# FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3)

Source: https://onco.cc/key-papers/paper-heinemann-fire-3-cetuximab-vs-bevacizumab-lancet-oncol-2014/  
OnCo record `paper-heinemann-fire-3-cetuximab-vs-bevacizumab-lancet-oncol-2014` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

Between 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.

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Tags: colorectal-evidence
- Journal: The Lancet Oncology
- Year: 2014
- DOI: 10.1016/S1470-2045(14)70330-4
- Authors: Heinemann V, von Weikersthal LF, Decker T, et al.
- 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.
- What it means: 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.

## Sources

- Lancet Oncol 2014: https://doi.org/10.1016/S1470-2045(14)70330-4
- PubMed: https://pubmed.ncbi.nlm.nih.gov/25088940/

## Connected records

- key papers: [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)](https://onco.cc/key-papers/paper-venook-calgb-80405-cetuximab-vs-bevacizumab-jama-2017/), [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](https://onco.cc/key-papers/paper-cremolini-tribe-folfoxiri-bevacizumab-lancet-oncol-2015/), [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/)
- cancers: [Colorectal cancer](https://onco.cc/cancers/colorectal/)
- fronts: [Targeted Therapy](https://onco.cc/fronts/targeted-therapy/)
- technologies: [Anti-angiogenic therapy](https://onco.cc/technologies/antiangiogenic/), [Monoclonal antibodies](https://onco.cc/technologies/monoclonal-antibody/)
- targets: [EGFR](https://onco.cc/targets/egfr/), [KRAS](https://onco.cc/targets/kras/), [VEGF / VEGFR](https://onco.cc/targets/vegf/)
- drugs: [Bevacizumab](https://onco.cc/drugs/bevacizumab/), [Cetuximab](https://onco.cc/drugs/cetuximab/), [FOLFIRI (5-FU, leucovorin, irinotecan)](https://onco.cc/drugs/folfiri/), [Irinotecan (and liposomal irinotecan)](https://onco.cc/drugs/irinotecan/)
- terms: [Sidedness (left vs right colon)](https://onco.cc/terms/sidedness/)
- trials: [CRYSTAL & FIRE-3](https://onco.cc/trials/crystal-fire3/)
- people: [Volker Heinemann](https://onco.cc/people/volker-heinemann/)
- journals: [The Lancet Oncology](https://onco.cc/journals/lancet-oncology/)
- 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/)

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