affiliation wicri:level="1"><inist:fA14 i1="19"><s1>Hôpital de la Timone</s1><s2>Marseille</s2><s3>FRA</s3><sZ>10 aut.</sZ></inist:fA14><country>France</country></affiliation></author><author><name sortKey="Chiarion Sileni, V" sort="Chiarion Sileni, V" uniqKey="Chiarion Sileni V" first="V." last="Chiarion Sileni">V. Chiarion Sileni</name><affiliation wicri:level="1"><inist:fA14 i1="08"><s1>Veneto Oncology Institute-IRCCS</s1><s2>Padua</s2><s3>ITA</s3><sZ>11 aut.</sZ></inist:fA14><country>Italie</country></affiliation></author><author><name sortKey="Lebbe, C" sort="Lebbe, C" uniqKey="Lebbe C" first="C." last="Lebbe">C. Lebbe</name><affiliation wicri:level="1"><inist:fA14 i1="20"><s1>Hôpital Saint-Louis</s1><s2>Paris</s2><s3>FRA</s3><sZ>12 aut.</sZ></inist:fA14><country>France</country></affiliation></author><author><name sortKey="Mandala, M" sort="Mandala, M" uniqKey="Mandala M" first="M." last="Mandala">M. Mandala</name><affiliation wicri:level="1"><inist:fA14 i1="09"><s1>Papa Giovanni XXIII Hospital</s1><s2>Bergamo</s2><s3>ITA</s3><sZ>13 aut.</sZ></inist:fA14><country>Italie</country></affiliation></author><author><name sortKey="Millward, M" sort="Millward, M" uniqKey="Millward M" first="M." last="Millward">M. Millward</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Sir Charles Gairdner Hospital</s1><s2>Perth, WA</s2><s3>AUS</s3><sZ>14 aut.</sZ></inist:fA14><country>Australie</country></affiliation></author><author><name sortKey="Arance, A" sort="Arance, A" uniqKey="Arance A" first="A." last="Arance">A. Arance</name><affiliation wicri:level="1"><inist:fA14 i1="22"><s1>Hospital Clinic</s1><s2>Barcelona</s2><s3>GBR</s3><sZ>15 aut.</sZ></inist:fA14><country>Royaume-Uni</country></affiliation></author><author><name sortKey="Bondarenko, I" sort="Bondarenko, I" uniqKey="Bondarenko I" first="I." last="Bondarenko">I. Bondarenko</name><affiliation wicri:level="1"><inist:fA14 i1="23"><s1>Dnipropetrovsk Medical Academy, Clinical Hospital #4</s1><s3>UKR</s3><sZ>16 aut.</sZ></inist:fA14><country>Ukraine</country></affiliation></author><author><name sortKey="Haanen, J B A G" sort="Haanen, J B A G" uniqKey="Haanen J" first="J. B. A. G." last="Haanen">J. B. A. G. Haanen</name><affiliation wicri:level="1"><inist:fA14 i1="25"><s1>Netherlands Cancer Institute</s1><s2>Amsterdam</s2><s3>NLD</s3><sZ>17 aut.</sZ></inist:fA14><country>Pays-Bas</country></affiliation></author><author><name sortKey="Hansson, J" sort="Hansson, J" uniqKey="Hansson J" first="J." last="Hansson">J. Hansson</name></author><author><name sortKey="Utikal, J" sort="Utikal, J" uniqKey="Utikal J" first="J." last="Utikal">J. Utikal</name><affiliation wicri:level="1"><inist:fA14 i1="15"><s1>German Cancer Research Center (DKFZ) and University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg</s1><s2>Mannheim and Heidelberg</s2><s3>DEU</s3><sZ>19 aut.</sZ></inist:fA14><country>Allemagne</country></affiliation></author><author><name sortKey="Ferraresi, V" sort="Ferraresi, V" uniqKey="Ferraresi V" first="V." last="Ferraresi">V. Ferraresi</name><affiliation wicri:level="1"><inist:fA14 i1="10"><s1>Regina Elena National Cancer Institute</s1><s2>Rome</s2><s3>ITA</s3><sZ>20 aut.</sZ></inist:fA14><country>Italie</country></affiliation></author><author><name sortKey="Kovalenko, N" sort="Kovalenko, N" uniqKey="Kovalenko N" first="N." last="Kovalenko">N. Kovalenko</name><affiliation wicri:level="1"><inist:fA14 i1="05"><s1>Volograd Regional Oncology Dispensary #3</s1><s2>Volzhsky</s2><s3>RUS</s3><sZ>21 aut.