TY - JOUR
T1 - Prognostic and predictive value of metformin in the European Organisation for Research and Treatment of Cancer 1325/KEYNOTE-054 phase III trial of pembrolizumab versus placebo in resected high-risk stage III melanoma
AU - Kennedy, Oliver John
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 - Boers-Sonderen, Marye
AU - di Giacomo, Anna Maria
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 EORTC1325/KEYNOTE-054 phase III trial work was supported by Merck Sharp & Dohme LLC,a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. For this study, no specific funding was received. Funding Information: We are grateful to Merck Sharp & Dohme LLC, a subsidiary of Merck & Co. Inc. Rahway, NJ, USA for supporting this independent EORTC study. We thank all the investigators who participated in this study (Supplementary List A1). We 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's success (S. Janssen, R. Louis, N. Elaut, L. Wijnen, N. Jha, S. Rivrain and G. de Schaetzen) as well as Merck & Co. Inc. Rahway, NJ, USA team members (D. Grebennik, C. Krepler, N. Ibrahim, A. Purushotham, S. Sayed, and R. Kloss Silverman). Publisher Copyright: © 2023
PY - 2023/8/1
Y1 - 2023/8/1
N2 - Background: Metformin is a commonly prescribed and well-tolerated medication. In laboratory studies, metformin suppresses BRAF wild-type melanoma cells but accelerates the growth of BRAF-mutated cells. This study investigated the prognostic and predictive value of metformin, including with respect to BRAF mutation status, in the European Organisation for Research and Treatment of Cancer 1325/KEYNOTE-054 randomised controlled trial. Methods: Patients with resected high-risk stage IIIA, IIIB, or IIIC melanoma received 200 mg of pembrolizumab (n = 514) or placebo (n = 505) every 3 weeks for twelve months. Pembrolizumab prolonged recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) at approximately 42 months median follow-up (Eggermont et al., TLO, 2021). Multivariable Cox regression was used to estimate associations of metformin with RFS and DMFS. Interaction terms were used to model effect modification by treatment and BRAF mutation. Results: Fifty-four patients (0.5%) used metformin at baseline. Metformin was not significantly associated with RFS (hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.52–1.45) and DMFS (HR 0.82, 95% CI 0.47–1.44). The interaction between metformin and the treatment arm was not significant for either RFS (p = 0.92) or DMFS (p = 0.93). Among patients with mutated BRAF, the association of metformin with RFS (HR 0.70, 95% CI 0.37–1.33) was greater in magnitude though not significantly different to those without mutated BRAF (HR 0.98, 95% CI 0.56–1.69). Conclusions: There was no significant impact of metformin use on pembrolizumab efficacy in resected high-risk stage III melanoma. However, larger studies or pooled analyses are needed, particularly to explore a possible effect of metformin in BRAF-mutated melanoma.
AB - Background: Metformin is a commonly prescribed and well-tolerated medication. In laboratory studies, metformin suppresses BRAF wild-type melanoma cells but accelerates the growth of BRAF-mutated cells. This study investigated the prognostic and predictive value of metformin, including with respect to BRAF mutation status, in the European Organisation for Research and Treatment of Cancer 1325/KEYNOTE-054 randomised controlled trial. Methods: Patients with resected high-risk stage IIIA, IIIB, or IIIC melanoma received 200 mg of pembrolizumab (n = 514) or placebo (n = 505) every 3 weeks for twelve months. Pembrolizumab prolonged recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) at approximately 42 months median follow-up (Eggermont et al., TLO, 2021). Multivariable Cox regression was used to estimate associations of metformin with RFS and DMFS. Interaction terms were used to model effect modification by treatment and BRAF mutation. Results: Fifty-four patients (0.5%) used metformin at baseline. Metformin was not significantly associated with RFS (hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.52–1.45) and DMFS (HR 0.82, 95% CI 0.47–1.44). The interaction between metformin and the treatment arm was not significant for either RFS (p = 0.92) or DMFS (p = 0.93). Among patients with mutated BRAF, the association of metformin with RFS (HR 0.70, 95% CI 0.37–1.33) was greater in magnitude though not significantly different to those without mutated BRAF (HR 0.98, 95% CI 0.56–1.69). Conclusions: There was no significant impact of metformin use on pembrolizumab efficacy in resected high-risk stage III melanoma. However, larger studies or pooled analyses are needed, particularly to explore a possible effect of metformin in BRAF-mutated melanoma.
KW - BRAF
KW - Immunomodulation
KW - Immunotherapy
KW - Melanoma
KW - Metformin
UR - http://www.scopus.com/inward/record.url?scp=85164108215&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.ejca.2023.04.016
DO - https://doi.org/10.1016/j.ejca.2023.04.016
M3 - Article
C2 - 37277264
SN - 0959-8049
VL - 189
JO - European Journal of Cancer
JF - European Journal of Cancer
M1 - 112900
ER -