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@ARTICLE{Livingstone:301264,
      author       = {E. Livingstone$^*$ and H. J. Gogas and L. Kandolf and F.
                      Meier and T. K. Eigentler and M. Ziemer and P. Terheyden and
                      A. Gesierich and R. A. Herbst and K. C. Kähler and D. C.
                      Ziogas and Ž. Mijušković and M. Garzarolli and C. Garbe
                      and A. Roesch$^*$ and S. Ugurel$^*$ and R. Gutzmer and C.
                      Gaudy-Marqueste and F. Kiecker and J. Utikal$^*$ and M.
                      Hartmann and S. Miethe and S. Eckhardt and L. Zimmer$^*$ and
                      D. Schadendorf$^*$},
      title        = {{E}arly switch from run-in with targeted to immunotherapy
                      in advanced {BRAFV}600-positive melanoma: final results of
                      the randomised phase {II} {I}mmuno{C}obi{V}em trial.},
      journal      = {ESMO open},
      volume       = {10},
      number       = {5},
      issn         = {2059-7029},
      address      = {[London]},
      publisher    = {Elsevier},
      reportid     = {DKFZ-2025-00949},
      pages        = {105053},
      year         = {2025},
      abstract     = {Optimal sequencing of immune checkpoint inhibitors (ICIs)
                      and targeted therapies (TTs) in BRAFV600-positive advanced
                      melanoma should achieve rapid tumour control and durable
                      progression-free survival (PFS), translating into prolonged
                      overall survival (OS).The 1 : 1 randomised phase II
                      ImmunoCobiVem trial compared-after a 3-month run-in phase
                      with vemurafenib (VEM, 960 mg twice daily) and cobimetinib
                      (COB, 60 mg daily days 21-28, q4w)-continuous VEM + COB
                      until disease progression (PD1) and second-line atezolizumab
                      (ATEZO, 1200 mg, q3w) in arm A versus early switch to ATEZO
                      after run-in, followed by crossover to VEM + COB at PD1, in
                      arm B. PFS from the start of run-in until PD1 was the
                      primary endpoint (PFS1); secondary efficacy endpoints were
                      OS, overall PFS (PFS2) and PFS3 (time from PD1 to PD after
                      crossover, i.e. PD2) and best overall response rates
                      (BORRs).The final analysis (median follow-up 57.0 months,
                      interquartile range 22.7-63.0 months) confirmed longer PFS1
                      for continuous TT [arm A (69 patients) versus arm B (early
                      switch, 66 patients); hazard ratio (HR) 0.61, $95\%$
                      confidence interval (CI) 0.41-0.91, P = 0.006], but early
                      switch to ICIs resulted in better long-term OS [4- and
                      5-year landmark OS $42\%$ $(95\%$ CI $29\%$ to $55\%)$ and
                      $40\%$ $(95\%$ CI $27\%$ to $53\%)$ for arm A, and $53\%$
                      $(95\%$ CI $38\%$ to $65\%)$ and $45\%$ $(95\%$ CI $31\%$ to
                      $58\%)$ for arm B; descriptive HR 1.17, $95\%$ CI
                      0.71-1.91]. Absolute BORRs were $81\%$ and $89\%,$
                      respectively, with 15 $(22\%)$ and 19 $(29\%)$ patients
                      achieving a complete response at least once along each
                      sequence. At crossover, TT retreatment (arm B) resulted in
                      higher PFS3 than second-line ICI (arm A).Early switch to
                      ICIs after TT run-in (arm B) led to an improved, although
                      not statistically significant, 4- and 5-year landmark OS
                      compared with arm A. No subgroups were identified for which
                      a TT run-in provided clinical benefit. The number of
                      patients developing brain metastasis and the time to brain
                      metastasis were not improved by an early TT to ICI switch.},
      keywords     = {crossover design (Other) / immunotherapy (Other) / melanoma
                      (Other) / sequential therapy (Other) / targeted therapy
                      (Other)},
      cin          = {ED01 / A370},
      ddc          = {610},
      cid          = {I:(DE-He78)ED01-20160331 / I:(DE-He78)A370-20160331},
      pnm          = {311 - Zellbiologie und Tumorbiologie (POF4-311)},
      pid          = {G:(DE-HGF)POF4-311},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40345056},
      doi          = {10.1016/j.esmoop.2025.105053},
      url          = {https://inrepo02.dkfz.de/record/301264},
}