Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study

被引:880
作者
Robert, Caroline [1 ]
Ribas, Antoni [2 ]
Schachter, Jacob [3 ]
Arance, Ana [4 ]
Grob, Jean-Jacques [5 ]
Mortier, Laurent [6 ]
Daud, Adil [7 ]
Carlino, Matteo S. [8 ,9 ,10 ]
McNeil, Catriona M. [11 ,12 ]
Lotem, Michal [13 ]
Larkin, James M. G. [14 ]
Lorigan, Paul [15 ,16 ]
Neyns, Bart [17 ]
Blank, Christian U. [18 ]
Petrella, Teresa M. [19 ]
Hamid, Omid [20 ]
Su, Shu-Chih [21 ]
Krepler, Clemens [21 ]
Ibrahim, Nageatte [21 ]
Long, Georgina, V [22 ,23 ]
机构
[1] Univ Paris Sud, Inst Cancerol Gustave Roussy, Villejuif, France
[2] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA
[3] Sheba Med Ctr Tel HaShomer, Ramat Gan, Israel
[4] Hosp Clin Barcelona, Barcelona, Spain
[5] Aix Marseille Univ, Hop la Timone, Marseille, France
[6] Univ Lille, CHRU Lille, Lille, France
[7] Univ Calif San Francisco, San Francisco, CA 94143 USA
[8] Westmead Hosp, Melanoma Inst Australia, Westmead, NSW, Australia
[9] Blacktown Hosp, Melanoma Inst Australia, Blacktown, NSW, Australia
[10] Univ Sydney, Sydney, NSW, Australia
[11] Royal Prince Alfred Hosp, Chris OBrien Lifehouse, Camperdown, NSW, Australia
[12] Melanoma Inst Australia, Camperdown, NSW, Australia
[13] Hadassah Hebrew Med Ctr, Sharett Inst Oncol, Jerusalem, Israel
[14] Royal Marsden Hosp, London, England
[15] Univ Manchester, Manchester, Lancs, England
[16] Christie NHS Fdn Trust, Manchester, Lancs, England
[17] Univ Ziekenhuis Brussel, Brussels, Belgium
[18] Netherlands Canc Inst, Amsterdam, Netherlands
[19] Sunnybrook Hlth Sci Ctr, Toronto, ON, Canada
[20] Angeles Clin & Res Inst, Los Angeles, CA USA
[21] Merck & Co Inc, Kenilworth, NJ USA
[22] Univ Sydney, Melanoma Inst Australia, Mater Hosp, Sydney, NSW, Australia
[23] Royal North Shore Hosp, Sydney, NSW, Australia
关键词
SURVIVAL; NIVOLUMAB;
D O I
10.1016/S1470-2045(19)30388-2
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background Pembrolizumab improved progression-free survival and overall survival versus ipilimumab in patients with advanced melanoma and is now a standard of care in the first-line setting. However, the optimal duration of anti-PD-1 administration is unknown. We present results from 5 years of follow-up of patients in KEYNOTE-006. Methods KEYNOTE-006 was an open-label, multicentre, randomised, controlled, phase 3 study done at 87 academic institutions, hospitals, and cancer centres in 16 countries. Patients aged at least 18 years with Eastern Cooperative Oncology Group performance status of 0 or 1, ipilimumab-naive histologically confirmed advanced melanoma with known BRAF(V600) status and up to one previous systemic therapy were randomly assigned (1:1:1) to intravenous pembrolizumab 10 mg/kg every 2 weeks or every 3 weeks or four doses of intravenous ipilimumab 3 mg/kg every 3 weeks. Treatments were assigned using a centralised, computer-generated allocation schedule with blocked randomisation within strata. Exploratory combination of data from the two pembrolizumab dosing regimen groups was not protocol-specified. Pembrolizumab treatment continued for up to 24 months. Eligible patients who discontinued pembrolizumab with stable disease or better after receiving at least 24 months of pembrolizumab or discontinued with complete response