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@ARTICLE{Franklin:275350,
      author       = {C. Franklin and P. Mohr and L. Bluhm and F. Meier and M.
                      Garzarolli and M. Weichenthal and K. Kähler and I.
                      Grimmelmann and R. Gutzmer and J. Utikal$^*$ and P.
                      Terheyden and R. Herbst and S. Haferkamp and C. Pfoehler and
                      A. Forschner and U. Leiter and F. Ziller and F. Meiss and J.
                      Ulrich and A. Kreuter and C. Gebhardt and J. Welzel and B.
                      Schilling and M. Kaatz and K. Scharfetter-Kochanek and E.
                      Dippel and D. Nashan and M. Sachse and C. Weishaupt and H.
                      Löffler and T. Gambichler and C. Loquai and L. Heinzerling
                      and S. Grabbe and D. Debus and G. Schley and J. C. Hassel
                      and G. Weyandt and M. Trommer and G. Lodde$^*$ and J.-M.
                      Placke$^*$ and L. Zimmer$^*$ and E. Livingstone$^*$ and J.
                      Becker$^*$ and S. Horn$^*$ and D. Schadendorf$^*$ and S.
                      Ugurel$^*$},
      title        = {{B}rain metastasis and survival outcomes after first-line
                      therapy in metastatic melanoma: a multicenter {D}e{COG}
                      study on 1704 patients from the prospective skin cancer
                      registry {ADOREG}.},
      journal      = {Journal for ImmunoTherapy of Cancer},
      volume       = {11},
      number       = {4},
      issn         = {2051-1426},
      address      = {London},
      publisher    = {BioMed Central},
      reportid     = {DKFZ-2023-00719},
      pages        = {e005828},
      year         = {2023},
      abstract     = {Despite the availability of effective systemic therapies, a
                      significant number of advanced melanoma patients develops
                      brain metastases. This study investigated differences in
                      incidence and time to diagnosis of brain metastasis and
                      survival outcomes dependent on the type of first-line
                      therapy.Patients with metastatic, non-resectable melanoma
                      (AJCCv8 stage IIIC-V) without brain metastasis at start of
                      first-line therapy (1L-therapy) were identified from the
                      prospective multicenter real-world skin cancer registry
                      ADOREG. Study endpoints were incidence of brain metastasis,
                      brain metastasis-free survival (BMFS), progression-free
                      survival (PFS), and overall survival (OS).Of 1704 patients,
                      916 were BRAF wild-type (BRAFwt) and 788 were BRAF V600
                      mutant (BRAFmut). Median follow-up time after start of
                      1L-therapy was 40.4 months. BRAFwt patients received
                      1L-therapy with immune checkpoint inhibitors (ICI) against
                      CTLA-4+PD-1 (n=281) or PD-1 (n=544). In BRAFmut patients,
                      1L-therapy was ICI in 415 patients (CTLA-4+PD-1, n=108;
                      PD-1, n=264), and BRAF+MEK targeted therapy (TT) in 373
                      patients. After 24 months, 1L-therapy with BRAF+MEK resulted
                      in a higher incidence of brain metastasis compared with
                      PD-1±CTLA-4 (BRAF+MEK, $30.3\%;$ CTLA-4+PD-1, $22.2\%;$
                      PD-1, $14.0\%).$ In multivariate analysis, BRAFmut patients
                      developed brain metastases earlier on 1L-therapy with
                      BRAF+MEK than with PD-1±CTLA-4 (CTLA-4+PD-1: HR 0.560,
                      $95\%$ CI 0.332 to 0.945, p=0.030; PD-1: HR 0.575, $95\%$ CI
                      0.372 to 0.888, p=0.013). Type of 1L-therapy, tumor stage,
                      and age were independent prognostic factors for BMFS in
                      BRAFmut patients. In BRAFwt patients, tumor stage was
                      independently associated with longer BMFS; ECOG Performance
                      status (ECOG-PS), lactate dehydrogenase (LDH), and tumor
                      stage with OS. CTLA-4+PD-1 did not result in better BMFS,
                      PFS, or OS than PD-1 in BRAFwt patients. For BRAFmut
                      patients, multivariate Cox regression revealed ECOG-PS, type
                      of 1L-therapy, tumor stage, and LDH as independent
                      prognostic factors for PFS and OS. 1L-therapy with
                      CTLA-4+PD-1 led to longer OS than PD-1 (HR 1.97, $95\%$ CI
                      1.122 to 3.455, p=0.018) or BRAF+MEK (HR 2.41, $95\%$ CI
                      1.432 to 4.054, p=0.001), without PD-1 being superior to
                      BRAF+MEK.In BRAFmut patients 1L-therapy with PD-1±CTLA-4
                      ICI resulted in a delayed and less frequent development of
                      brain metastasis compared with BRAF+MEK TT. 1L-therapy with
                      CTLA-4+PD-1 showed superior OS compared with PD-1 and
                      BRAF+MEK. In BRAFwt patients, no differences in brain
                      metastasis and survival outcomes were detected for
                      CTLA-4+PD-1 compared with PD-1.},
      keywords     = {melanoma (Other)},
      cin          = {A370 / ED01},
      ddc          = {610},
      cid          = {I:(DE-He78)A370-20160331 / I:(DE-He78)ED01-20160331},
      pnm          = {311 - Zellbiologie und Tumorbiologie (POF4-311)},
      pid          = {G:(DE-HGF)POF4-311},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37028819},
      doi          = {10.1136/jitc-2022-005828},
      url          = {https://inrepo02.dkfz.de/record/275350},
}