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@ARTICLE{Kennedy:276423,
      author       = {O. J. Kennedy and M. Kicinski and S. Valpione and S.
                      Gandini and S. Suciu and C. U. Blank and G. V. Long and V.
                      G. Atkinson and S. Dalle and A. M. Haydon and A.
                      Meshcheryakov and A. Khattak and M. S. Carlino and S. Sandhu
                      and J. Larkin and S. Puig and P. A. Ascierto and P.
                      Rutkowski and D. Schadendorf$^*$ and M. Boers-Sonderen and
                      A. M. Di Giacomo and A. J. M. van den Eertwegh and J.-J.
                      Grob and R. Gutzmer and R. Jamal and A. C. J. van Akkooi and
                      C. Robert and A. M. M. Eggermont and P. Lorigan and M.
                      Mandala},
      title        = {{P}rognostic and predictive value of metformin in the
                      {E}uropean {O}rganisation for {R}esearch and {T}reatment of
                      {C}ancer 1325/{KEYNOTE}-054 phase {III} trial of
                      pembrolizumab versus placebo in resected high-risk stage
                      {III} melanoma.},
      journal      = {European journal of cancer},
      volume       = {189},
      issn         = {0014-2964},
      address      = {Amsterdam [u.a.]},
      publisher    = {Elsevier},
      reportid     = {DKFZ-2023-01106},
      pages        = {112900},
      year         = {2023},
      note         = {2023 Aug;189:112900},
      abstract     = {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.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.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).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.},
      keywords     = {BRAF (Other) / Immunomodulation (Other) / Immunotherapy
                      (Other) / Melanoma (Other) / Metformin (Other)},
      cin          = {ED01},
      ddc          = {610},
      cid          = {I:(DE-He78)ED01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37277264},
      doi          = {10.1016/j.ejca.2023.04.016},
      url          = {https://inrepo02.dkfz.de/record/276423},
}