after at least 6 months of pembrolizumab and then progressed could receive an additional 17 cycles of pembrolizumab. Co-primary endpoints were overall survival and progression-free survival. Efficacy was analysed in all randomly assigned patients, and safety was analysed in all randomly assigned patients who received at least one dose of study treatment. Exploratory assessment of efficacy and safety at 5 years' follow-up was not specified in the protocol. Data cutoff for this analysis was Dec 3, 2018. Recruitment is closed; the study is ongoing. This study is registered with ClinicalTrials.gov, number NCT01866319. Findings Between Sept 18, 2013, and March 3, 2014, 834 patients were enrolled and randomly assigned to receive pembrolizumab (every 2 weeks, n= 279; every 3 weeks, n= 277), or ipilimumab (n= 278). After a median follow-up of 57 . 7 months (IQR 56 . 7-59 . 2) in surviving patients, median overall survival was 32 . 7 months (95% CI 24 . 5-41 . 6) in the combined pembrolizumab groups and 15 . 9 months (13 . 3-22 . 0) in the ipilimumab group (hazard ratio [HR] 0 . 73, 95% CI 0 . 61-0 . 88, p= 0 . 00049). Median progression-free survival was 8 . 4 months (95% CI 6 . 6-11 . 3) in the combined pembrolizumab groups versus 3 . 4 months (2 . 9-4 . 2) in the ipilimumab group (HR 0 . 57, 95% CI 0 . 48-0 . 67, p<0 . 0001). Grade 3-4 treatment-related adverse events occurred in 96 (17%) of 555 patients in the combined pembrolizumab groups and in 50 (20%) of 256 patients in the ipilimumab group; the most common of these events were colitis (11 [2%] vs 16 [6%]), diarrhoea (ten [2%] vs seven [3%]), and fatigue (four[<1%] vs three [1%]). Any-grade serious treatment-related adverse events occurred in 75 (14%) patients in the combined pembrolizumab groups and in 45 (18%) patients in the ipilimumab group. One patient assigned to pembrolizumab died from treatment-related sepsis. Interpretation Pembrolizumab continued to show superiority over ipilimumab after almost 5 years of follow-up. These results provide further support for use of pembrolizumab in patients with advanced melanoma. Copyright (C) 2019 Elsevier Ltd. All rights reserved.
引用
收藏
页码:1239 / 1251
页数:13
相关论文
共 25 条
[1]   Survival Outcomes in Patients With Previously Untreated BRAF Wild-Type Advanced Melanoma Treated With Nivolumab Therapy Three-Year Follow-up of a Randomized Phase 3 Trial [J].
Ascierto, Paolo A. ;
Long, Georgina V. ;
Robert, Caroline ;
Brady, Benjamin ;
Dutriaux, Caroline ;
Di Giacomo, Anna Maria ;
Mortier, Laurent ;
Hassel, Jessica C. ;
Rutkowski, Piotr ;
McNeil, Catriona ;
Kalinka-Warzocha, Ewa ;
Savage, Kerry J. ;
Hernberg, Micaela M. ;
Lebbe, Celeste ;
Charles, Julie ;
Mihalcioiu, Catalin ;
Chiarion-Sileni, Vanna ;
Mauch, Cornelia ;
Cognetti, Francesco ;
Ny, Lars ;
Arance, Ana ;
Svane, Inge Marie ;
Schadendorf, Dirk ;
Gogas, Helen ;
Saci, Abdel ;
Jiang, Joel ;
Rizzo, Jasmine ;
Atkinson, Victoria .
JAMA ONCOLOGY, 2019, 5 (02) :187-194
[2]   Combination Therapy with Anti-CTLA-4 and Anti-PD-1 Leads to Distinct Immunologic Changes In Vivo [J].
Das, Rituparna ;
Verma, Rakesh ;
Sznol, Mario ;
Boddupalli, Chandra Sekhar ;
Gettinger, Scott N. ;
Kluger, Harriet ;
Callahan, Margaret ;
Wolchok, Jedd D. ;
Halaban, Ruth ;
Dhodapkar, Madhav V. ;
Dhodapkar, Kavita M. .
