Prognostic and predictive value of β-blockers in the EORTC 1325/KEYNOTE-054 phase III trial of pembrolizumab versus placebo in resected high-risk stage III melanoma

被引：21

作者：

Kennedy, Oliver J. ^{[1
]}

Kicinski, Michal ^{[2
]}

Valpione, Sara ^{[3
]}

Gandini, Sara ^{[4
]}

Suciu, Stefan ^{[2
]}

Blank, Christian U. ^{[5
]}

Long, Georgina, V ^{[6
,7
]}

Atkinson, Victoria G. ^{[8
]}

Dalle, Stephane ^{[9
]}

Haydon, Andrew M. ^{[10
]}

Meshcheryakov, Andrey ^{[11
]}

Khattak, Adnan ^{[12
,13
]}

Carlino, Matteo S. ^{[14
,15
]}

Sandhu, Shahneen ^{[16
]}

Larkin, James ^{[17
]}

Puig, Susana ^{[18
,19
]}

Ascierto, Paolo A. ^{[20
]}

Rutkowski, Piotr ^{[21
]}

Schadendorf, Dirk ^{[22
]}

Koornstra, Rutger ^{[23
]}

Hernandez-Aya, Leonel ^{[24
]}

Di Giacomo, Anna M. ^{[25
]}

van den Eertwegh, Alfonsus J. M. ^{[26
]}

Grob, Jean-Jacques ^{[27
]}

Gutzmer, Ralf ^{[28
,29
]}

Jamal, Rahima ^{[30
]}

van Akkooi, Alexander C. J. ^{[5
]}

Robert, Caroline ^{[31
]}

Eggermont, Alexander M. M. ^{[32
,33
,34
]}

Lorigan, Paul ^{[35
,36
]}

Mandala, Mario ^{[37
]}

机构：

[1] Univ Manchester, Oxford Rd, Manchester M13 9PL, Lancs, England

[2] EORTC Headquarters, Brussels, Belgium

[3] Manchester & Christie NHS Fdn Trust, Canc Res UK Manchester Inst, Manchester, Lancs, England

[4] IRCCS, Mol & Pharmaco Epidemiol Unit, European Inst Oncol, Milan, Italy

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

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

[7] Mater & Royal North Shore Hosp, Sydney, NSW, Australia

[8] Princess Alexandra Hosp, Brisbane, Qld, Australia

[9] Hosp Civils Lyon, Canc Inst, Lyon, France

[10] Alfred Hosp, Melbourne, Vic, Australia

[11] NN Blokhin Canc Res Ctr, Moscow, Russia

[12] Fiona Stanley Hosp, Perth, WA, Australia

[13] Edith Cowan Univ, Perth, WA, Australia

[14] Westmead & Blacktown Hosp, Melanoma Inst Australia, Sydney, NSW, Australia

[15] Univ Sydney, Sydney, NSW, Australia

[16] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia

[17] Royal Marsden Hosp, London, England

[18] Univ Barcelona, Hosp Clin Barcelona, Barcelona, Spain

[19] Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Barcelona, Spain

[20] Ist Nazl Tumori IRCCS Fdn G Pascale, Naples, Italy

[21] Maria Sklodowska Curie Natl Res Inst Oncol, Warsaw, Poland

[22] Univ Hosp Essen, Essen & German Canc Consortium, Heidelberg, Germany

[23] Radboud Univ Nijmegen, Med Ctr Nijmegen, Nijmegen, Netherlands

[24] Washington Univ, Sch Med, St Louis, MO USA

[25] Univ Hosp Siena, Ctr Immunooncol, Siena, Italy

[26] Univ Amsterdam, Med Ctr, Locat VUMC, Amsterdam, Netherlands

[27] Aix Marseille Univ, Hop Timone, Marseille, France

[28] Hannover Med Sch, Skin Canc Ctr, Hannover, Germany

[29] Ruhr Univ Bochum, Johannes Wesling Klinikum Minden, Dept Dermatol, Minden, Germany

[30] Ctr Hosp Univ Montreal CHUM, Ctr Rech Chum, Montreal, PQ, Canada

[31] Gustave Roussy & Paris Saclay Univ, Villejuif, France

[32] Comprehens Canc Ctr Munich, Munich, Germany

[33] Princess Maxima Ctr, Utrecht, Netherlands

[34] Univ Med Ctr Utrecht, Utrecht, Netherlands

[35] Univ Manchester, Div Canc Sci, Manchester, Lancs, England

[36] Christie NHS Fdn Trust, Manchester, Lancs, England

[37] Univ Perugia, Santa Maria Misericordia Hosp, Perugia, Italy

来源：

EUROPEAN JOURNAL OF CANCER | 2022年 / 165卷

关键词：

Melanoma; Immunotherapy; Beta-blockers; Immunomodulation; Adrenergic beta-antagonists; METASTATIC MELANOMA; MALIGNANT-MELANOMA; SURVIVAL; RECURRENCE; OUTCOMES;

D O I：

10.1016/j.ejca.2022.01.017

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Background: fi-adrenergic receptors are upregulated in melanoma cells and contribute to an immunosuppressive, pro-tumorigenic microenvironment. This study investigated the prognostic and predictive value of fi-adrenoreceptor blockade by fi-blockers in the EORTC1325/KEYNOTE-054 randomised controlled trial. Methods: Patients with resected stage IIIA, IIIB or IIIC melanoma and regional lymphadenectomy received 200 mg of adjuvant pembrolizumab (n = 514) or placebo (n = 505) every three weeks for one year or until recurrence or unacceptable toxicity. At a median follow-up of 3 years, pembrolizumab prolonged recurrence-free survival (RFS) compared to placebo (hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.47-0.68). fi-blocker use was defined as oral administration of any fi-blocker within 30 days of randomisation. A multivariable Cox proportional hazard model was used to estimate the HR for the association between the use of fi-blockers and RFS. Results: Ninety-nine (10%) of 1019 randomised patients used fi-blockers at baseline. fi- blockers had no independent prognostic effect on RFS: HR 0.96 (95% CI 0.70-1.31). The HRs of RFS associated with fi-blocker use were 0.67 (95% CI 0.38-1.19) in the pembrolizumab arm and 1.15 (95% CI 0.80-1.66) in the placebo arm. The HR of RFS associated with pembrolizumab compared to placebo was 0.34 (95% CI 0.18-0.65) among fi-blocker users and 0.59 (95% CI 0.48-0.71) among those not using fi-blockers. Conclusions: This study suggests no prognostic effect of fi-blockers in resected high-risk stage III melanoma. However, fi-blockers may predict improved efficacy of adjuvant pembrolizumab treatment. The combination of immunotherapy with fi-blockers merits further investigation. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-00494437. (c)& nbsp;& nbsp;& nbsp;2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). <comment>Superscript/Subscript Available</comment

引用

页码：97 / 112

页数：16

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