</sZ></inist:fA14><country>Russie</country></affiliation></author><author><name sortKey="Mohr, P" sort="Mohr, P" uniqKey="Mohr P" first="P." last="Mohr">P. Mohr</name><affiliation wicri:level="1"><inist:fA14 i1="16"><s1>Elbe Kliniken Stade-Buxtehude</s1><s2>Buxtehude</s2><s3>DEU</s3><sZ>22 aut.</sZ></inist:fA14><country>Allemagne</country></affiliation></author><author><name sortKey="Probachai, V" sort="Probachai, V" uniqKey="Probachai V" first="V." last="Probachai">V. Probachai</name><affiliation wicri:level="1"><inist:fA14 i1="24"><s1>Dnipropetrovsk Clinical Oncology Center of Dnipropetrovsk State Council</s1><s2>Dnipropetrovsk</s2><s3>UKR</s3><sZ>23 aut.</sZ></inist:fA14><country>Ukraine</country></affiliation></author><author><name sortKey="Schadendorf, D" sort="Schadendorf, D" uniqKey="Schadendorf D" first="D." last="Schadendorf">D. Schadendorf</name><affiliation wicri:level="1"><inist:fA14 i1="17"><s1>University Hospital Essen</s1><s2>Essen</s2><s3>DEU</s3><sZ>24 aut.</sZ></inist:fA14><country>Allemagne</country></affiliation></author><author><name sortKey="Nathan, P" sort="Nathan, P" uniqKey="Nathan P" first="P." last="Nathan">P. Nathan</name><affiliation wicri:level="1"><inist:fA14 i1="12"><s1>Mount Vernon Cancer Centre</s1><s2>Northwood</s2><s3>GBR</s3><sZ>25 aut.</sZ></inist:fA14><country>Royaume-Uni</country></affiliation></author><author><name sortKey="Robert, C" sort="Robert, C" uniqKey="Robert C" first="C." last="Robert">C. Robert</name><affiliation wicri:level="1"><inist:fA14 i1="21"><s1>Institut Gustave Roussy</s1><s2>Villejuif-Paris</s2><s3>FRA</s3><sZ>26 aut.</sZ></inist:fA14><country>France</country></affiliation></author><author><name sortKey="Ribas, A" sort="Ribas, A" uniqKey="Ribas A" first="A." last="Ribas">A. Ribas</name></author><author><name sortKey="Demarini, D J" sort="Demarini, D J" uniqKey="Demarini D" first="D. J." last="Demarini">D. J. Demarini</name></author><author><name sortKey="Irani, J G" sort="Irani, J G" uniqKey="Irani J" first="J. G." last="Irani">J. G. Irani</name></author><author><name sortKey="Casey, M" sort="Casey, M" uniqKey="Casey M" first="M." last="Casey">M. Casey</name></author><author><name sortKey="Ouellet, D" sort="Ouellet, D" uniqKey="Ouellet D" first="D." last="Ouellet">D. Ouellet</name></author><author><name sortKey="Martin, A M" sort="Martin, A M" uniqKey="Martin A" first="A.-M." last="Martin">A.-M. Martin</name></author><author><name sortKey="Le, N" sort="Le, N" uniqKey="Le N" first="N." last="Le">N. Le</name></author><author><name sortKey="Patel, K" sort="Patel, K" uniqKey="Patel K" first="K." last="Patel">K. Patel</name></author><author><name sortKey="Flaherty, K" sort="Flaherty, K" uniqKey="Flaherty K" first="K." last="Flaherty">K. Flaherty</name></author></titleStmt><publicationStmt><idno type="wicri:source">INIST</idno><idno type="inist">14-0265574</idno><date when="2014">2014</date><idno type="stanalyst">PASCAL 14-0265574 INIST</idno><idno type="RBID">Pascal:14-0265574</idno><idno type="wicri:Area/PascalFrancis/Corpus">000206</idno><idno type="wicri:Area/PascalFrancis/Curation">005C59</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">Combined BRAF and MEK Inhibition versus BRAF Inhibition Alone in Melanoma</title><author><name sortKey="Long, G V" sort="Long, G V" uniqKey="Long G" first="G. V." last="Long">G. V. Long</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Melanoma Institute Australia, University of Sydney, Mater Hospital</s1><s2>Sydney</s2><s3>AUS</s3><sZ>1 aut.