Prognostic and predictive value of beta-blockers in the EORTC 1325/KEYNOTE-054 phase III trial of pembrolizumab versus placebo in resected high-risk stage III melanoma
- Author(s)
- Kennedy, OJ; Kicinski, M; Valpione, S; Gandini, S; Suciu, S; Blank, CU; Long, GV; Atkinson, VG; Dalle, S; Haydon, AM; Meshcheryakov, A; Khattak, A; Carlino, MS; Sandhu, S; Larkin, J; Puig, S; Ascierto, PA; Rutkowski, P; Schadendorf, D; Koornstra, R; Hernandez-Aya, L; Di Giacomo, AM; van den Eertwegh, AJM; Grob, JJ; Gutzmer, R; Jamal, R; van Akkooi, ACJ; Robert, C; Eggermont, AMM; Lorigan, P; Mandala, M;
- Journal Title
- European Journal of Cancer
- Publication Type
- Research article
- Abstract
- BACKGROUND: beta-adrenergic receptors are upregulated in melanoma cells and contribute to an immunosuppressive, pro-tumorigenic microenvironment. This study investigated the prognostic and predictive value of beta-adrenoreceptor blockade by beta-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). beta-blocker use was defined as oral administration of any beta-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 beta-blockers and RFS. RESULTS: Ninety-nine (10%) of 1019 randomised patients used beta-blockers at baseline. beta-blockers had no independent prognostic effect on RFS: HR 0.96 (95% CI 0.70-1.31). The HRs of RFS associated with beta-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 beta-blocker users and 0.59 (95% CI 0.48-0.71) among those not using beta-blockers. CONCLUSIONS: This study suggests no prognostic effect of beta-blockers in resected high-risk stage III melanoma. However, beta-blockers may predict improved efficacy of adjuvant pembrolizumab treatment. The combination of immunotherapy with beta-blockers merits further investigation. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37.
- Keywords
- Adjuvants, Immunologic/therapeutic use; Adrenergic beta-Antagonists/therapeutic use; Antibodies, Monoclonal, Humanized/therapeutic use; Humans; *Melanoma/drug therapy/pathology/surgery; Neoplasm Staging; Prognosis; *Skin Neoplasms/drug therapy/pathology/surgery; Tumor Microenvironment; Adrenergic beta-antagonists; Beta-blockers; Immunomodulation; Immunotherapy; Melanoma
- Department(s)
- Medical Oncology
- PubMed ID
- 35220182
- Publisher's Version
- https://doi.org/10.1016/j.ejca.2022.01.017
- Open Access at Publisher's Site
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- Refer to copyright notice on published article.
Creation Date: 2024-12-20 02:34:28
Last Modified: 2024-12-20 02:39:05