{"entity":{"id":"paper-heinemann-fire-3-cetuximab-vs-bevacizumab-lancet-oncol-2014","kind":"paper","name":"FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3)","aka":[],"tldr":"A head-to-head of the two antibodies. They tied on response and progression, but patients on the EGFR antibody lived 3.7 months longer, a result nobody had predicted from the primary endpoint.","summary":"Heinemann, von Weikersthal, Decker and colleagues recruited patients aged 18 to 75 with stage IV histologically confirmed colorectal cancer, ECOG performance status 0 to 2 and KRAS exon 2 codon 12/13 wild-type tumours from centres in Germany and Austria, randomising them 1:1 to FOLFIRI plus cetuximab or FOLFIRI plus bevacizumab. The primary endpoint was objective response, analysed by intention to treat.\n\nBetween January 2007 and September 2012, 592 patients with KRAS exon 2 wild-type tumours were randomised and treated. The discordance between response, progression-free survival and overall survival in this trial is the reason later analyses went looking for sidedness.","asOf":"2026-09-24","links":[{"label":"Lancet Oncol 2014","url":"https://doi.org/10.1016/S1470-2045(14)70330-4"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/25088940/"}],"tags":["colorectal-evidence"],"related":["paper-venook-calgb-80405-cetuximab-vs-bevacizumab-jama-2017","paper-arnold-primary-tumour-side-ras-wild-type-ann-oncol-2017"],"cancers":["colorectal"],"sections":["targeted-therapy"],"technologies":["monoclonal-antibody","antiangiogenic"],"targets":["egfr","vegf","kras"],"drugs":["cetuximab","bevacizumab","folfiri","irinotecan"],"companies":[],"institutions":[],"pathways":[],"terms":["sidedness"],"trials":["crystal-fire3"],"people":["volker-heinemann"],"bottlenecks":[],"keyPapers":[],"journals":["lancet-oncology"],"dependsOn":[],"notes":[],"journal":"The Lancet Oncology","year":2014,"doi":"10.1016/S1470-2045(14)70330-4","pmid":"25088940","authors":"Heinemann V, von Weikersthal LF, Decker T, et al.","paperType":"rct","findings":["Objective response 62.0 percent (95 percent CI 56.2 to 67.5) with cetuximab against 58.0 percent (52.1 to 63.7) with bevacizumab: odds ratio 1.18 (0.85 to 1.64, p=0.18).","Median progression-free survival 10.0 against 10.3 months (hazard ratio 1.06, 0.88 to 1.26, p=0.55).","Median overall survival 28.7 months (24.0 to 36.6) against 25.0 months (22.7 to 27.6): hazard ratio 0.77 (0.62 to 0.96, p=0.017).","Grade 3 or worse skin reactions in 77 of 297 (26 percent) on cetuximab against six of 295 (2 percent) on bevacizumab."],"whatItMeans":"Together with PARADIGM it makes the EGFR antibody the preferred first partner for chemotherapy in left-sided RAS wild-type disease; the survival gain without a progression-free survival gain remains one of the field's unexplained results.","caveats":["The primary endpoint was negative; the practice-changing result is a secondary endpoint.","KRAS exon 2 testing only at randomisation; extended RAS and sidedness analyses came afterwards.","German and Austrian centres, funded by the manufacturer of cetuximab."],"changedPractice":true,"participants":592},"route":"/key-papers/paper-heinemann-fire-3-cetuximab-vs-bevacizumab-lancet-oncol-2014/","neighbours":{"paper":[{"id":"paper-venook-calgb-80405-cetuximab-vs-bevacizumab-jama-2017","kind":"paper","name":"Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in KRAS wild-type advanced or metastatic colorectal cancer (CALGB/SWOG 80405)","route":"/key-papers/paper-venook-calgb-80405-cetuximab-vs-bevacizumab-jama-2017/"},{"id":"paper-cremolini-tribe-folfoxiri-bevacizumab-lancet-oncol-2015","kind":"paper","name":"FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of TRIBE","route":"/key-papers/paper-cremolini-tribe-folfoxiri-bevacizumab-lancet-oncol-2015/"},{"id":"paper-arnold-primary-tumour-side-ras-wild-type-ann-oncol-2017","kind":"paper","name":"Prognostic and predictive value of primary tumour side in patients with RAS wild-type metastatic colorectal cancer treated with chemotherapy and EGFR directed antibodies in six randomized trials","route":"/key-papers/paper-arnold-primary-tumour-side-ras-wild-type-ann-oncol-2017/"}],"cancer":[{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"}],"section":[{"id":"targeted-therapy","kind":"section","name":"Targeted Therapy","route":"/fronts/targeted-therapy/"}],"technology":[{"id":"antiangiogenic","kind":"technology","name":"Anti-angiogenic therapy","route":"/technologies/antiangiogenic/"},{"id":"monoclonal-antibody","kind":"technology","name":"Monoclonal antibodies","route":"/technologies/monoclonal-antibody/"}],"target":[{"id":"egfr","kind":"target","name":"EGFR","route":"/targets/egfr/"},{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/"},{"id":"vegf","kind":"target","name":"VEGF / VEGFR","route":"/targets/vegf/"}],"drug":[{"id":"bevacizumab","kind":"drug","name":"Bevacizumab","route":"/drugs/bevacizumab/"},{"id":"cetuximab","kind":"drug","name":"Cetuximab","route":"/drugs/cetuximab/"},{"id":"folfiri","kind":"drug","name":"FOLFIRI (5-FU, leucovorin, irinotecan)","route":"/drugs/folfiri/"},{"id":"irinotecan","kind":"drug","name":"Irinotecan (and liposomal irinotecan)","route":"/drugs/irinotecan/"}],"term":[{"id":"sidedness","kind":"term","name":"Sidedness (left vs right colon)","route":"/terms/sidedness/"}],"trial":[{"id":"crystal-fire3","kind":"trial","name":"CRYSTAL & FIRE-3","route":"/trials/crystal-fire3/"}],"person":[{"id":"volker-heinemann","kind":"person","name":"Volker Heinemann","route":"/people/volker-heinemann/"}],"journal":[{"id":"lancet-oncology","kind":"journal","name":"The Lancet Oncology","route":"/journals/lancet-oncology/"}],"roadmap":[{"id":"colorectal-roadmap","kind":"roadmap","name":"Colorectal cancer roadmap: from the adenoma-carcinoma sequence and the first screening trials to total mesorectal excision, oxaliplatin, RAS testing, immunotherapy for mismatch repair-deficient disease, ctDNA-guided treatment and organ preservation","route":"/roadmaps/colorectal-roadmap/"}]}}