</sZ></inist:fA14><country>Australie</country></affiliation></author><author><name sortKey="Stroyakovskiy, D" sort="Stroyakovskiy, D" uniqKey="Stroyakovskiy D" first="D." last="Stroyakovskiy">D. Stroyakovskiy</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Moscow City Oncology Hospital #62</s1><s2>Moscow</s2><s3>RUS</s3><sZ>2 aut.</sZ></inist:fA14><country>Russie</country></affiliation></author><author><name sortKey="Gogas, H" sort="Gogas, H" uniqKey="Gogas H" first="H." last="Gogas">H. Gogas</name><affiliation wicri:level="1"><inist:fA14 i1="06"><s1>University of Athens</s1><s2>Athens</s2><s3>GRC</s3><sZ>3 aut.</sZ></inist:fA14><country>Grèce</country></affiliation></author><author><name sortKey="Levchenko, E" sort="Levchenko, E" uniqKey="Levchenko E" first="E." last="Levchenko">E. Levchenko</name><affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Petrov Research Institute of Oncology</s1><s2>Saint Petersburg</s2><s3>RUS</s3><sZ>4 aut.</sZ></inist:fA14><country>Russie</country></affiliation></author><author><name sortKey="De Braud, F" sort="De Braud, F" uniqKey="De Braud F" first="F." last="De Braud">F. De Braud</name><affiliation wicri:level="1"><inist:fA14 i1="07"><s1>Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori</s1><s2>Milan</s2><s3>ITA</s3><sZ>5 aut.</sZ></inist:fA14><country>Italie</country></affiliation></author><author><name sortKey="Larkin, J" sort="Larkin, J" uniqKey="Larkin J" first="J." last="Larkin">J. Larkin</name><affiliation wicri:level="1"><inist:fA14 i1="11"><s1>Royal Marsden NHS Foundation Trust</s1><s2>London</s2><s3>GBR</s3><sZ>6 aut.</sZ></inist:fA14><country>Royaume-Uni</country></affiliation></author><author><name sortKey="Garbe, C" sort="Garbe, C" uniqKey="Garbe C" first="C." last="Garbe">C. Garbe</name><affiliation wicri:level="1"><inist:fA14 i1="13"><s1>University of Tübingen</s1><s2>Tübingen</s2><s3>DEU</s3><sZ>7 aut.</sZ></inist:fA14><country>Allemagne</country></affiliation></author><author><name sortKey="Jouary, T" sort="Jouary, T" uniqKey="Jouary T" first="T." last="Jouary">T. Jouary</name><affiliation wicri:level="1"><inist:fA14 i1="18"><s1>Hopital Francois Mitterrand</s1><s2>Pau</s2><s3>FRA</s3><sZ>8 aut.</sZ></inist:fA14><country>France</country></affiliation></author><author><name sortKey="Hauschild, A" sort="Hauschild, A" uniqKey="Hauschild A" first="A." last="Hauschild">A. Hauschild</name><affiliation wicri:level="1"><inist:fA14 i1="14"><s1>University Hospital Schleswig-Holstein, Campus Kiel</s1><s2>Kiel</s2><s3>DEU</s3><sZ>9 aut.</sZ></inist:fA14><country>Allemagne</country></affiliation></author><author><name sortKey="Grob, J J" sort="Grob, J J" uniqKey="Grob J" first="J. J." last="Grob">J. J. Grob</name><affiliation wicri:level="1"><inist:fA14 i1="19"><s1>Hôpital de la Timone</s1><s2>Marseille</s2><s3>FRA</s3><sZ>10 aut.</sZ></inist:fA14><country>France</country></affiliation></author><author><name sortKey="Chiarion Sileni, V" sort="Chiarion Sileni, V" uniqKey="Chiarion Sileni V" first="V." last="Chiarion Sileni">V. Chiarion Sileni</name><affiliation wicri:level="1"><inist:fA14 i1="08"><s1>Veneto Oncology Institute-IRCCS</s1><s2>Padua</s2><s3>ITA</s3><sZ>11 aut.