Baseline Biomarkers for Outcome of Melanoma Patients Treated with Pembrolizumab

被引：469

作者：

Weide, Benjamin ^{[1
,2
]}

Martens, Alexander ^{[1
]}

Hassel, Jessica C. ^{[3
,4
,5
]}

Berking, Carola ^{[5
,6
]}

Postow, Michael A. ^{[7
,8
]}

Bisschop, Kees ^{[9
]}

Simeone, Ester ^{[10
]}

Mangana, Johanna ^{[11
]}

Schilling, Bastian ^{[5
,12
]}

Di Giacomo, Anna Maria ^{[13
]}

Brenner, Nicole ^{[14
]}

Kaehler, Katharina ^{[15
]}

Heinzerling, Lucie ^{[16
]}

Gutzmer, Ralf ^{[17
]}

Bender, Armin ^{[18
]}

Gebhardt, Christoffer ^{[5
,19
,20
]}

Romano, Emanuela ^{[21
]}

Meier, Friedegund ^{[5
,22
]}

Martus, Peter ^{[23
,24
]}

Maio, Michele ^{[13
]}

Blank, Christian ^{[25
]}

Schadendorf, Dirk ^{[5
,12
]}

Dummer, Reinhard ^{[11
]}

Ascierto, Paolo A. ^{[10
]}

Hospers, Geke ^{[9
]}

Garbe, Claus ^{[1
,5
]}

Wolchok, Jedd D. ^{[7
,8
]}

机构：

[1] Univ Med Ctr Tubingen, Dept Dermatol, Tubingen, Germany

[2] Univ Tubingen, Dept Immunol, Tubingen, Germany

[3] Univ Heidelberg Hosp, Dept Dermatol, Heidelberg, Germany

[4] Univ Heidelberg Hosp, Natl Ctr Tumor Dis, Heidelberg, Germany

[5] German Canc Consortium DKTK, Heidelberg, Germany

[6] Univ Hosp Munich, Dept Dermatol, Munich, Germany

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

[8] Weill Cornell Med Coll, New York, NY USA

[9] Univ Groningen, Univ Med Ctr Groningen, Dept Med Oncol, Groningen, Netherlands

[10] Fdn Pascale, Ist Nazl Tumori, Naples, Italy

[11] Univ Zurich, Dept Dermatol, Zurich, Switzerland

[12] Univ Duisburg Essen, Univ Hosp, West German Canc Ctr, Dept Dermatol, Essen, Germany

[13] Univ Hosp Siena, Div Med Oncol & Immunotherapy, Siena, Italy

[14] Univ Hosp Cologne, Dept Dermatol & Venereol, Cologne, Germany

[15] Univ Hosp Schleswig Holstein, Dept Dermatol, Kiel, Germany

[16] Univ Hosp Erlangen, Dept Dermatol, Erlangen, Germany

[17] Hannover Med Sch, Dept Dermatol, Skin Canc Ctr, Hannover, Germany

[18] Univ Hosp Marburg, Det Dermatol & Allergol, Marburg, Germany

[19] German Canc Res Ctr, Skin Canc Unit, Heidelberg, Germany

[20] Ruprecht Karl Univ Heidelberg, Univ Med Ctr Mannheim, Dept Dermatol, Mannheim, Germany

[21] Inst Curie, Med Oncol Serv, Dept Oncol, Paris, France

[22] Univ Med Ctr Dresden, Dept Dermatol, Dresden, Germany

[23] Univ Tubingen, Dept Clin Epidemiol, Tubingen, Germany

[24] Univ Tubingen, Dept Appl Biostat, Tubingen, Germany

[25] Netherlands Canc Inst, Dept Med Oncol, Amsterdam, Netherlands

来源：

CLINICAL CANCER RESEARCH | 2016年 / 22卷 / 22期

关键词：

CELL LUNG-CANCER; METASTATIC MELANOMA; LACTATE-DEHYDROGENASE; UNTREATED MELANOMA; PD-1; BLOCKADE; T-CELLS; IPILIMUMAB; NIVOLUMAB; SAFETY; RESPONSES;

D O I：

10.1158/1078-0432.CCR-16-0127

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose: Biomarkers for outcome after immune-checkpoint blockade are strongly needed as these may influence individual treatment selection or sequence. We aimed to identify baseline factors associated with overall survival (OS) after pembrolizumab treatment in melanoma patients. Experimental Design: Serum lactate dehydrogenase (LDH), routine blood count parameters, and clinical characteristics were investigated in 616 patients. Endpoints were OS and best overall response following pembrolizumab treatment. Kaplan-Meier analysis and Cox regression were applied for survival analysis. Results: Relative eosinophil count (REC) >= 1.5%, relative lymphocyte count (RLC) >= 17.5%, <= 2.5-fold elevation of LDH, and the absence of metastasis other than soft-tissue/lung were associated with favorable OS in the discovery (n = 177) and the confirmation (n = 182) cohort and had independent positive impact (all P < 0.001). Their independent role was subsequently confirmed in the validation cohort (n = 257; all P < 0.01). The number of favorable factors was strongly associated with prognosis. One-year OS probabilities of 83.9% versus 14.7% and response rates of 58.3% versus 3.3% were observed in patients with four of four compared to those with none of four favorable baseline factors present, respectively. Conclusions: High REC and RLC, low LDH, and absence of metastasis other than soft-tissue/lung are independent baseline characteristics associated with favorable OS of patients with melanoma treated with pembrolizumab. Presence of four favorable factors in combination identifies a subgroup with excellent prognosis. In contrast, patients with no favorable factors present have a poor prognosis, despite pembrolizumab, and additional treatment advances are still needed. A potential predictive impact needs to be further investigated. (C)2016 AACR.

