Combined BRAF and MEK Inhibition versus BRAF Inhibition Alone in Melanoma

被引：1453

作者：

Long, G. V. ^{[1
]}

Stroyakovskiy, D. ^{[3
,20
]}

Gogas, H. ^{[6
]}

Levchenko, E. ^{[4
]}

de Braud, F. ^{[7
]}

Larkin, J. ^{[11
]}

Garbe, C. ^{[13
]}

Jouary, T. ^{[21
]}

Hauschild, A. ^{[14
]}

Grob, J. J. ^{[22
]}

Sileni, V. Chiarion ^{[8
]}

Lebbe, C. ^{[23
]}

Mandala, M. ^{[9
]}

Millward, M. ^{[2
]}

Arance, A. ^{[25
]}

Bondarenko, I. ^{[26
]}

Haanen, J. B. A. G. ^{[28
]}

Hansson, J. ^{[29
]}

Utikal, J. ^{[15
,16
,17
,18
]}

Ferraresi, V. ^{[10
]}

Kovalenko, N. ^{[5
]}

Mohr, P. ^{[19
]}

Probachai, V. ^{[27
]}

Schadendorf, D.

Nathan, P. ^{[12
]}

Robert, C. ^{[24
]}

Ribas, A. ^{[30
]}

DeMarini, D. J. ^{[31
]}

Irani, J. G. ^{[31
]}

Casey, M. ^{[31
]}

Ouellet, D. ^{[32
]}

Martin, A. -M. ^{[31
]}

Le, N. ^{[31
]}

Patel, K. ^{[31
]}

Flaherty, K. ^{[33
]}

机构：

[1] Univ Sydney, Melanoma Inst Australia, Mater Hosp, Sydney, NSW 2006, Australia

[2] Sir Charles Gairdner Hosp, Perth, WA, Australia

[3] Moscow City Oncol Hosp 62, Moscow, Russia

[4] Petrov Res Inst Oncol, St Petersburg, Russia

[5] Volograd Reg Oncol Dispensary 3, Volzhsky, Russia

[6] Univ Athens, GR-10679 Athens, Greece

[7] Fdn IRCCS Ist Nazl Tumori, Milan, Italy

[8] Veneto Oncol Inst IRCCS, Padua, Italy

[9] Papa Giovanni XXIII Hosp, Bergamo, Italy

[10] Regina Elena Inst Canc Res, Rome, Italy

[11] Royal Marsden NHS Fdn Trust, London, England

[12] Mt Vernon Canc Ctr, Northwood, Middx, England

[13] Univ Tubingen, Tubingen, Germany

[14] Univ Hosp Schleswig Holstein, Kiel, Germany

[15] Heidelberg Univ, German Canc Res Ctr DKFZ, Mannheim, Germany

[16] Heidelberg Univ, Univ Med Ctr Mannheim, Mannheim, Germany

[17] Heidelberg Univ, German Canc Res Ctr DKFZ, Heidelberg, Germany

[18] Heidelberg Univ, Univ Med Ctr Mannheim, Heidelberg, Germany

[19] Elbe Kliniken Stade Buxtehude, Buxtehude, Germany

[20] Univ Hosp Essen, Essen, Germany

[21] Hop Francois Mitterrand, Pau, France

[22] Hop Enfants La Timone, Marseille, France

[23] Hop St Louis, Paris, France

[24] Inst Gustave Roussy, Villejuif, France

[25] Hosp Clin Barcelona, Barcelona, Spain

[26] Dnipropetrovsk Med Acad, Clin Hosp 4, Dnepropetrovsk, Ukraine

[27] Dnipropetrovsk State Council, Dnipropetrovsk Clin Oncol Ctr, Dnepropetrovsk, Ukraine

[28] Netherlands Canc Inst, Amsterdam, Netherlands

[29] Karolinska Inst, Stockholm, Sweden

[30] Univ Calif Los Angeles, Los Angeles, CA USA

[31] GlaxoSmithKline, Collegeville, PA USA

[32] GlaxoSmithKline, Res Triangle Pk, NC USA

[33] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA

来源：

NEW ENGLAND JOURNAL OF MEDICINE | 2014年 / 371卷 / 20期

关键词：

METASTATIC MELANOMA; RAF INHIBITORS; ACQUIRED-RESISTANCE; IMPROVED SURVIVAL; SOLID TUMORS; DABRAFENIB; MUTATIONS; TRIAL; VEMURAFENIB; PROGRESSION;

D O I：

10.1056/NEJMoa1406037

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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.

引用

页码：1877 / 1888

页数：12

共 30 条

[1]

[Anonymous], 2009, COMM TERM CRIT ADV E

[2] Phase II Trial (BREAK-2) of the BRAF Inhibitor Dabrafenib (GSK2118436) in Patients With Metastatic Melanoma [J].

Ascierto, Paolo A. ;

Minor, David ;

Ribas, Antoni ;

Lebbe, Celeste ;

O'Hagan, Anne ;

Arya, Niki ;

Guckert, Mary ;

Schadendorf, Dirk ;

Kefford, Richard F. ;

Grob, Jean-Jacques ;

Hamid, Omid ;

Amaravadi, Ravi ;

Simeone, Ester ;

Wilhelm, Tabea ;

Kim, Kevin B. ;

Long, Georgina V. ;

Martin, Anne-Marie ;

Mazumdar, Jolly ;

Goodman, Vicki L. ;

Trefzer, Uwe .

JOURNAL OF CLINICAL ONCOLOGY, 2013, 31 (26) :3205-+

[3] Progression of RAS-Mutant Leukemia during RAF Inhibitor Treatment [J].