</sZ></inist:fA14><country>Italie</country></affiliation></author><author><name sortKey="Lebbe, C" sort="Lebbe, C" uniqKey="Lebbe C" first="C." last="Lebbe">C. Lebbe</name><affiliation wicri:level="1"><inist:fA14 i1="20"><s1>Hôpital Saint-Louis</s1><s2>Paris</s2><s3>FRA</s3><sZ>12 aut.</sZ></inist:fA14><country>France</country></affiliation></author><author><name sortKey="Mandala, M" sort="Mandala, M" uniqKey="Mandala M" first="M." last="Mandala">M. Mandala</name><affiliation wicri:level="1"><inist:fA14 i1="09"><s1>Papa Giovanni XXIII Hospital</s1><s2>Bergamo</s2><s3>ITA</s3><sZ>13 aut.</sZ></inist:fA14><country>Italie</country></affiliation></author><author><name sortKey="Millward, M" sort="Millward, M" uniqKey="Millward M" first="M." last="Millward">M. Millward</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Sir Charles Gairdner Hospital</s1><s2>Perth, WA</s2><s3>AUS</s3><sZ>14 aut.</sZ></inist:fA14><country>Australie</country></affiliation></author><author><name sortKey="Arance, A" sort="Arance, A" uniqKey="Arance A" first="A." last="Arance">A. Arance</name><affiliation wicri:level="1"><inist:fA14 i1="22"><s1>Hospital Clinic</s1><s2>Barcelona</s2><s3>GBR</s3><sZ>15 aut.</sZ></inist:fA14><country>Royaume-Uni</country></affiliation></author><author><name sortKey="Bondarenko, I" sort="Bondarenko, I" uniqKey="Bondarenko I" first="I." last="Bondarenko">I. Bondarenko</name><affiliation wicri:level="1"><inist:fA14 i1="23"><s1>Dnipropetrovsk Medical Academy, Clinical Hospital #4</s1><s3>UKR</s3><sZ>16 aut.</sZ></inist:fA14><country>Ukraine</country></affiliation></author><author><name sortKey="Haanen, J B A G" sort="Haanen, J B A G" uniqKey="Haanen J" first="J. B. A. G." last="Haanen">J. B. A. G. Haanen</name><affiliation wicri:level="1"><inist:fA14 i1="25"><s1>Netherlands Cancer Institute</s1><s2>Amsterdam</s2><s3>NLD</s3><sZ>17 aut.</sZ></inist:fA14><country>Pays-Bas</country></affiliation></author><author><name sortKey="Hansson, J" sort="Hansson, J" uniqKey="Hansson J" first="J." last="Hansson">J. Hansson</name></author><author><name sortKey="Utikal, J" sort="Utikal, J" uniqKey="Utikal J" first="J." last="Utikal">J. Utikal</name><affiliation wicri:level="1"><inist:fA14 i1="15"><s1>German Cancer Research Center (DKFZ) and University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg</s1><s2>Mannheim and Heidelberg</s2><s3>DEU</s3><sZ>19 aut.</sZ></inist:fA14><country>Allemagne</country></affiliation></author><author><name sortKey="Ferraresi, V" sort="Ferraresi, V" uniqKey="Ferraresi V" first="V." last="Ferraresi">V. Ferraresi</name><affiliation wicri:level="1"><inist:fA14 i1="10"><s1>Regina Elena National Cancer Institute</s1><s2>Rome</s2><s3>ITA</s3><sZ>20 aut.</sZ></inist:fA14><country>Italie</country></affiliation></author><author><name sortKey="Kovalenko, N" sort="Kovalenko, N" uniqKey="Kovalenko N" first="N." last="Kovalenko">N. Kovalenko</name><affiliation wicri:level="1"><inist:fA14 i1="05"><s1>Volograd Regional Oncology Dispensary #3</s1><s2>Volzhsky</s2><s3>RUS</s3><sZ>21 aut.</sZ></inist:fA14><country>Russie</country></affiliation></author><author><name sortKey="Mohr, P" sort="Mohr, P" uniqKey="Mohr P" first="P." last="Mohr">P. Mohr</name><affiliation wicri:level="1"><inist:fA14 i1="16"><s1>Elbe Kliniken Stade-Buxtehude</s1><s2>Buxtehude</s2><s3>DEU</s3><sZ>22 aut.</sZ></inist:fA14><country>Allemagne</country></affiliation></author><author><name sortKey="Probachai, V" sort="Probachai, V" uniqKey="Probachai V" first="V." last="Probachai">V. Probachai</name><affiliation wicri:level="1"><inist:fA14 i1="24"><s1>Dnipropetrovsk Clinical Oncology Center of Dnipropetrovsk State Council</s1><s2>Dnipropetrovsk</s2><s3>UKR</s3><sZ>23 aut.