Targeted Therapy in Advanced Melanoma With Rare BRAF Mutations

被引：89

作者：

Menzer, Christian ^{[1
,2
]}

Menzies, Alexander M. ^{[3
,4
,5
]}

Carlino, Matteo S. ^{[3
,6
]}

Reijers, Irene ^{[7
]}

Groen, Emma J. ^{[7
]}

Eigentler, Thomas ^{[8
]}

de Groot, Jan Willem B. ^{[9
]}

van der Veldt, Astrid A. M. ^{[10
]}

Johnson, Douglas B. ^{[11
]}

Meiss, Frank ^{[12
,13
]}

Schlaak, Max ^{[14
,15
]}

Schilling, Bastian ^{[16
]}

Westgeest, Hans M. ^{[17
]}

Gutzmer, Ralf ^{[18
]}

Pfoehler, Claudia ^{[19
]}

Meier, Friedegund ^{[20
]}

Zimmer, Lisa ^{[21
]}

Suijkerbuijk, Karijn P. M. ^{[22
]}

Haalck, Thomas ^{[23
]}

Thoms, Kai-Martin ^{[24
]}

Herbschleb, Karin ^{[25
]}

Leichsenring, Jonas ^{[1
]}

Menzer, Alexander ^{[26
]}

Kopp-Schneider, Annette ^{[27
]}

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

Kefford, Richard ^{[3
,28
]}

Enk, Alexander ^{[1
]}

Blank, Christian U. ^{[7
]}

Hassel, Jessica C. ^{[1
]}

机构：

[1] Heidelberg Univ Hosp, Heidelberg, Germany

[2] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA

[3] Univ Sydney, Sydney, NSW, Australia

[4] Royal North Shore Hosp, Sydney, NSW, Australia

[5] Mater Hosp, Sydney, NSW, Australia

[6] Crown Princess Mary Canc Ctr Westmead, Sydney, NSW, Australia

[7] Antoni van Leeuwenhoek, Netherlands Canc Inst, Amsterdam, Netherlands

[8] Univ Med Ctr Tubingen, Tubingen, Germany

[9] Isala Zwolle, Zwolle, Netherlands

[10] Erasmus MC, Inst Canc, Rotterdam, Netherlands

[11] Vanderbilt Univ, Med Ctr, Nashville, TN USA

[12] Univ Freiburg, Med Ctr, Freiburg, Germany

[13] Univ Freiburg, Freiburg, Germany

[14] Univ Hosp Cologne, Cologne, Germany

[15] Ludwig Maximilians Univ Munchen, Univ Hosp, Munich, Germany

[16] Univ Hosp Wurzburg, Wurzburg, Germany

[17] Amphia Hosp, Breda, Netherlands

[18] Hannover Med Sch, Hannover, Germany

[19] Saarland Univ, Med Ctr, Homburg, Germany

[20] Dresden Univ Hosp, Dresden, Germany

[21] Univ Duisburg Essen, Univ Hosp Essen, Essen, Germany

[22] Univ Med Ctr Utrecht, Ctr Canc, Utrecht, Netherlands

[23] Univ Hosp Hamburg Eppendorf, Hamburg, Germany

[24] Univ Med Ctr Gottingen, Gottingen, Germany

[25] Radboudumc, Nijmegen, Netherlands

[26] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Mainz, Germany

[27] German Canc Res Ctr, Heidelberg, Germany

[28] Macquarie Univ, Sydney, NSW, Australia

来源：

JOURNAL OF CLINICAL ONCOLOGY | 2019年 / 37卷 / 33期

关键词：

CUTANEOUS MELANOMA; CLINICOPATHOLOGICAL FEATURES; BRAF(L597) MUTATIONS; CLINICAL-OUTCOMES; DOUBLE-BLIND; DABRAFENIB; TRAMETINIB; VEMURAFENIB; INHIBITOR; SURVIVAL;

