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@ARTICLE{Pouyiourou:284981,
      author       = {M. Pouyiourou$^*$ and B. Kraft$^*$ and T. Wohlfromm$^*$ and
                      M. Stahl and B. Kubuschok and H. Löffler and U. T. Hacker
                      and G. Hübner and L. Weiss and M. Bitzer and T. Ernst and
                      P. Schütt and T. Hielscher$^*$ and S. Delorme$^*$ and M.
                      Kirchner and D. Kazdal and M. Ball and K. Kluck and A.
                      Stenzinger and T. Bochtler$^*$ and A. Krämer$^*$},
      title        = {{N}ivolumab and ipilimumab in recurrent or refractory
                      cancer of unknown primary: a phase {II} trial.},
      journal      = {Nature Communications},
      volume       = {14},
      number       = {1},
      issn         = {2041-1723},
      address      = {[London]},
      publisher    = {Nature Publishing Group UK},
      reportid     = {DKFZ-2023-02165},
      pages        = {6761},
      year         = {2023},
      note         = {#EA:A360#LA:A360#},
      abstract     = {Cancer of unknown primary has a dismal prognosis,
                      especially following failure of platinum-based chemotherapy.
                      $10-20\%$ of patients have a high tumor mutational burden
                      (TMB), which predicts response to immunotherapy in many
                      cancer types. In this prospective, non-randomized,
                      open-label, multicenter Phase II trial (EudraCT
                      2018-004562-33; NCT04131621), patients relapsed or
                      refractory after platinum-based chemotherapy received
                      nivolumab and ipilimumab following TMBhigh vs. TMBlow
                      stratification. Progression-free survival (PFS) represented
                      the primary endpoint; overall survival (OS), response rates,
                      duration of clinical benefit and safety were the secondary
                      endpoints. The trial was prematurely terminated in March
                      2021 before reaching the preplanned sample size (n = 194).
                      Among 31 evaluable patients, $16\%$ had a high TMB ( > 12
                      mutations/Mb). Overall response rate was $16\%$ $(95\%$ CI
                      $6-34\%),$ with $7.7\%$ $(95\%$ CI $1-25\%)$ vs. $60\%$
                      $(95\%$ CI $15-95\%)$ in TMBlow and TMBhigh, respectively.
                      Although the primary endpoint was not met, high TMB was
                      associated with better median PFS (18.3 vs. 2.4 months) and
                      OS (18.3 vs. 3.6 months). Severe immune-related adverse
                      events were reported in $29\%$ of cases. Assessing
                      on-treatment dynamics of circulating tumor DNA using
                      combined targeted hotspot mutation and shallow whole genome
                      sequencing as part of a predefined exploratory analysis
                      identified patients benefiting from immunotherapy
                      irrespective of initial radiologic response.},
      cin          = {A360 / C060 / E010},
      ddc          = {500},
      cid          = {I:(DE-He78)A360-20160331 / I:(DE-He78)C060-20160331 /
                      I:(DE-He78)E010-20160331},
      pnm          = {311 - Zellbiologie und Tumorbiologie (POF4-311)},
      pid          = {G:(DE-HGF)POF4-311},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37875494},
      doi          = {10.1038/s41467-023-42400-5},
      url          = {https://inrepo02.dkfz.de/record/284981},
}