# CRYSTAL & FIRE-3

Source: https://onco.cc/trials/crystal-fire3/  
OnCo record `crystal-fire3` (Trial). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Fields

- Kind: Trial
- Status: positive
- Last checked: 2026-09-07
- Also known as: CRYSTAL; FIRE-3; CRYSTAL and FIRE-3
- Registry id: NCT00154102
- Phase: 3
- Setting: First-line metastatic colorectal cancer: FOLFIRI ± cetuximab (CRYSTAL); FOLFIRI + cetuximab vs FOLFIRI + bevacizumab (FIRE-3)
- Sponsor: Merck KGaA; AIO (Germany)
- Enrolled: 1198
- Result: CRYSTAL KRAS-WT OS 23.5 vs 20.0 months; FIRE-3 OS 28.7 vs 25.0 months.
- Outcomes: Overall survival, KRAS wild-type (CRYSTAL): FOLFIRI + cetuximab 23.5 months vs FOLFIRI 20 months, HR 0.8; CRYSTAL: progression-free survival (KRAS wild-type): FOLFIRI plus cetuximab 0.68 hazard ratio vs FOLFIRI 1 hazard ratio, HR 0.68; FIRE-3: overall survival (KRAS exon 2 wild-type): FOLFIRI plus cetuximab 28.7 months vs FOLFIRI plus bevacizumab 25 months, HR 0.77; FIRE-3: objective response (primary endpoint): FOLFIRI plus cetuximab 62 percent vs FOLFIRI plus bevacizumab 58 percent
- Replication: Replicated by PRIME (panitumumab + FOLFOX) and PARADIGM.

## Sources

- CRYSTAL, NEJM 2009: https://www.nejm.org/doi/full/10.1056/NEJMoa0805019
- ClinicalTrials.gov NCT00154102: https://clinicaltrials.gov/study/NCT00154102
- ClinicalTrials.gov NCT00433927: https://clinicaltrials.gov/study/NCT00433927
- CRYSTAL: cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer (New England Journal of Medicine 2009): https://doi.org/10.1056/NEJMoa0805019
- FIRE-3: FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment (Lancet Oncology 2014): https://doi.org/10.1016/S1470-2045(14)70330-4

## Connected records

- cancers: [Colon cancer (adenocarcinoma of the colon)](https://onco.cc/cancers/colon-cancer/), [Colorectal cancer](https://onco.cc/cancers/colorectal/)
- technologies: [Monoclonal antibodies](https://onco.cc/technologies/monoclonal-antibody/)
- targets: [EGFR](https://onco.cc/targets/egfr/), [KRAS](https://onco.cc/targets/kras/)
- drugs: [Bevacizumab](https://onco.cc/drugs/bevacizumab/), [Cetuximab](https://onco.cc/drugs/cetuximab/), [FOLFIRI (5-FU, leucovorin, irinotecan)](https://onco.cc/drugs/folfiri/)
- companies: [AIO (Arbeitsgemeinschaft Internistische Onkologie)](https://onco.cc/companies/aio/)
- terms: [Sidedness (left vs right colon)](https://onco.cc/terms/sidedness/)
- trials: [CALGB/SWOG 80405](https://onco.cc/trials/calgb-80405/), [NCIC CO.17](https://onco.cc/trials/co-17/), [OPUS](https://onco.cc/trials/opus/), [PRIME](https://onco.cc/trials/prime/)
- people: [Eric Van Cutsem](https://onco.cc/people/eric-van-cutsem/), [Volker Heinemann](https://onco.cc/people/volker-heinemann/)
- key papers: [Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer (CRYSTAL)](https://onco.cc/key-papers/paper-van-cutsem-crystal-cetuximab-folfiri-nejm-2009/), [FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3)](https://onco.cc/key-papers/paper-heinemann-fire-3-cetuximab-vs-bevacizumab-lancet-oncol-2014/), [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](https://onco.cc/key-papers/paper-tejpar-tumour-location-crystal-fire3-jama-oncol-2017/), [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](https://onco.cc/key-papers/paper-arnold-primary-tumour-side-ras-wild-type-ann-oncol-2017/)
- pairings: [Anti-EGFR antibody + chemotherapy in left-sided RAS/BRAF wild-type mCRC](https://onco.cc/pairings/anti-egfr-left-sided/)
- roadmaps: [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](https://onco.cc/roadmaps/colorectal-roadmap/)
- biomarkers: [RAS wild-type (extended KRAS and NRAS testing)](https://onco.cc/biomarkers/ras-wild-type/)

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