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@ARTICLE{Serrano:275647,
      author       = {C. Serrano and S. Bauer$^*$ and D. Gómez-Peregrina and
                      Y.-K. Kang and R. L. Jones and P. Rutkowski and O. Mir and
                      M. C. Heinrich and W. D. Tap and K. Newberry and A. Grassian
                      and H. Shi and S. Bialick and P. Schöffski and M. A.
                      Pantaleo and M. von Mehren and J. C. Trent and S. George},
      title        = {{C}irculating tumor {DNA} analysis of the phase {III}
                      {VOYAGER} trial: {KIT} mutational landscape and outcomes in
                      patients with advanced gastrointestinal stromal tumor
                      treated with avapritinib or regorafenib.},
      journal      = {Annals of oncology},
      volume       = {34},
      number       = {7},
      issn         = {0923-7534},
      address      = {Amsterdam [u.a.},
      publisher    = {Elsevier},
      reportid     = {DKFZ-2023-00835},
      pages        = {615-625},
      year         = {2023},
      note         = {2023 Jul;34(7):615-625},
      abstract     = {The current treatment paradigm of imatinib-resistant
                      metastatic gastrointestinal stromal tumor (GIST) does not
                      incorporate KIT/PDGFRA genotypes in therapeutic drug
                      sequencing, except for PDGFRA exon 18-mutant GIST that are
                      indicated for avapritinib treatment. Here, ctDNA sequencing
                      was used to analyze plasma samples prospectively collected
                      in the phase III VOYAGER trial to understand how the
                      KIT/PDGFRA mutational landscape contributes to
                      tyrosine-kinase inhibitor (TKI) resistance and to determine
                      its clinical validity and utility.VOYAGER (N=476) compared
                      avapritinib with regorafenib in patients with
                      KIT/PDGFRA-mutant GIST previously treated with imatinib and
                      1 or 2 additional TKIs (NCT03465722). KIT/PDGFRA ctDNA
                      mutation profiling of plasma samples at baseline and
                      end-of-treatment was assessed with 74-gene Guardant360®
                      CDx. Molecular subgroups were determined and correlated with
                      outcomes.386/476 patients with KIT/PDGFRA-mutant tumors
                      underwent baseline (pre-trial treatment) ctDNA analysis; 196
                      received avapritinib, and 190 received regorafenib. KIT and
                      PDGFRA mutations were detected in $75.1\%$ and $5.4\%,$
                      respectively. KIT resistance mutations were found in the
                      activation loop (A-loop; $80.4\%)$ and ATP-binding pocket
                      (ATP-BP; $40.8\%);$ $23.4\%$ had both. An average of 2.6 KIT
                      mutations were detected per patient; $17.2\%$ showed 4-14
                      different KIT resistance mutations. Of all pathogenic KIT
                      variants, $28.0\%$ were novel, including alterations in
                      exons/codons previously unreported. PDGFRA mutations showed
                      similar patterns. ctDNA-detected KIT ATP-BP mutations
                      negatively prognosticated avapritinib activity, with a
                      median progression-free survival (mPFS) of 1.9 versus 5.6
                      months for regorafenib. mPFS for regorafenib did not vary
                      regardless of the presence or absence of ATP-BP/A-loop
                      mutants and was greater than mPFS with avapritinib in this
                      population. Secondary KIT ATP-BP pocket mutation variants,
                      particularly V654A, were enriched upon disease progression
                      with avapritinib.CtDNA sequencing efficiently detects
                      KIT/PDGFRA mutations and prognosticates outcomes in patients
                      with TKI-resistant GIST treated with avapritinib. ctDNA
                      analysis can be used to monitor disease progression and
                      provide more personalized treatment.},
      keywords     = {Avapritinib (Other) / GIST (Other) / KIT (Other) / PDGFRA
                      (Other) / ctDNA (Other) / regorafenib (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:37105265},
      doi          = {10.1016/j.annonc.2023.04.006},
      url          = {https://inrepo02.dkfz.de/record/275647},
}