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

Oliver J. Kennedy, Michal Kicinski, Sara Valpione, Sara Gandini, Stefan Suciu, Christian U. Blank, Georgina V. Long, Victoria G. Atkinson, Stéphane Dalle, Andrew M. Haydon, Andrey Meshcheryakov, Adnan Khattak, Matteo S. Carlino, Shahneen Sandhu, James Larkin, Susana Puig, Paolo A. Ascierto, Piotr Rutkowski, Dirk Schadendorf, Rutger KoornstraLeonel Hernandez-Aya, Anna M. Di Giacomo, Alfonsus J.M. van den Eertwegh, Jean Jacques Grob, Ralf Gutzmer, Rahima Jamal, Alexander C.J. van Akkooi, Caroline Robert, Alexander M.M. Eggermont, Paul Lorigan, Mario Mandala

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3 Citaten (Scopus)

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)97-112
Aantal pagina's16
TijdschriftEuropean Journal of Cancer
Volume165
DOI's
StatusGepubliceerd - apr. 2022
Extern gepubliceerdJa

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