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@ARTICLE{Grimm:284788,
      author       = {M.-O. Grimm and E. Esteban and P. Barthélémy and M.
                      Schmidinger and J. Busch and B. P. Valderrama and N.
                      Charnley and M. Schmitz$^*$ and U. Schumacher and K. Leucht
                      and S. Foller and G. Baretton and I. Duran and G. de Velasco
                      and F. Priou and P. Maroto and L. Albiges},
      collaboration = {T. s. group},
      othercontributors = {C. Barone and D. Castellano and C. Chevreau and P. Gajate
                          Borau and S. Gopalakrishnan and E. Grande and A. Hamid and
                          J. Heinzelbecker and M. Janssen and J. Kopecký and E.
                          Kubala and W. Loidl and A. Lorch and B. Melichar and N.
                          Lainez Milagro and G. Niegisch and C. Ohlmann and A. Sacré
                          and N. Sarwar and G. Schinzari and D. Schrijvers and S.
                          Tartas and M. Wirth and P. Wolter and M. Zemanova},
      title        = {{T}ailored immunotherapy approach with nivolumab with or
                      without nivolumab plus ipilimumab as immunotherapeutic boost
                      in patients with metastatic renal cell carcinoma
                      ({TITAN}-{RCC}): a multicentre, single-arm, phase 2 trial.},
      journal      = {The lancet / Oncology},
      volume       = {24},
      number       = {11},
      issn         = {1470-2045},
      address      = {London},
      publisher    = {The Lancet Publ. Group},
      reportid     = {DKFZ-2023-02099},
      pages        = {1252-1265},
      year         = {2023},
      note         = {2023 Nov;24(11):1252-1265},
      abstract     = {Nivolumab plus ipilimumab is approved as first-line regimen
                      for intermediate-risk or poor-risk metastatic renal cell
                      carcinoma, and nivolumab monotherapy as second-line therapy
                      for all risk groups. We aimed to examine the efficacy and
                      safety of nivolumab monotherapy and nivolumab plus
                      ipilimumab combination as an immunotherapeutic boost after
                      no response to nivolumab monotherapy in patients with
                      intermediate-risk and poor-risk clear-cell metastatic renal
                      cell carcinoma.TITAN-RCC is a multicentre, single-arm, phase
                      2 trial, done at 28 hospitals and cancer centres across
                      Europe (Austria, Belgium, Czech Republic, France, Germany,
                      Italy, Spain, and the UK). Adults (aged ≥18 years) with
                      histologically confirmed intermediate-risk or poor-risk
                      clear-cell metastatic renal cell carcinoma who were formerly
                      untreated (first-line population) or pretreated with one
                      previous systemic therapy (anti-angiogenic or temsirolimus;
                      second-line population) were eligible. Patients had to have
                      a Karnofsky Performance Status score of at least 70 and
                      measurable disease per Response Evaluation Criteria in Solid
                      Tumours (version 1.1). Patients started with intravenous
                      nivolumab 240 mg once every 2 weeks. On early progressive
                      disease (week 8) or non-response at week 16, patients
                      received two or four doses of intravenous nivolumab (3
                      mg/kg) and ipilimumab (1 mg/kg) boosts (once every 3 weeks),
                      whereas responders continued with intravenous nivolumab (240
                      mg, once every 2 weeks), but could receive two to four boost
                      doses of nivolumab plus ipilimumab for subsequent
                      progressive disease. The primary endpoint was confirmed
                      investigator-assessed objective response rate in the full
                      analysis set, which included all patients who received at
                      least one dose of study medication; safety was also assessed
                      in this population. An objective response rate of more than
                      $25\%$ was required to reject the null hypothesis and show
                      improvement, on the basis of results from the pivotal phase
                      3 CheckMate-025 trial. This study is registered with
                      ClinicalTrials.gov, NCT02917772, and is complete.Between Oct
                      28, 2016, and Nov 30, 2018, 207 patients were enrolled and
                      all received nivolumab induction (109 patients in the
                      first-line group; 98 patients in the second-line group). 60
                      $(29\%)$ of 207 patients were female and 147 $(71\%)$ were
                      male. 147 $(71\%)$ of 207 patients had intermediate-risk
                      metastatic renal cell carcinoma and 51 $(25\%)$ had
                      poor-risk disease. After median follow-up of 27·6 months
                      (IQR 10·5-34·8), 39 $(36\%,$ $90\%$ CI 28-44; p=0·0080)
                      of 109 patients in the first-line group and 31 $(32\%,$
                      24-40; p=0·083) of 98 patients in the second-line group had
                      a confirmed objective response for nivolumab with and
                      without nivolumab plus ipilimumab. Confirmed response to
                      nivolumab at week 8 or 16 was observed in 31 $(28\%)$ of 109
                      patients in the first-line group and 18 $(18\%)$ of 98
                      patients in the second-line group. The most frequent grade
                      3-4 treatment-related adverse events (reported in $≥5\%$
                      of patients) were increased lipase (15 $[7\%]$ of 207
                      patients), colitis (13 $[6\%]),$ and diarrhoea (13 $[6\%]).$
                      Three deaths were reported that were deemed to be
                      treatment-related: one due to possible ischaemic stroke, one
                      due to respiratory failure, and one due to pneumonia.In
                      treatment-naive patients, nivolumab induction with or
                      without nivolumab plus ipilimumab boosts significantly
                      improved the objective response rate compared with that
                      reported for nivolumab monotherapy in the CheckMate-025
                      trial. However, overall efficacy seemed inferior when
                      compared with approved upfront nivolumab plus ipilimumab.
                      For second-line treatment, nivolumab plus ipilimumab could
                      be a rescue strategy on progression with approved nivolumab
                      monotherapy.Bristol Myers Squibb.},
      cin          = {DD01},
      ddc          = {610},
      cid          = {I:(DE-He78)DD01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37844597},
      doi          = {10.1016/S1470-2045(23)00449-7},
      url          = {https://inrepo02.dkfz.de/record/284788},
}