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

• Published in: European journal of cancer (1990) Vol. 165; pp. 97 - 112
• Main Authors: Kennedy, Oliver J., Kicinski, Michal, Valpione, Sara, Gandini, Sara, Suciu, Stefan, Blank, Christian U., Long, Georgina V., Atkinson, Victoria G., Dalle, Stéphane, Haydon, Andrew M., Meshcheryakov, Andrey, Khattak, Adnan, Carlino, Matteo S., Sandhu, Shahneen, Larkin, James, Puig, Susana, Ascierto, Paolo A., Rutkowski, Piotr, Schadendorf, Dirk, Koornstra, Rutger, Hernandez-Aya, Leonel, Di Giacomo, Anna M., van den Eertwegh, Alfonsus J.M., Grob, Jean-Jacques, Gutzmer, Ralf, Jamal, Rahima, van Akkooi, Alexander C.J., Robert, Caroline, Eggermont, Alexander M.M., Lorigan, Paul, Mandala, Mario
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.04.2022
• Subjects: Adjuvants, Immunologic - therapeutic use; Adrenergic beta-antagonists; Adrenergic beta-Antagonists - therapeutic use; Antibodies, Monoclonal, Humanized - therapeutic use; Beta-blockers; Humans; Immunomodulation; Immunotherapy; Melanoma; Melanoma - drug therapy; Melanoma - pathology; Melanoma - surgery; Melanoma, Cutaneous Malignant; Neoplasm Staging; Prognosis; Skin Neoplasms - drug therapy; Skin Neoplasms - pathology; Skin Neoplasms - surgery; Tumor Microenvironment; Beta-blockers; Immunomodulation; Immunotherapy; Melanoma; Adrenergic beta-antagonists
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/j.ejca.2022.01.017

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. 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. 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. 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. •β-blockers have no independent prognostic effect on recurrence-free survival in resected melanoma.•However, β-blockers may prolong recurrence-free survival when combined with adjuvant pembrolizumab.•Our results warrant further investigation of β-blockers combined with immunotherapy.