Combined BRAF and MEK Inhibition versus BRAF Inhibition Alone in Melanoma
Identifieur interne : 004243 ( Main/Exploration ); précédent : 004242; suivant : 004244Combined 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.
Affiliations:
- Allemagne, Australie, France, Grèce, Italie, Pays-Bas, Royaume-Uni, Russie, Ukraine
- Angleterre, Aquitaine, Attique (région), Bade-Wurtemberg, Catalogne, District de Tübingen, District fédéral central, Grand Londres, Hollande-Septentrionale, Latium, Lombardie, Nouvelle-Aquitaine, Nouvelle-Galles du Sud, Provence-Alpes-Côte d'Azur, Schleswig-Holstein, Île-de-France
- Amsterdam, Athènes, Barcelone, Kiel, Londres, Marseille, Milan, Moscou, Paris, Pau, Rome, Sydney, Tübingen
- Université de Sydney
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Grob</name><affiliation wicri:level="3"><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><placeName><region type="region">Provence-Alpes-Côte d'Azur</region><region type="old region">Provence-Alpes-Côte d'Azur</region><settlement type="city">Marseille</settlement></placeName></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><wicri:noRegion>Veneto Oncology Institute-IRCCS</wicri:noRegion></affiliation></author><author><name sortKey="Lebbe, C" sort="Lebbe, C" uniqKey="Lebbe C" first="C." last="Lebbe">C. Lebbe</name><affiliation wicri:level="3"><inist:fA14 i1="20"><s1>Hôpital Saint-Louis</s1><s2>Paris</s2><s3>FRA</s3><sZ>12 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></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><wicri:noRegion>Papa Giovanni XXIII Hospital</wicri:noRegion></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><wicri:noRegion>Sir Charles Gairdner Hospital</wicri:noRegion></affiliation></author><author><name sortKey="Arance, A" sort="Arance, A" uniqKey="Arance A" first="A." last="Arance">A. Arance</name><affiliation wicri:level="3"><inist:fA14 i1="22"><s1>Hospital Clinic</s1><s2>Barcelona</s2><s3>GBR</s3><sZ>15 aut.</sZ></inist:fA14><country>Royaume-Uni</country><placeName><settlement type="city">Barcelone</settlement><region nuts="2" type="region">Catalogne</region></placeName></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><wicri:noRegion>Dnipropetrovsk Medical Academy, Clinical Hospital #4</wicri:noRegion></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="3"><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><placeName><settlement type="city">Amsterdam</settlement><region nuts="2" type="province">Hollande-Septentrionale</region></placeName></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><wicri:noRegion>Mannheim and Heidelberg</wicri:noRegion><wicri:noRegion>Ruprecht-Karl University of Heidelberg</wicri:noRegion><wicri:noRegion>Mannheim and Heidelberg</wicri:noRegion></affiliation></author><author><name sortKey="Ferraresi, V" sort="Ferraresi, V" uniqKey="Ferraresi V" first="V." last="Ferraresi">V. Ferraresi</name><affiliation wicri:level="3"><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><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></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><wicri:noRegion>Volograd Regional Oncology Dispensary #3</wicri:noRegion></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><wicri:noRegion>Buxtehude</wicri:noRegion><wicri:noRegion>Elbe Kliniken Stade-Buxtehude</wicri:noRegion><wicri:noRegion>Elbe Kliniken Stade-Buxtehude</wicri:noRegion></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><wicri:noRegion>Dnipropetrovsk Clinical Oncology Center of Dnipropetrovsk State Council</wicri:noRegion></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><wicri:noRegion>Essen</wicri:noRegion><wicri:noRegion>University Hospital Essen</wicri:noRegion><wicri:noRegion>University Hospital Essen</wicri:noRegion></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><wicri:noRegion>Mount Vernon Cancer Centre</wicri:noRegion></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><wicri:noRegion>Villejuif-Paris</wicri:noRegion><wicri:noRegion>Institut Gustave Roussy</wicri:noRegion><wicri:noRegion>Institut