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@ARTICLE{Heinrich:306677,
      author       = {K. Heinrich$^*$ and S. Stintzing$^*$ and L. F. v.
                      Weikersthal and T. Decker and A. Kiani and F. Kaiser and
                      S.-E. Al-Batran and T. Heintges and C. Lerchenmüller and C.
                      Kahl and G. Seipelt and F. Kullmann and M. Moehler and W.
                      Scheithauer and A. Jung and J. W. Holch$^*$ and S. Held and
                      D. P. Modest and V. Heinemann$^*$},
      title        = {{I}mpact of sex on efficacy and safety of 1st-line
                      treatment with {FOLFIRI} plus cetuximab or bevacizumab in
                      {RAS}/{BRAF} wildtype metastatic colorectal cancer - {A}
                      subgroup analysis of the {FIRE}-3 ({AIO} {KRK}-0306) trial.},
      journal      = {European journal of cancer},
      volume       = {232},
      issn         = {0959-8049},
      address      = {Amsterdam [u.a.]},
      publisher    = {Elsevier},
      reportid     = {DKFZ-2025-02670},
      pages        = {116133},
      year         = {2026},
      abstract     = {Clinical trials in metastatic colorectal cancer (mCRC) are
                      usually conducted irrespectively of sex. However,
                      differences relating to safety and efficacy in the treatment
                      of mCRC between male and female patients are of growing
                      interest.The randomized FIRE-3 study compared first-line
                      treatment with folinic acid, 5-fluorouracil and irinotecan
                      (FOLFIRI) plus cetuximab to FOLFIRI plus bevacizumab in
                      patients with RAS wildtype (RAS WT) mCRC. The present
                      analysis focusses on the impact of sex and primary tumor
                      (PT) sidedness on outcome parameters.Of 352 patients with
                      RAS WT tumors, 249 (71 $\%)$ were male and 103 (29 $\%)$
                      female. In male patients with left-sided RAS/BRAF WT tumors,
                      a significant benefit from cetuximab was noted with regard
                      to ORR (OR 1.15; P = 0.035) and OS (0.66; P = 0.010), while
                      in right-sided patients cetuximab improved ORR (OR 2.92) and
                      had no significant effect on PFS or OS. In female patients
                      with left-sided, RAS/BRAF WT PT, a comparable effect of
                      cetuximab versus bevacizumab was observed with regard to ORR
                      (OR 1.05; P > 0.999), while a numerical OS benefit was noted
                      in the cetuximab-arm (HR 0.78; P = 0.385). By contrast, in
                      female patients with right-sided PT, a clearly detrimental
                      effect of cetuximab-based therapy was observed for ORR (OR
                      0.44; P = 0.617), PFS (HR 4.95; P = 0.005), and OS (HR 2.58;
                      P = 0.080). In the bevacizumab arm, neutropenia grade ≥ 3
                      was more frequent in female versus male patients (30.6 $\%$
                      versus 18.3 $\%;$ P = 0.063). Otherwise, there was no
                      significant difference of grade ≥ 3 adverse events between
                      male and female patients.The exploratory analysis of FIRE-3
                      suggests that the efficacy of cetuximab combined with
                      FOLFIRI in RAS wild-type mCRC is related to sex and primary
                      tumor sidedness. The results support the inclusion of
                      patient sex into the design of future trials.},
      keywords     = {Anti-EGFR (Other) / Cetuximab (Other) / Colorectal cancer
                      (Other) / Gender (Other) / Sex (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:41319450},
      doi          = {10.1016/j.ejca.2025.116133},
      url          = {https://inrepo02.dkfz.de/record/306677},
}