JOURNAL OF IMMUNOLOGY, 2015, 194 (03) :950-959
[3]   CD103+ Tumor-Resident CD8+ T Cells Are Associated with Improved Survival in Immunotherapy-Naive Melanoma Patients and Expand Significantly During Anti-PD-1 Treatment [J].
Edwards, Jarem ;
Wilmott, James S. ;
Madore, Jason ;
Gide, Tuba Nur ;
Quek, Camelia ;
Tasker, Annie ;
Ferguson, Angela ;
Chen, Jinbiao ;
Hewavisenti, Rehana ;
Hersey, Peter ;
Gebhardt, Thomas ;
Weninger, Wolfgang ;
Britton, Warwick J. ;
Saw, Robyn P. M. ;
Thompson, John F. ;
Menzies, Alexander M. ;
Long, Georgina V. ;
Scolyer, Richard A. ;
Palendira, Umaimainthan .
CLINICAL CANCER RESEARCH, 2018, 24 (13) :3036-3045
[4]   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
[5]   Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001 [J].
Hamid, O. ;
Robert, C. ;
Daud, A. ;
Hodi, F. S. ;
Hwu, W. J. ;
Kefford, R. ;
Wolchok, J. D. ;
Hersey, P. ;
Joseph, R. ;
Weber, J. S. ;
Dronca, R. ;
Mitchell, T. C. ;
Patnaik, A. ;
Zarour, H. M. ;
Joshua, A. M. ;
Zhao, Q. ;
Jensen, E. ;
Ahsan, S. ;
Ibrahim, N. ;
Ribas, A. .
ANNALS OF ONCOLOGY, 2019, 30 (04) :582-588
[6]   Improved Survival with Ipilimumab in Patients with Metastatic Melanoma [J].
Hodi, F. Stephen ;
O'Day, Steven J. ;
McDermott, David F. ;
Weber, Robert W. ;
Sosman, Jeffrey A. ;
Haanen, John B. ;
Gonzalez, Rene ;
Robert, Caroline ;
Schadendorf, Dirk ;
Hassel, Jessica C. ;
Akerley, Wallace ;
van den Eertwegh, Alfons J. M. ;
Lutzky, Jose ;
Lorigan, Paul ;
Vaubel, Julia M. ;
Linette, Gerald P. ;
Hogg, David ;
Ottensmeier, Christian H. ;
Lebbe, Celeste ;
Peschel, Christian ;
Quirt, Ian ;
Clark, Joseph I. ;
Wolchok, Jedd D. ;
Weber, Jeffrey S. ;
Tian, Jason ;
Yellin, Michael J. ;
Nichol, Geoffrey M. ;
Hoos, Axel ;
Urba, Walter J. .
NEW ENGLAND JOURNAL OF MEDICINE, 2010, 363 (08) :711-723
[7]   Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial [J].
Hodi, Frank Stephen ;
Chiarion-Sileni, Vanna ;
Gonzalez, Rene ;
Grob, Jean-Jacques ;
Rutkowski, Piotr ;
Cowey, Charles Lance ;
Lao, Christopher D. ;
Schadendorf, Dirk ;
Wagstaff, John ;
Dummer, Reinhard ;
Ferrucci, Pier Francesco ;
Smylie, Michael ;
Hill, Andrew ;
Hogg, David ;
Marquez-Rodas, Ivan ;
Jiang, Joel ;
Rizzo, Jasmine ;
Larkin, James ;
Wolchok, Jedd D. .
LANCET ONCOLOGY, 2018, 19 (11) :1480-1492
[8]  
Jansen Y, 2017, P AM SOC CLIN ON S15, V35, P9539
[9]  
Jansen YJ, 2018, PIGM CELL MELANOMA R, V32, P168
[10]   Pembrolizumab KEYNOTE-001: an adaptive study leading to accelerated approval for two indications and a companion diagnostic [J].
Kang, S. P. ;
Gergich, K. ;
Lubiniecki, G. M. ;
de Alwis, D. P. ;
Chen, C. ;
Tice, M. A. B. ;
Rubin, E. H. .
ANNALS OF ONCOLOGY, 2017, 28 (06) :1388-1398