</sZ></inist:fA14><country>Ukraine</country></affiliation></author><author><name sortKey="Schadendorf, D" sort="Schadendorf, D" uniqKey="Schadendorf D" first="D." last="Schadendorf">D. Schadendorf</name><affiliation wicri:level="1"><inist:fA14 i1="17"><s1>University Hospital Essen</s1><s2>Essen</s2><s3>DEU</s3><sZ>24 aut.</sZ></inist:fA14><country>Allemagne</country></affiliation></author><author><name sortKey="Nathan, P" sort="Nathan, P" uniqKey="Nathan P" first="P." last="Nathan">P. Nathan</name><affiliation wicri:level="1"><inist:fA14 i1="12"><s1>Mount Vernon Cancer Centre</s1><s2>Northwood</s2><s3>GBR</s3><sZ>25 aut.</sZ></inist:fA14><country>Royaume-Uni</country></affiliation></author><author><name sortKey="Robert, C" sort="Robert, C" uniqKey="Robert C" first="C." last="Robert">C. Robert</name><affiliation wicri:level="1"><inist:fA14 i1="21"><s1>Institut Gustave Roussy</s1><s2>Villejuif-Paris</s2><s3>FRA</s3><sZ>26 aut.</sZ></inist:fA14><country>France</country></affiliation></author><author><name sortKey="Ribas, A" sort="Ribas, A" uniqKey="Ribas A" first="A." last="Ribas">A. Ribas</name></author><author><name sortKey="Demarini, D J" sort="Demarini, D J" uniqKey="Demarini D" first="D. J." last="Demarini">D. J. Demarini</name></author><author><name sortKey="Irani, J G" sort="Irani, J G" uniqKey="Irani J" first="J. G." last="Irani">J. G. Irani</name></author><author><name sortKey="Casey, M" sort="Casey, M" uniqKey="Casey M" first="M." last="Casey">M. Casey</name></author><author><name sortKey="Ouellet, D" sort="Ouellet, D" uniqKey="Ouellet D" first="D." last="Ouellet">D. Ouellet</name></author><author><name sortKey="Martin, A M" sort="Martin, A M" uniqKey="Martin A" first="A.-M." last="Martin">A.-M. Martin</name></author><author><name sortKey="Le, N" sort="Le, N" uniqKey="Le N" first="N." last="Le">N. Le</name></author><author><name sortKey="Patel, K" sort="Patel, K" uniqKey="Patel K" first="K." last="Patel">K. Patel</name></author><author><name sortKey="Flaherty, K" sort="Flaherty, K" uniqKey="Flaherty K" first="K." last="Flaherty">K. Flaherty</name></author></analytic><series><title level="j" type="main">The New England journal of medicine</title><title level="j" type="abbreviated">N. Engl. j. med.</title><idno type="ISSN">0028-4793</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">The New England journal of medicine</title><title level="j" type="abbreviated">N. Engl. j. med.</title><idno type="ISSN">0028-4793</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Comparative study</term><term>Malignant melanoma</term><term>Medicine</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Mélanome malin</term><term>Etude comparative</term><term>Médecine</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Médecine</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">BACKGROUND Combined BRAF and MEK inhibition, as compared with BRAF inhibition alone, delays the emergence of resistance and reduces toxic effects in patients who have melanoma with BRAF V600E or V600K mutations. METHODS In this phase 3 trial, we randomly assigned 423 previously untreated patients who had unresectable stage IIIC or stage IV melanoma with a BRAF V600E or V600K mutation to receive a combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily) or