{"entity":{"id":"crystal-fire3","kind":"trial","name":"CRYSTAL & FIRE-3","aka":["CRYSTAL","FIRE-3","CRYSTAL and FIRE-3"],"tldr":"The trials that established EGFR antibodies in bowel cancer and discovered they only work when the RAS gene is normal.","summary":"CRYSTAL (NEJM 2009) showed cetuximab + FOLFIRI improved PFS and, in KRAS wild-type tumours, OS (23.5 vs 20.0 months). Retrospective RAS analyses defined the first negative predictive biomarker in CRC. FIRE-3 (Lancet Oncology 2014) showed longer OS with cetuximab than bevacizumab in KRAS wild-type disease (28.7 vs 25.0 months), later shown to be driven by left-sided tumours.","status":"positive","asOf":"2026-09-07","links":[{"label":"CRYSTAL, NEJM 2009","url":"https://www.nejm.org/doi/full/10.1056/NEJMoa0805019"},{"label":"ClinicalTrials.gov NCT00154102","url":"https://clinicaltrials.gov/study/NCT00154102"},{"label":"ClinicalTrials.gov NCT00433927","url":"https://clinicaltrials.gov/study/NCT00433927"},{"label":"CRYSTAL: cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer (New England Journal of Medicine 2009)","url":"https://doi.org/10.1056/NEJMoa0805019"},{"label":"FIRE-3: FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment (Lancet Oncology 2014)","url":"https://doi.org/10.1016/S1470-2045(14)70330-4"}],"tags":[],"related":[],"cancers":["colorectal"],"sections":[],"technologies":["monoclonal-antibody"],"targets":["egfr","kras"],"drugs":["cetuximab","bevacizumab","folfiri"],"companies":["aio"],"institutions":[],"pathways":[],"terms":["sidedness"],"trials":["prime","opus","calgb-80405"],"people":["volker-heinemann","eric-van-cutsem"],"bottlenecks":[],"keyPapers":["paper-tejpar-tumour-location-crystal-fire3-jama-oncol-2017","paper-arnold-primary-tumour-side-ras-wild-type-ann-oncol-2017"],"journals":[],"dependsOn":[],"notes":[],"nct":"NCT00154102","phase":"3","setting":"First-line metastatic colorectal cancer: FOLFIRI ± cetuximab (CRYSTAL); FOLFIRI + cetuximab vs FOLFIRI + bevacizumab (FIRE-3)","sponsor":"Merck KGaA; AIO (Germany)","result":"CRYSTAL KRAS-WT OS 23.5 vs 20.0 months; FIRE-3 OS 28.7 vs 25.0 months.","started":"2004-05","yearReported":2009,"enrolled":1198,"enrolledBasis":"randomised","enrolledNote":"Two trials under one record: CRYSTAL (NCT00154102) randomised 1,198 patients, 599 per arm, and FIRE-3 (NCT00433927) treated 592 patients with KRAS exon 2 wild-type tumours.","outcomes":[{"endpoint":"Overall survival, KRAS wild-type (CRYSTAL)","unit":"months","arms":[{"name":"FOLFIRI + cetuximab","value":23.5},{"name":"FOLFIRI","value":20}],"hr":0.8,"source":"https://www.nejm.org/doi/full/10.1056/NEJMoa0805019"},{"endpoint":"CRYSTAL: progression-free survival (KRAS wild-type)","unit":"hazard ratio","arms":[{"name":"FOLFIRI plus cetuximab","value":0.68},{"name":"FOLFIRI","value":1}],"hr":0.68,"ci":[0.5,0.94],"source":"https://doi.org/10.1056/NEJMoa0805019"},{"endpoint":"FIRE-3: overall survival (KRAS exon 2 wild-type)","unit":"months","arms":[{"name":"FOLFIRI plus cetuximab","n":297,"value":28.7},{"name":"FOLFIRI plus bevacizumab","n":295,"value":25}],"hr":0.77,"ci":[0.62,0.96],"p":"0.017","source":"https://doi.org/10.1016/S1470-2045(14)70330-4"},{"endpoint":"FIRE-3: objective response (primary endpoint)","primary":true,"unit":"percent","arms":[{"name":"FOLFIRI plus cetuximab","n":297,"value":62},{"name":"FOLFIRI plus bevacizumab","n":295,"value":58}],"p":"0.18","source":"https://doi.org/10.1016/S1470-2045(14)70330-4"}],"replication":"Replicated by PRIME (panitumumab + FOLFOX) and PARADIGM."},"route":"/trials/crystal-fire3/","neighbours":{"cancer":[{"id":"colon-cancer","kind":"cancer","name":"Colon cancer (adenocarcinoma of the colon)","route":"/cancers/colon-cancer/"},{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"}],"technology":[{"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/"}],"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/"}],"company":[{"id":"aio","kind":"company","name":"AIO (Arbeitsgemeinschaft Internistische Onkologie)","route":"/companies/aio/"}],"term":[{"id":"sidedness","kind":"term","name":"Sidedness (left vs right colon)","route":"/terms/sidedness/"}],"trial":[{"id":"calgb-80405","kind":"trial","name":"CALGB/SWOG 80405","route":"/trials/calgb-80405/"},{"id":"co-17","kind":"trial","name":"NCIC CO.17","route":"/trials/co-17/"},{"id":"opus","kind":"trial","name":"OPUS","route":"/trials/opus/"},{"id":"prime","kind":"trial","name":"PRIME","route":"/trials/prime/"}],"person":[{"id":"eric-van-cutsem","kind":"person","name":"Eric Van Cutsem","route":"/people/eric-van-cutsem/"},{"id":"volker-heinemann","kind":"person","name":"Volker Heinemann","route":"/people/volker-heinemann/"}],"paper":[{"id":"paper-van-cutsem-crystal-cetuximab-folfiri-nejm-2009","kind":"paper","name":"Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer (CRYSTAL)","route":"/key-papers/paper-van-cutsem-crystal-cetuximab-folfiri-nejm-2009/"},{"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)","route":"/key-papers/paper-heinemann-fire-3-cetuximab-vs-bevacizumab-lancet-oncol-2014/"},{"id":"paper-tejpar-tumour-location-crystal-fire3-jama-oncol-2017","kind":"paper","name":"Prognostic and predictive relevance of primary tumor location in patients with RAS wild-type metastatic colorectal cancer: retrospective analyses of the CRYSTAL and FIRE-3 trials","route":"/key-papers/paper-tejpar-tumour-location-crystal-fire3-jama-oncol-2017/"},{"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/"}],"pairing":[{"id":"anti-egfr-left-sided","kind":"pairing","name":"Anti-EGFR antibody + chemotherapy in left-sided RAS/BRAF wild-type mCRC","route":"/pairings/anti-egfr-left-sided/"}],"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/"}],"biomarker":[{"id":"ras-wild-type","kind":"biomarker","name":"RAS wild-type (extended KRAS and NRAS testing)","route":"/biomarkers/ras-wild-type/"}]}}