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@ARTICLE{Holch:300251,
      author       = {J. W. Holch$^*$ and A. J. Ohnmacht and S. Stintzing$^*$ and
                      K. Heinrich$^*$ and A.-L. Weiss$^*$ and V. Probst$^*$ and A.
                      Stahler$^*$ and L. Fischer von Weikersthal and T. Decker and
                      A. Kiani and F. Kaiser and T. Heintges and C. Kahl and F.
                      Kullmann and H. Link and H.-G. Höffkes and M. Moehler and
                      D. P. Modest and M. P. Menden and V. Heinemann},
      title        = {{FOLFIRI} with cetuximab or bevacizumab in {RAS} wild-type
                      metastatic colorectal cancer: {R}efining first-line
                      treatment selection by combining clinical parameters: {A}
                      post hoc analysis of the randomized open-label phase {III}
                      trial {FIRE}-3/{AIO} {KRK}0306.},
      journal      = {European journal of cancer},
      volume       = {220},
      issn         = {0959-8049},
      address      = {Amsterdam [u.a.]},
      publisher    = {Elsevier},
      reportid     = {DKFZ-2025-00712},
      pages        = {115388},
      year         = {2025},
      abstract     = {Primary tumor sidedness (PTS) with discrimination of
                      left-sided (LC) and right-sided tumors (RC) guides patient
                      selection for targeted first-line therapy in RAS wild-type
                      (RAS-WT) metastatic colorectal cancer (mCRC). This study
                      assessed the hypothesis whether considering PTS with
                      additional clinical parameters better predicts the treatment
                      benefit of targeted first-line treatment.In FIRE-3,
                      first-line treatment with folinic acid, fluorouracil and
                      irinotecan (FOLFIRI) plus cetuximab (FOLFIRI/Cet) was
                      compared to FOLFIRI plus bevacizumab (FOLFIRI/Bev) in
                      patients with RAS-WT mCRC and unresectable metastasis. We
                      evaluated whether combining PTS with number of metastatic
                      sites (NOM), liver-limited disease status (LLD), age, sex,
                      or carcinoembryonic antigen level (CEA) better predicts
                      treatment benefit regarding overall survival (OS). Here, Cox
                      regression models with second-order interactions were
                      applied. Further, the results were validated by policy
                      learning and Lasso regression analysis.Among 400 RAS-WT mCRC
                      patients, combining PTS with LLD status in a Cox regression
                      model outperformed PTS alone for predicted treatment benefit
                      (P = 0·005; c‑index=0·603). Significant OS benefit from
                      FOLFIRI/Cet over FOLFIRI/Bev was observed in LC/non-LLD
                      patients (HR=0·62; 95 $\%-confidence$ interval
                      [CI]=0·46-0·82; P = 0·002), but mitigated in LC/LLD
                      patients (HR=0·83; 95 $\%-CI=0·53-1·29;$ P = 0·400). In
                      RC/non-LLD patients, FOLFIRI/Bev demonstrated a significant
                      OS advantage over FOLFIRI/Cet (HR=2·09; 95
                      $\%‑CI=1·20-3·63;$ P = 0·010). However, RC/LLD patients
                      showed potential benefit from FOLFIRI/Cet, though not
                      statistically significant (HR=0·59; 95 $\%-CI=0·25-1·39;$
                      P = 0·218).Incorporating PTS and LLD status might improve
                      selection of targeted first-line treatment in RAS-WT mCRC
                      patients. FOLFIRI/Cet appears to be particularly beneficial
                      for LC/non-LLD patients with mitigated benefit in patients
                      with LC/LLD. In contrast, FOLFIRI/Bev is significantly
                      favoured over FOLFIRI/Cet in patients with RC/non-LLD.
                      Notably, RC/LLD patients may still benefit from anti-EGFR
                      therapy despite right-sided primary tumor. These results are
                      hypothesis-generating and warrant further validation.},
      keywords     = {Bevacizumab (Other) / Biomarker combination (Other) /
                      Cetuximab (Other) / Comprehensive statistical modeling
                      (Other) / FOLFIRI (Other) / Liver-limited disease (Other) /
                      Metastatic colorectal cancer (Other) / Metastatic pattern
                      (Other) / Predictive biomarker (Other) / Primary tumor
                      sidedness (Other)},
      cin          = {MU01 / BE01},
      ddc          = {610},
      cid          = {I:(DE-He78)MU01-20160331 / I:(DE-He78)BE01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40179821},
      doi          = {10.1016/j.ejca.2025.115388},
      url          = {https://inrepo02.dkfz.de/record/300251},
}