dabrafenib and placebo. The primary end point was progression-free survival. Secondary end points included overall survival, response rate, response duration, and safety. A preplanned interim overall survival analysis was conducted. RESULTS The median progression-free survival was 9.3 months in the dabrafenib-trametinib group and 8.8 months in the dabrafenib-only group (hazard ratio for progression or death in the dabrafenib-trametinib group, 0.75; 95% confidence interval [CI], 0.57 to 0.99; P=0.03). The overall response rate was 67% in the dabrafenib-trametinib group and 51% in the dabrafenib-only group (P=0.002). At 6 months, the interim overall survival rate was 93% with dabrafenib-trametinib and 85% with dabrafenib alone (hazard ratio for death, 0.63; 95% CI, 0.42 to 0.94; P=0.02). However, a specified efficacy-stopping boundary (two-sided P=0.00028) was not crossed. Rates of adverse events were similar in the two groups, although more dose modifications occurred in the dabrafenib-trametinib group. The rate of cutaneous squamous-cell carcinoma was lower in the dabrafenib-trametinib group than in the dabrafenib-only group (2% vs. 9%), whereas pyrexia occurred in more patients (51% vs. 28%) and was more often severe (grade 3, 6% vs. 2%) in the dabrafenib-trametinib group. CONCLUSIONS A combination of dabrafenib and trametinib, as compared with dabrafenib alone, improved the rate of progression-free survival in previously untreated patients who had metastatic melanoma with BRAF V600E or V600K mutations.</div></front></TEI><inist><standard h6="B"><pA><fA01 i1="01" i2="1"><s0>0028-4793</s0></fA01><fA02 i1="01"><s0>NEJMAG</s0></fA02><fA03 i2="1"><s0>N. Engl. j. med.</s0></fA03><fA05><s2>371</s2></fA05><fA06><s2>20</s2></fA06><fA08 i1="01" i2="1" l="ENG"><s1>Combined BRAF and MEK Inhibition versus BRAF Inhibition Alone in Melanoma</s1></fA08><fA11 i1="01" i2="1"><s1>LONG (G. V.)</s1></fA11><fA11 i1="02" i2="1"><s1>STROYAKOVSKIY (D.)</s1></fA11><fA11 i1="03" i2="1"><s1>GOGAS (H.)</s1></fA11><fA11 i1="04" i2="1"><s1>LEVCHENKO (E.)</s1></fA11><fA11 i1="05" i2="1"><s1>DE BRAUD (F.)</s1></fA11><fA11 i1="06" i2="1"><s1>LARKIN (J.)</s1></fA11><fA11 i1="07" i2="1"><s1>GARBE (C.)</s1></fA11><fA11 i1="08" i2="1"><s1>JOUARY (T.)</s1></fA11><fA11 i1="09" i2="1"><s1>HAUSCHILD (A.)</s1></fA11><fA11 i1="10" i2="1"><s1>GROB (J. J.)</s1></fA11><fA11 i1="11" i2="1"><s1>CHIARION SILENI (V.)</s1></fA11><fA11 i1="12" i2="1"><s1>LEBBE (C.)</s1></fA11><fA11 i1="13" i2="1"><s1>MANDALA (M.)</s1></fA11><fA11 i1="14" i2="1"><s1>MILLWARD (M.)</s1></fA11><fA11 i1="15" i2="1"><s1>ARANCE (A.)</s1></fA11><fA11 i1="16" i2="1"><s1>BONDARENKO (I.)</s1></fA11><fA11 i1="17" i2="1"><s1>HAANEN (J. B. A. G.)</s1></fA11><fA11 i1="18" i2="1"><s1>HANSSON (J.)</s1></fA11><fA11 i1="19" i2="1"><s1>UTIKAL (J.)</s1></fA11><fA11 i1="20" i2="1"><s1>FERRARESI (V.)</s1></fA11><fA11 i1="21" i2="1"><s1>KOVALENKO (N.)</s1></fA11><fA11 i1="22" i2="1"><s1>MOHR (P.)</s1></fA11><fA11 i1="23" i2="1"><s1>PROBACHAI (V.)</s1></fA11><fA11 i1="24" i2="1"><s1>SCHADENDORF (D.)</s1></fA11><fA11 i1="25" i2="1"><s1>NATHAN (P.)</s1></fA11><fA11 i1="26" i2="1"><s1>ROBERT (C.)</s1></fA11><fA11 i1="27" i2="1"><s1>RIBAS (A.)</s1></fA11><fA11 i1="28" i2="1"><s1>DEMARINI (D. J.)</s1></fA11><fA11 i1="29" i2="1"><s1>IRANI (J. G.)</s1></fA11><fA11 i1="30" i2="1"><s1>CASEY (M.)</s1></fA11><fA11 i1="31" i2="1"><s1>OUELLET (D.)