# Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer (CRYSTAL)

Source: https://onco.cc/key-papers/paper-van-cutsem-crystal-cetuximab-folfiri-nejm-2009/  
OnCo record `paper-van-cutsem-crystal-cetuximab-folfiri-nejm-2009` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

The trial that added an EGFR antibody to first-line chemotherapy and, in the same paper, showed the benefit belongs only to patients whose KRAS gene is normal. It is the first negative predictive biomarker in bowel cancer.

## Summary

Van Cutsem, Köhne, Hitre and colleagues randomly assigned patients with EGFR-positive colorectal cancer and unresectable metastases to FOLFIRI alone or with cetuximab, with progression-free survival as the primary end point, and sought associations between tumour KRAS mutation status and response. A total of 599 patients received cetuximab plus FOLFIRI and 599 received FOLFIRI alone.

Grade 3 or 4 skin reactions occurred in 19.7 percent of the cetuximab group against 0.2 percent, infusion-related reactions in 2.5 against 0 percent and diarrhoea in 15.7 against 10.5 percent.

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Tags: colorectal-evidence
- Journal: New England Journal of Medicine
- Year: 2009
- DOI: 10.1056/NEJMoa0805019
- Authors: Van Cutsem E, Köhne CH, Hitre E, et al.
- Findings: Progression-free survival hazard ratio 0.85 (95 percent CI 0.72 to 0.99, p=0.048) overall.; No significant difference in overall survival overall (hazard ratio 0.93, 0.81 to 1.07, p=0.31).; Significant interaction between treatment and KRAS status for tumour response (p=0.03) but not for progression-free survival (p=0.07) or overall survival (p=0.44).; In KRAS wild-type tumours, progression-free survival hazard ratio 0.68 (0.50 to 0.94) in favour of cetuximab.
- What it means: Biomarker-directed treatment in colorectal cancer starts here: RAS testing became mandatory before an EGFR antibody, and the corpus's updated CRYSTAL analysis (paper-kras-colorectal-j-clin-oncol-2011) carries the mature survival figures in the wild-type group.
- Caveats: The overall trial was positive only for progression-free survival, and narrowly; the important result is the subgroup defined by a biomarker tested retrospectively.; Only exon 2 KRAS was tested; the extended RAS analysis in PRIME four years later removed a further 17 percent of apparently eligible patients.; Sidedness, which turned out to matter more than the trial's own stratification factors, was not analysed.

## Sources

- N Engl J Med 2009: https://doi.org/10.1056/NEJMoa0805019
- PubMed: https://pubmed.ncbi.nlm.nih.gov/19339720/

## Connected records

- key papers: [Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status](https://onco.cc/key-papers/paper-kras-colorectal-j-clin-oncol-2011/), [Hurwitz 2004: bevacizumab with chemotherapy for metastatic colorectal cancer, the first anti-angiogenic drug to extend life](https://onco.cc/key-papers/paper-hurwitz-bevacizumab-crc-nejm-2004/), [Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer (PRIME)](https://onco.cc/key-papers/paper-douillard-prime-panitumumab-ras-nejm-2013/), [Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer](https://onco.cc/key-papers/paper-kras-colorectal-j-clin-oncol-2008/)
- cancers: [Colorectal cancer](https://onco.cc/cancers/colorectal/)
- fronts: [Targeted Therapy](https://onco.cc/fronts/targeted-therapy/)
- technologies: [Monoclonal antibodies](https://onco.cc/technologies/monoclonal-antibody/)
- targets: [EGFR](https://onco.cc/targets/egfr/), [KRAS](https://onco.cc/targets/kras/)
- drugs: [Cetuximab](https://onco.cc/drugs/cetuximab/), [Fluorouracil (5-FU)](https://onco.cc/drugs/fluorouracil/), [FOLFIRI (5-FU, leucovorin, irinotecan)](https://onco.cc/drugs/folfiri/), [Irinotecan (and liposomal irinotecan)](https://onco.cc/drugs/irinotecan/)
- pathways: [RAS / RAF / MEK / ERK (MAPK)](https://onco.cc/pathways/ras-mapk/)
- terms: [Sidedness (left vs right colon)](https://onco.cc/terms/sidedness/)
- trials: [CRYSTAL & FIRE-3](https://onco.cc/trials/crystal-fire3/)
- people: [Eric Van Cutsem](https://onco.cc/people/eric-van-cutsem/)
- bottlenecks: [Biomarkers are not validated or standardised](https://onco.cc/bottlenecks/b-biomarker-validation/)
- journals: [New England Journal of Medicine](https://onco.cc/journals/nejm/)
- 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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