Three-year pooled analysis of factors associated with clinical outcomes across dabrafenib and trametinib combination therapy phase 3 randomised trials

被引：145

作者：

Schadendorf, Dirk ^{[1
,2
]}

Long, Georgina V. ^{[3
,4
,5
]}

Stroiakovski, Daniil ^{[6
]}

Karaszewska, Boguslawa ^{[7
]}

Hauschild, Axel ^{[8
]}

Levchenko, Evgeny ^{[9
]}

Chiarion-Sileni, Vanna ^{[10
]}

Schachter, Jacob ^{[11
]}

Garbe, Claus ^{[12
]}

Dutriaux, Caroline ^{[13
]}

Gogas, Helen ^{[14
]}

Mandala, Mario ^{[15
]}

Haanen, John B. A. G. ^{[16
]}

Lebbe, Celeste ^{[17
,18
]}

Mackiewicz, Andrzej ^{[19
]}

Rutkowski, Piotr ^{[20
,21
]}

Grob, Jean-Jacques ^{[22
]}

Nathan, Paul ^{[23
]}

Ribas, Antoni ^{[24
]}

Davies, Michael A. ^{[25
]}

Zhang, Ying ^{[26
]}

Kaper, Mathilde ^{[26
]}

Mookerjee, Bijoyesh ^{[26
]}

Legos, Jeffrey J. ^{[26
]}

Flaherty, Keith T. ^{[27
,28
]}

Robert, Caroline ^{[29
,30
]}

机构：

[1] Univ Hosp Essen, Dept Dermatol, Hufelandstr 55, D-45122 Essen, Germany

[2] German Canc Consortium, D-69117 Heidelberg, Germany

[3] Univ Sydney, Melanoma Inst Australia, Sydney, NSW, Australia

[4] Mater Hosp, Sydney, NSW, Australia

[5] Royal North Shore Hosp, St Leonards, NSW, Australia

[6] Moscow City Oncol Hosp 62, Moscow 143423, Russia

[7] Przychodnia Lekarska KOMED, Wojska Polskiego 6, PL-62500 Konin, Poland

[8] Univ Med Ctr Schleswig Holstein, Dept Dermatol, Arnold Heller Str 3, D-24105 Kiel, Germany

[9] Petrov Res Inst Oncol, 68 Leningradskaya St, St Petersburg 197758, Russia

[10] Veneto Oncol Inst IRCCS, Melanoma & Esophageal Oncol Unit, Via Gattamelata 64, I-35128 Padua, Italy

[11] Sheba Med Ctr, Oncol Div, Emek HaEla St 1, Ramat Gan, Israel

[12] Univ Tubingen, Dept Dermatol, Geschwister Scholl Pl, D-72074 Tubingen, Germany

[13] Hop St Andre, Serv Dermatol & Dermatol Pediat, 1 Rue Jean Burguet, F-33000 Bordeaux, France

[14] Univ Athens, Dept Med 1, Laiko Gen Hosp, Athens 15772, Greece

[15] Papa Giovanni XXIII Hosp, Dept Hematol & Oncol, Bergamo, Italy

[16] Netherlands Canc Inst, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands

[17] Univ Paris Diderot, AP HP, INSERM U976, Dermatol Dept, Paris, France

[18] Univ Paris Diderot, AP HP, INSERM U976, CIC Dept, Paris, France

[19] Poznan Univ Med Sci, Dept Canc Immunol, 15 Garbary St, PL-61866 Poznan, Poland

[20] Maria Sklodowska Curie Mem Canc, Dept Soft Tissue Bone Sarcoma & Melanoma, Wawelska 15B, PL-02034 Warsaw, Poland

[21] Inst Oncol, Wawelska 15B, PL-02034 Warsaw, Poland

[22] Aix Marseille Univ, Dept Dermatol, Univ Hosp Ctr, Timone Hosp, 264 Rue St Pierre, F-13885 Marseille 05, France

[23] Mt Vernon Canc Ctr, Rickmansworth Rd, Northwood HA6 2RN, Middx, England

[24] UCLA Med Ctr, Dept Med, Hematol Oncol, 100 UCLA Med Plaza,Suite 550, Los Angeles, CA USA

[25] Univ Texas MD Anderson Canc Ctr, Melanoma Med Oncol & Syst Biol, 1515 Holcombe Blvd, Houston, TX 77030 USA

[26] Novartis Pharmaceut, 1 Hlth Plaza, E Hanover, NJ 07936 USA

[27] Massachusetts Gen Hosp, Dev Therapeut Program, Ctr Canc, 55 Fruit St, Boston, MA 02114 USA

[28] Massachusetts Gen Hosp, Melanoma Program, Ctr Canc, 55 Fruit St, Boston, MA 02114 USA

[29] Univ Paris South, Dermatol Serv, Dept Med Oncol, Gustave Roussy Comprehens Canc Ctr, F-94805 Villejuif, France

[30] Univ Paris South, Fac Med, F-94805 Villejuif, France

来源：

EUROPEAN JOURNAL OF CANCER | 2017年 / 82卷

关键词：

Dabrafenib; Trametinib; Vemurafenib; Melanoma; Multivariate analysis; ADVANCED MELANOMA; COMBINED BRAF; DOUBLE-BLIND; SURVIVAL; PEMBROLIZUMAB; IPILIMUMAB; EFFICACY; MULTICENTER; VEMURAFENIB; NIVOLUMAB;

D O I：

10.1016/j.ejca.2017.05.033

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Aim: Understanding predictors of long-term benefit with currently available melanoma therapies is the key for optimising individualised treatments. A prior pooled analysis of dabrafenib plus trametinib (D + T)-erandomised trials (median follow-up, 20.0 months) identified baseline lactate dehydrogenase (LDH) and number of organ sites with metastasis as predictive factors for progression-free (PFS) and overall (OS) survival. However, longer-term follow-up analyses are needed to confirm which patients treated with D + T can achieve maximum benefit. Methods: Three-year landmark data were retrospectively pooled for D + T patients in phase 3 trials (COMBI-d [NCT01584648]; COMBI-v [NCT01597908]). Univariate and multivariate analyses assessed prognostic values of predefined baseline factors; regression tree analysis determined hierarchy and interactions between variables. Results: Long-term pooled outcomes were consistent with individual trial results (N = 563; 3-year PFS, 23%; 3-year OS, 44%). Baseline LDH level and number of organ sites remained strongly associated with and/or predictive of PFS and OS. In addition, baseline sum of lesion diameters (SLD) was identified as a predictor for progression. In the most favourable prognostic group (normal LDH, SLD <66 mm, <3 organ sites; n = 183/563 [33%]), 3-year PFS was 42%. Baseline number of organ sites was also predictive of outcomes in patients with PFS >= 6 months. Conclusion: Using the largest phase 3 data set available for BRAF/MEK inhibitor combination therapy in melanoma, these results demonstrate that durable responses lasting >= 3 years are possible in subsets of patients with BRAF-mutant melanoma receiving D + T. Although the best predictive model evolved with longer follow-up, factors predicting clinical outcomes with the combination remained consistent with previous analyses. (C) 2017 Elsevier Ltd. All rights reserved.

引用

页码：45 / 55

页数：11

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