# K-ras mutations and benefit from cetuximab in advanced colorectal cancer

Source: https://onco.cc/key-papers/paper-karapetis-kras-cetuximab-colorectal-nejm-2008/  
OnCo record `paper-karapetis-kras-cetuximab-colorectal-nejm-2008` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

The first randomised proof that a mutation can say a drug will not work: in a trial of cetuximab against supportive care alone, only patients whose tumours had a normal K-ras gene lived longer.

## Summary

Tumour samples from 394 of 572 patients (68.9%) with colorectal cancer randomly assigned to cetuximab plus best supportive care or best supportive care alone were analysed for activating mutations in exon 2 of the K-ras gene. Of the tumours evaluated, 42.3% had at least one such mutation. The effectiveness of cetuximab was significantly associated with K-ras mutation status (interaction p = 0.01 for overall survival and p less than 0.001 for progression-free survival). In patients with wild-type tumours, cetuximab improved median overall survival from 4.8 to 9.5 months (hazard ratio 0.55) and progression-free survival from 1.9 to 3.7 months (hazard ratio 0.40). Among patients with mutated tumours there was no difference in overall survival (hazard ratio 0.98) or progression-free survival (hazard ratio 0.99). K-ras status was not associated with survival in the supportive-care group, so it is predictive rather than prognostic in this setting.

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Journal: New England Journal of Medicine
- Year: 2008
- DOI: 10.1056/NEJMoa0804385
- Authors: Karapetis CS, Khambata-Ford S, Jonker DJ, et al.
- Findings: K-ras exon 2 mutation in 42.3% of 394 evaluable tumours.; Wild-type: overall survival 9.5 against 4.8 months with cetuximab (hazard ratio 0.55).; Mutant: no benefit (overall survival hazard ratio 0.98).
- What it means: It created the negative predictive biomarker in solid tumour oncology and, with the panitumumab analysis of the same year, restricted EGFR antibodies to RAS wild-type disease worldwide.
- Caveats: Retrospective biomarker analysis of a randomised trial, with tissue for 69% of patients.; Exon 2 only; the other RAS codons came five years later (Douillard 2013).; Sidedness had not yet been recognised, so the wild-type group mixed left and right.

## Sources

- Karapetis et al., N Engl J Med 2008: K-ras mutation and benefit from cetuximab (CO.17, 394 tumours): https://doi.org/10.1056/NEJMoa0804385
- PubMed: https://pubmed.ncbi.nlm.nih.gov/18946061/

## Connected records

- cancers: [Colorectal cancer](https://onco.cc/cancers/colorectal/)
- targets: [EGFR](https://onco.cc/targets/egfr/), [KRAS](https://onco.cc/targets/kras/)
- drugs: [Cetuximab](https://onco.cc/drugs/cetuximab/), [therascreen companion diagnostic kits (KRAS, EGFR, PIK3CA, FGFR, BRAF)](https://onco.cc/drugs/therascreen-cdx/)
- pathways: [RAS / RAF / MEK / ERK (MAPK)](https://onco.cc/pathways/ras-mapk/)
- terms: [Driver mutation](https://onco.cc/terms/driver-mutation/), [Wild-type (WT)](https://onco.cc/terms/wild-type/)
- people: [Christos Karapetis](https://onco.cc/people/christos-karapetis/)
- journals: [New England Journal of Medicine](https://onco.cc/journals/nejm/)
- biomarkers: [KRAS G12D (and other non-G12C KRAS mutations)](https://onco.cc/biomarkers/kras-g12d/)

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