Callahan, Margaret K. ;

Rampal, Raajit ;

Harding, James J. ;

Klimek, Virginia M. ;

Chung, Young Rock ;

Merghoub, Taha ;

Wolchok, Jedd D. ;

Solit, David B. ;

Rosen, Neal ;

Abdel-Wahab, Omar ;

Levine, Ross L. ;

Chapman, Paul B. .

NEW ENGLAND JOURNAL OF MEDICINE, 2012, 367 (24) :2316-2321

[4]

Chapman PB, 2012, J CLIN ONCOL, V30

[5] Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation [J].

Chapman, Paul B. ;

Hauschild, Axel ;

Robert, Caroline ;

Haanen, John B. ;

Ascierto, Paolo ;

Larkin, James ;

Dummer, Reinhard ;

Garbe, Claus ;

Testori, Alessandro ;

Maio, Michele ;

Hogg, David ;

Lorigan, Paul ;

Lebbe, Celeste ;

Jouary, Thomas ;

Schadendorf, Dirk ;

Ribas, Antoni ;

O'Day, Steven J. ;

Sosman, Jeffrey A. ;

Kirkwood, John M. ;

Eggermont, Alexander M. M. ;

Dreno, Brigitte ;

Nolop, Keith ;

Li, Jiang ;

Nelson, Betty ;

Hou, Jeannie ;

Lee, Richard J. ;

Flaherty, Keith T. ;

McArthur, Grant A. .

NEW ENGLAND JOURNAL OF MEDICINE, 2011, 364 (26) :2507-2516

[6] New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1) [J].

Eisenhauer, E. A. ;

Therasse, P. ;

Bogaerts, J. ;

Schwartz, L. H. ;

Sargent, D. ;

Ford, R. ;

Dancey, J. ;

Arbuck, S. ;

Gwyther, S. ;

Mooney, M. ;

Rubinstein, L. ;

Shankar, L. ;

Dodd, L. ;

Kaplan, R. ;

Lacombe, D. ;

Verweij, J. .

EUROPEAN JOURNAL OF CANCER, 2009, 45 (02) :228-247

[7] Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial [J].

Falchook, Gerald S. ;

Long, Georgina V. ;

Kurzrock, Razelle ;

Kim, Kevin B. ;

Arkenau, Tobias H. ;

Brown, Michael P. ;

Hamid, Omid ;

Infante, Jeffrey R. ;

Millward, Michael ;

Pavlick, Anna C. ;

O'Day, Steven J. ;

Blackman, Samuel C. ;

Curtis, C. Martin ;

Lebowitz, Peter ;

Ma, Bo ;

Ouellet, Daniele ;

Kefford, Richard F. .

LANCET, 2012, 379 (9829) :1893-1901

[8] Combined BRAF and MEK Inhibition in Melanoma with BRAF V600 Mutations [J].

Flaherty, Keith T. ;

Infante, Jeffery R. ;

Daud, Adil ;

Gonzalez, Rene ;

Kefford, Richard F. ;

Sosman, Jeffrey ;

Hamid, Omid ;

Schuchter, Lynn ;

Cebon, Jonathan ;

Ibrahim, Nageatte ;

Kudchadkar, Ragini ;

Burris, Howard A., III ;

Falchook, Gerald ;

Algazi, Alain ;

Lewis, Karl ;

Long, Georgina V. ;

Puzanov, Igor ;

Lebowitz, Peter ;

Singh, Ajay ;

Little, Shonda ;

Sun, Peng ;

Allred, Alicia ;

Ouellet, Daniele ;

Kim, Kevin B. ;

Patel, Kiran ;

Weber, Jeffrey .

NEW ENGLAND JOURNAL OF MEDICINE, 2012, 367 (18) :1694-1703

[9] Improved Survival with MEK Inhibition in BRAF-Mutated Melanoma [J].

Flaherty, Keith T. ;

Robert, Caroline ;

Hersey, Peter ;

Nathan, Paul ;

Garbe, Claus ;

Milhem, Mohammed ;

Demidov, Lev V. ;

Hassel, Jessica C. ;

Rutkowski, Piotr ;

Mohr, Peter ;

Dummer, Reinhard ;

Trefzer, Uwe ;

Larkin, James M. G. ;

Utikal, Jochen ;

Dreno, Brigitte ;

Nyakas, Marta ;

Middleton, Mark R. ;

Becker, Juergen C. ;

Casey, Michelle ;

Sherman, Laurie J. ;

Wu, Frank S. ;

Ouellet, Daniele ;

Martin, Anne-Marie ;

Patel, Kiran ;

Schadendorf, Dirk .

NEW ENGLAND JOURNAL OF MEDICINE, 2012, 367 (02) :107-114

[10] RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth [J].

Hatzivassiliou, Georgia ;

Song, Kyung ;

Yen, Ivana ;

Brandhuber, Barbara J. ;

Anderson, Daniel J. ;

Alvarado, Ryan ;

Ludlam, Mary J. C. ;

Stokoe, David ;

Gloor, Susan L. ;

Vigers, Guy ;

Morales, Tony ;

Aliagas, Ignacio ;

Liu, Bonnie ;

Sideris, Steve ;

Hoeflich, Klaus P. ;

Jaiswal, Bijay S. ;

Seshagiri, Somasekar ;

Koeppen, Hartmut ;

Belvin, Marcia ;

Friedman, Lori S. ;

Malek, Shiva .

NATURE, 2010, 464 (7287) :431-U132

← 1 2 3 →