</s1></fA11><fA11 i1="32" i2="1"><s1>MARTIN (A.-M.)</s1></fA11><fA11 i1="33" i2="1"><s1>LE (N.)</s1></fA11><fA11 i1="34" i2="1"><s1>PATEL (K.)</s1></fA11><fA11 i1="35" i2="1"><s1>FLAHERTY (K.)</s1></fA11><fA14 i1="01"><s1>Melanoma Institute Australia, University of Sydney, Mater Hospital</s1><s2>Sydney</s2><s3>AUS</s3><sZ>1 aut.</sZ></fA14><fA14 i1="02"><s1>Sir Charles Gairdner Hospital</s1><s2>Perth, WA</s2><s3>AUS</s3><sZ>14 aut.</sZ></fA14><fA14 i1="03"><s1>Moscow City Oncology Hospital #62</s1><s2>Moscow</s2><s3>RUS</s3><sZ>2 aut.</sZ></fA14><fA14 i1="04"><s1>Petrov Research Institute of Oncology</s1><s2>Saint Petersburg</s2><s3>RUS</s3><sZ>4 aut.</sZ></fA14><fA14 i1="05"><s1>Volograd Regional Oncology Dispensary #3</s1><s2>Volzhsky</s2><s3>RUS</s3><sZ>21 aut.</sZ></fA14><fA14 i1="06"><s1>University of Athens</s1><s2>Athens</s2><s3>GRC</s3><sZ>3 aut.</sZ></fA14><fA14 i1="07"><s1>Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori</s1><s2>Milan</s2><s3>ITA</s3><sZ>5 aut.</sZ></fA14><fA14 i1="08"><s1>Veneto Oncology Institute-IRCCS</s1><s2>Padua</s2><s3>ITA</s3><sZ>11 aut.</sZ></fA14><fA14 i1="09"><s1>Papa Giovanni XXIII Hospital</s1><s2>Bergamo</s2><s3>ITA</s3><sZ>13 aut.</sZ></fA14><fA14 i1="10"><s1>Regina Elena National Cancer Institute</s1><s2>Rome</s2><s3>ITA</s3><sZ>20 aut.</sZ></fA14><fA14 i1="11"><s1>Royal Marsden NHS Foundation Trust</s1><s2>London</s2><s3>GBR</s3><sZ>6 aut.</sZ></fA14><fA14 i1="12"><s1>Mount Vernon Cancer Centre</s1><s2>Northwood</s2><s3>GBR</s3><sZ>25 aut.</sZ></fA14><fA14 i1="13"><s1>University of Tübingen</s1><s2>Tübingen</s2><s3>DEU</s3><sZ>7 aut.</sZ></fA14><fA14 i1="14"><s1>University Hospital Schleswig-Holstein, Campus Kiel</s1><s2>Kiel</s2><s3>DEU</s3><sZ>9 aut.</sZ></fA14><fA14 i1="15"><s1>German Cancer Research Center (DKFZ) and University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg</s1><s2>Mannheim and Heidelberg</s2><s3>DEU</s3><sZ>19 aut.</sZ></fA14><fA14 i1="16"><s1>Elbe Kliniken Stade-Buxtehude</s1><s2>Buxtehude</s2><s3>DEU</s3><sZ>22 aut.</sZ></fA14><fA14 i1="17"><s1>University Hospital Essen</s1><s2>Essen</s2><s3>DEU</s3><sZ>24 aut.</sZ></fA14><fA14 i1="18"><s1>Hopital Francois Mitterrand</s1><s2>Pau</s2><s3>FRA</s3><sZ>8 aut.</sZ></fA14><fA14 i1="19"><s1>Hôpital de la Timone</s1><s2>Marseille</s2><s3>FRA</s3><sZ>10 aut.</sZ></fA14><fA14 i1="20"><s1>Hôpital Saint-Louis</s1><s2>Paris</s2><s3>FRA</s3><sZ>12 aut.</sZ></fA14><fA14 i1="21"><s1>Institut Gustave Roussy</s1><s2>Villejuif-Paris</s2><s3>FRA</s3><sZ>26 aut.</sZ></fA14><fA14 i1="22"><s1>Hospital Clinic</s1><s2>Barcelona</s2><s3>GBR</s3><sZ>15 aut.</sZ></fA14><fA14 i1="23"><s1>Dnipropetrovsk Medical Academy, Clinical Hospital #4</s1><s3>UKR</s3><sZ>16 aut.</sZ></fA14><fA14 i1="24"><s1>Dnipropetrovsk Clinical Oncology Center of Dnipropetrovsk State Council</s1><s2>Dnipropetrovsk</s2><s3>UKR</s3><sZ>23 aut.</sZ></fA14><fA14 i1="25"><s1>Netherlands Cancer Institute</s1><s2>Amsterdam</s2><s3>NLD</s3><sZ>17 aut.</sZ></fA14><fA20><s1>1877-1888</s1></fA20><fA21><s1>2014</s1></fA21><fA23 i1="01"><s0>ENG</s0></fA23><fA43 i1="01"><s1>INIST</s1><s2>6013</s2><s5>354000502677080050</s5></fA43><fA44><s0>0000</s0><s1>© 2014 INIST-CNRS. All rights reserved.</s1></fA44><fA45><s0>30 ref.