Gustave Roussy</wicri:noRegion></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><idno type="wicri:Area/PascalFrancis/Checkpoint">000390</idno><idno type="wicri:explorRef" wicri:stream="PascalFrancis" wicri:step="Checkpoint">000390</idno><idno type="wicri:doubleKey">0028-4793:2014:Long G:combined:braf:and</idno><idno type="wicri:Area/Main/Merge">004314</idno><idno type="wicri:Area/Main/Curation">004243</idno><idno type="wicri:Area/Main/Exploration">004243</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="4"><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><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region><settlement type="city">Sydney</settlement></placeName><orgName type="university">Université de Sydney</orgName></affiliation></author><author><name sortKey="Stroyakovskiy, D" sort="Stroyakovskiy, D" uniqKey="Stroyakovskiy D" first="D." last="Stroyakovskiy">D. Stroyakovskiy</name><affiliation wicri:level="3"><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><placeName><settlement type="city">Moscou</settlement><region>District fédéral central</region></placeName></affiliation></author><author><name sortKey="Gogas, H" sort="Gogas, H" uniqKey="Gogas H" first="H." last="Gogas">H. Gogas</name><affiliation wicri:level="3"><inist:fA14 i1="06"><s1>University of Athens</s1><s2>Athens</s2><s3>GRC</s3><sZ>3 aut.</sZ></inist:fA14><country>Grèce</country><placeName><settlement type="city">Athènes</settlement><region nuts="2" type="region">Attique (région)</region></placeName></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><wicri:noRegion>Petrov Research Institute of Oncology</wicri:noRegion></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="3"><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><placeName><settlement type="city">Milan</settlement><region nuts="2">Lombardie</region></placeName></affiliation></author><author><name sortKey="Larkin, J" sort="Larkin, J" uniqKey="Larkin J" first="J." last="Larkin">J. Larkin</name><affiliation wicri:level="3"><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><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Garbe, C" sort="Garbe, C" uniqKey="Garbe C" first="C." last="Garbe">C. Garbe</name><affiliation wicri:level="3"><inist:fA14 i1="13"><s1>University of Tübingen</s1><s2>Tübingen</s2><s3>DEU</s3><sZ>7 aut.</sZ></inist:fA14><country>Allemagne</country><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Tübingen</region><settlement type="city">Tübingen</settlement></placeName></affiliation></author><author><name sortKey="Jouary, T" sort="Jouary, T" uniqKey="Jouary T" first="T." last="Jouary">T. Jouary</name><affiliation wicri:level="3"><inist:fA14 i1="18"><s1>Hopital Francois Mitterrand</s1><s2>Pau</s2><s3>FRA</s3><sZ>8 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Nouvelle-Aquitaine</region><region type="old region">Aquitaine</region><settlement type="city">Pau</settlement></placeName></affiliation></author><author><name sortKey="Hauschild, A" sort="Hauschild, A" uniqKey="Hauschild A" first="A." last="Hauschild">A. Hauschild</name><affiliation wicri:level="3"><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><placeName><region type="land" nuts="2">Schleswig-Holstein</region><settlement type="city">Kiel</settlement></placeName></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="3"><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><placeName><region type="region">Provence-Alpes-Côte d'Azur</region><region type="old region">Provence-Alpes-Côte d'Azur</region><settlement type="city">Marseille</settlement></placeName></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><wicri:noRegion>Veneto Oncology Institute-IRCCS</wicri:noRegion></affiliation></author><author><name sortKey="Lebbe, C" sort="Lebbe, C" uniqKey="Lebbe C" first="C." last="Lebbe">C. Lebbe</name><affiliation wicri:level="3"><inist:fA14 i1="20"><s1>Hôpital Saint-Louis</s1><s2>Paris</s2><s3>FRA</s3><sZ>12 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></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><wicri:noRegion>Papa Giovanni XXIII Hospital</wicri:noRegion></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><wicri:noRegion>Sir Charles Gairdner Hospital</wicri:noRegion></affiliation></author><author><name sortKey="Arance, A" sort="Arance, A" uniqKey="Arance A" first="A." last="Arance">A. Arance</name><affiliation wicri:level="3"><inist:fA14 i1="22"><s1>Hospital Clinic</s1><s2>Barcelona</s2><s3>GBR</s3><sZ>15 aut.