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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
Kennedy, O. J. Kicinski, M. Valpione, Sara Gandini, S. Suciu, S. Blank, C. U. Long, G. V. Atkinson, V. G. Dalle, S. Haydon, A. M.
Kennedy, O. J.
Kicinski, M.
Valpione, Sara
Gandini, S.
Suciu, S.
Blank, C. U.
Long, G. V.
Atkinson, V. G.
Dalle, S.
Haydon, A. M.
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Abstract
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.
Authors
Kennedy, O. J.
Kicinski, M.
Valpione, Sara
Gandini, S.
Suciu, S.
Blank, C. U.
Long, G. V.
Atkinson, V. G.
Dalle, S.
Haydon, A. M.
Meshcheryakov, A.
Khattak, A.
Carlino, M. S.
Sandhu, S.
Larkin, J.
Puig, S.
Ascierto, P. A.
Rutkowski, P.
Schadendorf, D.
Koornstra, R.
Hernandez-Aya, L.
Di Giacomo, A. M.
van den Eertwegh, A. J. M.
Grob, J. J.
Gutzmer, R.
Jamal, R.
van Akkooi, A. C. J.
Robert, C.
Eggermont, A. M. M.
Lorigan, Paul C
Mandala, M.
Kicinski, M.
Valpione, Sara
Gandini, S.
Suciu, S.
Blank, C. U.
Long, G. V.
Atkinson, V. G.
Dalle, S.
Haydon, A. M.
Meshcheryakov, A.
Khattak, A.
Carlino, M. S.
Sandhu, S.
Larkin, J.
Puig, S.
Ascierto, P. A.
Rutkowski, P.
Schadendorf, D.
Koornstra, R.
Hernandez-Aya, L.
Di Giacomo, A. M.
van den Eertwegh, A. J. M.
Grob, J. J.
Gutzmer, R.
Jamal, R.
van Akkooi, A. C. J.
Robert, C.
Eggermont, A. M. M.
Lorigan, Paul C
Mandala, M.
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Date
2022
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Citation
Kennedy OJ, Kicinski M, Valpione S, Gandini S, Suciu S, Blank CU, et al. 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 [Internet]. Vol. 165, European Journal of Cancer. Elsevier BV; 2022. p. 97–112.