</s0></fA45><fA47 i1="01" i2="1"><s0>14-0265574</s0></fA47><fA60><s1>P</s1></fA60><fA61><s0>A</s0></fA61><fA64 i1="01" i2="1"><s0>The New England journal of medicine</s0></fA64><fA66 i1="01"><s0>USA</s0></fA66><fC01 i1="01" l="ENG"><s0>BACKGROUND Combined BRAF and MEK inhibition, as compared with BRAF inhibition alone, delays the emergence of resistance and reduces toxic effects in patients who have melanoma with BRAF V600E or V600K mutations. METHODS In this phase 3 trial, we randomly assigned 423 previously untreated patients who had unresectable stage IIIC or stage IV melanoma with a BRAF V600E or V600K mutation to receive a combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily) or dabrafenib and placebo. The primary end point was progression-free survival. Secondary end points included overall survival, response rate, response duration, and safety. A preplanned interim overall survival analysis was conducted. RESULTS The median progression-free survival was 9.3 months in the dabrafenib-trametinib group and 8.8 months in the dabrafenib-only group (hazard ratio for progression or death in the dabrafenib-trametinib group, 0.75; 95% confidence interval [CI], 0.57 to 0.99; P=0.03). The overall response rate was 67% in the dabrafenib-trametinib group and 51% in the dabrafenib-only group (P=0.002). At 6 months, the interim overall survival rate was 93% with dabrafenib-trametinib and 85% with dabrafenib alone (hazard ratio for death, 0.63; 95% CI, 0.42 to 0.94; P=0.02). However, a specified efficacy-stopping boundary (two-sided P=0.00028) was not crossed. Rates of adverse events were similar in the two groups, although more dose modifications occurred in the dabrafenib-trametinib group. The rate of cutaneous squamous-cell carcinoma was lower in the dabrafenib-trametinib group than in the dabrafenib-only group (2% vs. 9%), whereas pyrexia occurred in more patients (51% vs. 28%) and was more often severe (grade 3, 6% vs. 2%) in the dabrafenib-trametinib group. CONCLUSIONS A combination of dabrafenib and trametinib, as compared with dabrafenib alone, improved the rate of progression-free survival in previously untreated patients who had metastatic melanoma with BRAF V600E or V600K mutations.</s0></fC01><fC02 i1="01" i2="X"><s0>002B01</s0></fC02><fC02 i1="02" i2="X"><s0>002B08A</s0></fC02><fC02 i1="03" i2="X"><s0>002B04C</s0></fC02><fC03 i1="01" i2="X" l="FRE"><s0>Mélanome malin</s0><s5>01</s5></fC03><fC03 i1="01" i2="X" l="ENG"><s0>Malignant melanoma</s0><s5>01</s5></fC03><fC03 i1="01" i2="X" l="SPA"><s0>Melanoma maligno</s0><s5>01</s5></fC03><fC03 i1="02" i2="X" l="FRE"><s0>Etude comparative</s0><s5>07</s5></fC03><fC03 i1="02" i2="X" l="ENG"><s0>Comparative study</s0><s5>07</s5></fC03><fC03 i1="02" i2="X" l="SPA"><s0>Estudio comparativo</s0><s5>07</s5></fC03><fC03 i1="03" i2="X" l="FRE"><s0>Médecine</s0><s5>08</s5></fC03><fC03 i1="03" i2="X" l="ENG"><s0>Medicine</s0><s5>08</s5></fC03><fC03 i1="03" i2="X" l="SPA"><s0>Medicina</s0><s5>08</s5></fC03><fC07 i1="01" i2="X" l="FRE"><s0>Tumeur maligne</s0><s2>NM</s2><s5>37</s5></fC07><fC07 i1="01" i2="X" l="ENG"><s0>Malignant tumor</s0><s2>NM</s2><s5>37</s5></fC07><fC07 i1="01" i2="X" l="SPA"><s0>Tumor maligno</s0><s2>NM</s2><s5>37</s5></fC07><fC07 i1="02" i2="X" l="FRE"><s0>Cancer</s0><s2>NM</s2></fC07><fC07 i1="02" i2="X" l="ENG"><s0>Cancer</s0><s2>NM</s2></fC07><fC07 i1="02" i2="X" l="SPA"><s0>Cáncer</s0><s2>NM</s2></fC07><fN21><s1>328</s1></fN21><fN44 i1="01"><s1>OTO</s1></fN44><fN82><s1>OTO</s1></fN82></pA></standard></inist></record>Pour manipuler ce document sous Unix (Dilib)
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