</sZ></inist:fA14><country>Royaume-Uni</country><placeName><settlement type="city">Barcelone</settlement><region nuts="2" type="region">Catalogne</region></placeName></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><wicri:noRegion>Dnipropetrovsk Medical Academy, Clinical Hospital #4</wicri:noRegion></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="3"><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><placeName><settlement type="city">Amsterdam</settlement><region nuts="2" type="province">Hollande-Septentrionale</region></placeName></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><wicri:noRegion>Mannheim and Heidelberg</wicri:noRegion><wicri:noRegion>Ruprecht-Karl University of Heidelberg</wicri:noRegion><wicri:noRegion>Mannheim and Heidelberg</wicri:noRegion></affiliation></author><author><name sortKey="Ferraresi, V" sort="Ferraresi, V" uniqKey="Ferraresi V" first="V." last="Ferraresi">V. Ferraresi</name><affiliation wicri:level="3"><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><placeName><settlement type="city">Rome</settlement><region nuts="2">Latium</region></placeName></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><wicri:noRegion>Volograd Regional Oncology Dispensary #3</wicri:noRegion></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><wicri:noRegion>Buxtehude</wicri:noRegion><wicri:noRegion>Elbe Kliniken Stade-Buxtehude</wicri:noRegion><wicri:noRegion>Elbe Kliniken Stade-Buxtehude</wicri:noRegion></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><wicri:noRegion>Dnipropetrovsk Clinical Oncology Center of Dnipropetrovsk State Council</wicri:noRegion></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><wicri:noRegion>Essen</wicri:noRegion><wicri:noRegion>University Hospital Essen</wicri:noRegion><wicri:noRegion>University Hospital Essen</wicri:noRegion></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><wicri:noRegion>Mount Vernon Cancer Centre</wicri:noRegion></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><wicri:noRegion>Villejuif-Paris</wicri:noRegion><wicri:noRegion>Institut Gustave Roussy</wicri:noRegion><wicri:noRegion>Institut Gustave Roussy</wicri:noRegion></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><affiliations><list><country><li>Allemagne</li><li>Australie</li><li>France</li><li>Grèce</li><li>Italie</li><li>Pays-Bas</li><li>Royaume-Uni</li><li>Russie</li><li>Ukraine</li></country><region><li>Angleterre</li><li>Aquitaine</li><li>Attique (région)</li><li>Bade-Wurtemberg</li><li>Catalogne</li><li>District de Tübingen</li><li>District fédéral central</li><li>Grand Londres</li><li>Hollande-Septentrionale</li><li>Latium</li><li>Lombardie</li><li>Nouvelle-Aquitaine</li><li>Nouvelle-Galles du Sud</li><li>Provence-Alpes-Côte d'Azur</li><li>Schleswig-Holstein</li><li>Île-de-France</li></region><settlement><li>Amsterdam</li><li>Athènes</li><li>Barcelone</li><li>Kiel</li><li>Londres</li><li>Marseille</li><li>Milan</li><li>Moscou</li><li>Paris</li><li>Pau</li><li>Rome</li><li>Sydney</li><li>Tübingen</li></settlement><orgName><li>Université de Sydney</li></orgName></list><tree><noCountry><name sortKey="Casey, M" sort="Casey, M" uniqKey="Casey M" first="M." last="Casey">M. Casey</name><name sortKey="Demarini, D J" sort="Demarini, D J" uniqKey="Demarini D" first="D. J." last="Demarini">D. J. Demarini</name><name sortKey="Flaherty, K" sort="Flaherty, K" uniqKey="Flaherty K" first="K." last="Flaherty">K. Flaherty</name><name sortKey="Hansson, J" sort="Hansson, J" uniqKey="Hansson J" first="J." last="Hansson">J. Hansson</name><name sortKey="Irani, J G" sort="Irani, J G" uniqKey="Irani J" first="J. G." last="Irani">J. G. Irani</name><name sortKey="Le, N" sort="Le, N" uniqKey="Le N" first="N." last="Le">N. Le</name><name sortKey="Martin, A M" sort="Martin, A M" uniqKey="Martin A" first="A.