TY - JOUR
T1 - 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
AU - Kennedy, Oliver J.
AU - Kicinski, Michal
AU - Valpione, Sara
AU - Gandini, Sara
AU - Suciu, Stefan
AU - Blank, Christian U.
AU - Long, Georgina V.
AU - Atkinson, Victoria G.
AU - Dalle, Stéphane
AU - Haydon, Andrew M.
AU - Meshcheryakov, Andrey
AU - Khattak, Adnan
AU - Carlino, Matteo S.
AU - Sandhu, Shahneen
AU - Larkin, James
AU - Puig, Susana
AU - Ascierto, Paolo A.
AU - Rutkowski, Piotr
AU - Schadendorf, Dirk
AU - Koornstra, Rutger
AU - Hernandez-Aya, Leonel
AU - Di Giacomo, Anna M.
AU - van den Eertwegh, Alfonsus J.M.
AU - Grob, Jean Jacques
AU - Gutzmer, Ralf
AU - Jamal, Rahima
AU - van Akkooi, Alexander C.J.
AU - Robert, Caroline
AU - Eggermont, Alexander M.M.
AU - Lorigan, Paul
AU - Mandala, Mario
N1 - Funding Information:
The authors are grateful to Merck & Co. Inc. Kenilworth, NJ, USA for supporting the independent EORTC study EORTC1325/KEYNOTE-054. We thank all the investigators who participated to this study, who have not been included among the co-author list of this publication (Supplementary List A1). The authors warmly thank all EORTC Headquarters team members who have not been included among the co-author list of this publication, and who contributed to the study success (S. Marreaud, S. Janssen, R. Louis, N. Elaut, L. Wijnen, N. Jha, S Rivrain and G. de Schaetzen) as well as Merck & Co. Inc. Kenilworth, NJ, USA team members (C. Krepler, N. Ibrahim, V. Rivas, R. Kloss Silverman and S. Diede).
Publisher Copyright:
© 2022 The Author(s)
PY - 2022/4
Y1 - 2022/4
N2 - Background: β-adrenergic receptors are upregulated in melanoma cells and contribute to an immunosuppressive, pro-tumorigenic microenvironment. This study investigated the prognostic and predictive value of β-adrenoreceptor blockade by β-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). β-blocker use was defined as oral administration of any β-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 β-blockers and RFS. Results: Ninety-nine (10%) of 1019 randomised patients used β-blockers at baseline. β-blockers had no independent prognostic effect on RFS: HR 0.96 (95% CI 0.70–1.31). The HRs of RFS associated with β-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 β-blocker users and 0.59 (95% CI 0.48–0.71) among those not using β-blockers. Conclusions: This study suggests no prognostic effect of β-blockers in resected high-risk stage III melanoma. However, β-blockers may predict improved efficacy of adjuvant pembrolizumab treatment. The combination of immunotherapy with β-blockers merits further investigation. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37.
AB - Background: β-adrenergic receptors are upregulated in melanoma cells and contribute to an immunosuppressive, pro-tumorigenic microenvironment. This study investigated the prognostic and predictive value of β-adrenoreceptor blockade by β-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). β-blocker use was defined as oral administration of any β-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 β-blockers and RFS. Results: Ninety-nine (10%) of 1019 randomised patients used β-blockers at baseline. β-blockers had no independent prognostic effect on RFS: HR 0.96 (95% CI 0.70–1.31). The HRs of RFS associated with β-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 β-blocker users and 0.59 (95% CI 0.48–0.71) among those not using β-blockers. Conclusions: This study suggests no prognostic effect of β-blockers in resected high-risk stage III melanoma. However, β-blockers may predict improved efficacy of adjuvant pembrolizumab treatment. The combination of immunotherapy with β-blockers merits further investigation. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37.
KW - adrenergic beta-antagonists
KW - beta-blockers
KW - immunomodulation
KW - immunotherapy
KW - melanoma
UR - http://www.scopus.com/inward/record.url?scp=85125200502&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/1a6fa980-5e0a-386f-893f-fbb10793ec47/
U2 - 10.1016/j.ejca.2022.01.017
DO - 10.1016/j.ejca.2022.01.017
M3 - Article
C2 - 35220182
AN - SCOPUS:85125200502
SN - 0959-8049
VL - 165
SP - 97
EP - 112
JO - European Journal of Cancer
JF - European Journal of Cancer
ER -