D O I：

10.1200/JCO.19.00489

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

PURPOSE BRAF/MEK inhibition is a standard of care for patients with BRAF V600E/K-mutated metastatic melanoma. For patients with less frequent BRAF mutations, however, efficacy data are limited. METHODS In the current study, 103 patients with metastatic melanoma with rare, activating non-V600E/K BRAF mutations that were treated with either a BRAF inhibitor (BRAFi), MEK inhibitor (MEKi), or the combination were included. BRAF mutation, patient and disease characteristics, response, and survival data were analyzed. RESULTS Fifty-eight patient tumors (56%) harbored a non-E/K V600 mutation, 38 (37%) a non-V600 mutation, and seven had both V600E and a rare BRAF mutation (7%). The most frequent mutations were V600R (43%; 44 of 103), L597P/Q/R/S (15%; 15 of 103), and K601E (11%; 11 of 103). Most patients had stage IV disease and 42% had elevated lactate dehydrogenase at BRAFi/MEKi initiation. Most patients received combined BRAFi/ MEKi (58%) or BRAFi monotherapy (37%). Of the 58 patients with V600 mutations, overall response rate to BRAFi monotherapy and combination BRAFi/MEKi was 27% (six of 22) and 56% (20 of 36), respectively, whereas median progression-free survival (PFS) was 3.7 months and 8.0 months, respectively (P = .002). Of the 38 patients with non-V600 mutations, overall response rate was 0% (zero of 15) to BRAFi, 40% (two of five) to MEKi, and 28% (five of 18) to combination treatment, with a median PFS of 1.8 months versus 3.7 months versus 3.3 months, respectively. Multivariable analyses revealed superior survival (PFS and overall survival) with combination over monotherapy in rare V600 and non-V600 mutated melanoma. CONCLUSION Patients with rare BRAF mutations can respond to targeted therapy, however, efficacy seems to be lower compared with V600E mutated melanoma. Combination BRAFi/MEKi seems to be the best regimen for both V600 and non-V600 mutations. Yet interpretation should be done with care because of the heterogeneity of patients with small sample sizes for some of the reported mutations. (C) 2019 by American Society of Clinical Oncology

引用

页码：3142 / +

页数：21

共 50 条

[1] The Role of BRAF-Targeted Therapy for Advanced Melanoma in the Immunotherapy Era
Vanella, Vito
Festino, Lucia
Trojaniello, Claudia
Vitale, Maria Grazia
Sorrentino, Antonio
Paone, Miriam
Ascierto, Paolo A.
[J]. CURRENT ONCOLOGY REPORTS, 2019, 21 (09)
[2] Stopping targeted therapy for complete responders in advanced BRAF mutant melanoma
L. Warburton
T. M. Meniawy
L. Calapre
M. Pereira
A. McEvoy
M. Ziman
E. S. Gray
M. Millward
[J]. Scientific Reports, 10
[3] Stopping targeted therapy for complete responders in advanced BRAF mutant melanoma
Warburton, L.
Meniawy, T. M.
Calapre, L.
Pereira, M.
McEvoy, A.
Ziman, M.
Gray, E. S.
Millward, M.
[J]. SCIENTIFIC REPORTS, 2020, 10 (01)
[4] The Role of BRAF-Targeted Therapy for Advanced Melanoma in the Immunotherapy Era
Vito Vanella
Lucia Festino
Claudia Trojaniello
Maria Grazia Vitale
Antonio Sorrentino
Miriam Paone
Paolo A. Ascierto
[J]. Current Oncology Reports, 2019, 21
[5] Neoadjuvant BRAF-targeted therapy in regionally advanced and oligometastatic melanoma
Eroglu, Zeynep
Eatrides, Jennifer
Naqvi, Syeda Mahrukh Hussnain
Kim, Youngchul
Rich, Jeani
Babacan, Nalan Akgul
Brohl, Andrew S.
Markowitz, Joseph
Sarnaik, Amod
Zager, Jonathan
Khushalani, Nikhil I.
Sondak, Vernon K.
Messina, Jane
[J]. PIGMENT CELL & MELANOMA RESEARCH, 2020, 33 (01) : 86 - 95
[6] BRAF/MEK inhibition in melanoma patients with rare BRAF mutations
Hassel, Jessica Cecile
Menzer, Christian
Menzies, Alexander M.
Carlino, Matteo S.
Long, Georgina V.
Kefford, Richard
Eigentler, Thomas K.
Johnson, Douglas Buckner
Schlaak, Max
Meiss, Frank
Schilling, Bastian
Gutzmer, Ralf
Pfoehler, Claudia
Meier, Friedegund Elke
Zimmer, Lisa
Haalck, Thomas
Thoms, Kai
Kopp-Schneider, Annette
Enk, Alexander
[J]. JOURNAL OF CLINICAL ONCOLOGY, 2018, 36 (15)
[7] Combined BRAF-Targeted Therapy with Immunotherapy in BRAF-Mutated Advanced Melanoma Patients
Pier Francesco Ferrucci
Marko Lens
Emilia Cocorocchio
[J]. Current Oncology Reports, 2021, 23
[8] Combined BRAF-Targeted Therapy with Immunotherapy in BRAF-Mutated Advanced Melanoma Patients
Ferrucci, Pier Francesco
Lens, Marko
Cocorocchio, Emilia
[J]. CURRENT ONCOLOGY REPORTS, 2021, 23 (12)
[9] Prognostic Clinical and Radiographic Biomarkers for BRAF-Targeted Therapy in Advanced Melanoma
Shah, Kaustav P.
Song, Haocan
Ye, Fei
Johnson, Douglas B.
[J]. ONCOLOGIST, 2021, 26 (02): : E333 - E335
[10] Resistance to BRAF-targeted therapy in melanoma
Sullivan, Ryan J.
Flaherty, Keith T.
[J]. EUROPEAN JOURNAL OF CANCER, 2013, 49 (06) : 1297 - 1304

← 1 2 3 4 5 →