-M." last="Martin">A.-M. Martin</name><name sortKey="Ouellet, D" sort="Ouellet, D" uniqKey="Ouellet D" first="D." last="Ouellet">D. Ouellet</name><name sortKey="Patel, K" sort="Patel, K" uniqKey="Patel K" first="K." last="Patel">K. Patel</name><name sortKey="Ribas, A" sort="Ribas, A" uniqKey="Ribas A" first="A." last="Ribas">A. Ribas</name></noCountry><country name="Australie"><region name="Nouvelle-Galles du Sud"><name sortKey="Long, G V" sort="Long, G V" uniqKey="Long G" first="G. V." last="Long">G. V. Long</name></region><name sortKey="Millward, M" sort="Millward, M" uniqKey="Millward M" first="M." last="Millward">M. Millward</name></country><country name="Russie"><region name="District fédéral central"><name sortKey="Stroyakovskiy, D" sort="Stroyakovskiy, D" uniqKey="Stroyakovskiy D" first="D." last="Stroyakovskiy">D. Stroyakovskiy</name></region><name sortKey="Kovalenko, N" sort="Kovalenko, N" uniqKey="Kovalenko N" first="N." last="Kovalenko">N. Kovalenko</name><name sortKey="Levchenko, E" sort="Levchenko, E" uniqKey="Levchenko E" first="E." last="Levchenko">E. Levchenko</name></country><country name="Grèce"><region name="Attique (région)"><name sortKey="Gogas, H" sort="Gogas, H" uniqKey="Gogas H" first="H." last="Gogas">H. Gogas</name></region></country><country name="Italie"><region name="Lombardie"><name sortKey="De Braud, F" sort="De Braud, F" uniqKey="De Braud F" first="F." last="De Braud">F. De Braud</name></region><name sortKey="Chiarion Sileni, V" sort="Chiarion Sileni, V" uniqKey="Chiarion Sileni V" first="V." last="Chiarion Sileni">V. Chiarion Sileni</name><name sortKey="Ferraresi, V" sort="Ferraresi, V" uniqKey="Ferraresi V" first="V." last="Ferraresi">V. Ferraresi</name><name sortKey="Mandala, M" sort="Mandala, M" uniqKey="Mandala M" first="M." last="Mandala">M. Mandala</name></country><country name="Royaume-Uni"><region name="Angleterre"><name sortKey="Larkin, J" sort="Larkin, J" uniqKey="Larkin J" first="J." last="Larkin">J. Larkin</name></region><name sortKey="Arance, A" sort="Arance, A" uniqKey="Arance A" first="A." last="Arance">A. Arance</name><name sortKey="Nathan, P" sort="Nathan, P" uniqKey="Nathan P" first="P." last="Nathan">P. Nathan</name></country><country name="Allemagne"><region name="Bade-Wurtemberg"><name sortKey="Garbe, C" sort="Garbe, C" uniqKey="Garbe C" first="C." last="Garbe">C. Garbe</name></region><name sortKey="Hauschild, A" sort="Hauschild, A" uniqKey="Hauschild A" first="A." last="Hauschild">A. Hauschild</name><name sortKey="Mohr, P" sort="Mohr, P" uniqKey="Mohr P" first="P." last="Mohr">P. Mohr</name><name sortKey="Schadendorf, D" sort="Schadendorf, D" uniqKey="Schadendorf D" first="D." last="Schadendorf">D. Schadendorf</name><name sortKey="Utikal, J" sort="Utikal, J" uniqKey="Utikal J" first="J." last="Utikal">J. Utikal</name></country><country name="France"><region name="Nouvelle-Aquitaine"><name sortKey="Jouary, T" sort="Jouary, T" uniqKey="Jouary T" first="T." last="Jouary">T. Jouary</name></region><name sortKey="Grob, J J" sort="Grob, J J" uniqKey="Grob J" first="J. J." last="Grob">J. J. Grob</name><name sortKey="Lebbe, C" sort="Lebbe, C" uniqKey="Lebbe C" first="C." last="Lebbe">C. Lebbe</name><name sortKey="Robert, C" sort="Robert, C" uniqKey="Robert C" first="C." last="Robert">C. Robert</name></country><country name="Ukraine"><noRegion><name sortKey="Bondarenko, I" sort="Bondarenko, I" uniqKey="Bondarenko I" first="I." last="Bondarenko">I. Bondarenko</name></noRegion><name sortKey="Probachai, V" sort="Probachai, V" uniqKey="Probachai V" first="V." last="Probachai">V. Probachai</name></country><country name="Pays-Bas"><region name="Hollande-Septentrionale"><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></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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