引用

页码：5487 / 5496

页数：10

共 41 条

[1]

[Anonymous], 2013, CLIN ONCOL-UK, DOI [DOI 10.1200/JCO.2013, DOI 10.1200/jco.2013.31.15_suppl.9024]

[2]

[Anonymous], J CLIN ONCOL S

[3] Final Version of 2009 AJCC Melanoma Staging and Classification [J].

Balch, Charles M. ;

Gershenwald, Jeffrey E. ;

Soong, Seng-jaw ;

Thompson, John F. ;

Atkins, Michael B. ;

Byrd, David R. ;

Buzaid, Antonio C. ;

Cochran, Alistair J. ;

Coit, Daniel G. ;

Ding, Shouluan ;

Eggermont, Alexander M. ;

Flaherty, Keith T. ;

Gimotty, Phyllis A. ;

Kirkwood, John M. ;

McMasters, Kelly M. ;

Mihm, Martin C., Jr. ;

Morton, Donald L. ;

Ross, Merrick I. ;

Sober, Arthur J. ;

Sondak, Vernon K. .

JOURNAL OF CLINICAL ONCOLOGY, 2009, 27 (36) :6199-6206

[4] Safety and Activity of Anti-PD-L1 Antibody in Patients with Advanced Cancer [J].

Brahmer, Julie R. ;

Tykodi, Scott S. ;

Chow, Laura Q. M. ;

Hwu, Wen-Jen ;

Topalian, Suzanne L. ;

Hwu, Patrick ;

Drake, Charles G. ;

Camacho, Luis H. ;

Kauh, John ;

Odunsi, Kunle ;

Pitot, Henry C. ;

Hamid, Omid ;

Bhatia, Shailender ;

Martins, Renato ;

Eaton, Keith ;

Chen, Shuming ;

Salay, Theresa M. ;

Alaparthy, Suresh ;

Grosso, Joseph F. ;

Korman, Alan J. ;

Parker, Susan M. ;

Agrawal, Shruti ;

Goldberg, Stacie M. ;

Pardoll, Drew M. ;

Gupta, Ashok ;

Wigginton, Jon M. .

NEW ENGLAND JOURNAL OF MEDICINE, 2012, 366 (26) :2455-2465

[5]

Callahan MK, 2013, J CLIN ONCOL, V31

[6] X-tile: A new bio-informatics tool for biomarker assessment and outcome-based cut-point optimization [J].

Camp, RL ;

Dolled-Filhart, M ;

Rimm, DL .

CLINICAL CANCER RESEARCH, 2004, 10 (21) :7252-7259

[7] Eosinophils orchestrate cancer rejection by normalizing tumor vessels and enhancing infiltration of CD8+ T cells [J].

Carretero, Rafael ;

Sektioglu, Ibrahim M. ;

Garbi, Natalio ;

Salgado, Oscar C. ;

Beckhove, Philipp ;

Haemmerling, Guenter J. .

NATURE IMMUNOLOGY, 2015, 16 (06) :609-+

[8]

Chen PL, 2015, PIGM CELL MELANOMA R, V28, P763

[9] Antitumor activity of the anti-PD-1 monoclonal antibody MK-3475 in melanoma(MEL): Correlation of tumor PD-L1 expression with outcome [J].

Daud, Adil I. ;

Hamid, Omid ;

Ribas, Antoni ;

Hodi, F. Stephen ;

Hwu, Wen-Jen ;

Kefford, Richard ;

Wolchok, Jedd ;

Hersey, Peter ;

Weber, Jeffrey S. ;

Joseph, Richard ;

Gangadhar, Tara C. ;

Dronca, Roxana S. ;

Patnaik, Amita ;

Zarour, Hassane ;

Joshua, Anthony M. ;

Gergich, Kevin ;

Wu, Dianna ;

Lunceford, Jared K. ;

Emancipator, Kenneth ;

Dolled-Filhart, Marisa ;

Li, Nicole ;

Ebbinghaus, Scot ;

Kang, S. Peter ;

Robert, Caroline .

CANCER RESEARCH, 2014, 74 (19)

[10] Experience in daily practice with ipilimumab for the treatment of patients with metastatic melanoma: an early increase in lymphocyte and eosinophil counts is associated with improved survival [J].

Delyon, J. ;

Mateus, C. ;

Lefeuvre, D. ;

Lanoy, E. ;

Zitvogel, L. ;

Chaput, N. ;

Roy, S. ;

Eggermont, A. M. M. ;

Routier, E. ;

Robert, C. .

ANNALS OF ONCOLOGY, 2013, 24 (06) :1697-1703

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