# Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer

Source: https://onco.cc/key-papers/paper-douillard-prime-extended-ras-panitumumab-nejm-2013/  
OnCo record `paper-douillard-prime-extended-ras-panitumumab-nejm-2013` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Testing only the two commonest spots in KRAS was not enough: another one in six patients called wild-type turned out to carry a RAS mutation somewhere else, and they did no better on the antibody than the ones already excluded.

## Summary

In a prospective-retrospective analysis of the PRIME trial, the efficacy and safety of panitumumab plus FOLFOX4 against FOLFOX4 alone were assessed by RAS (KRAS or NRAS) and BRAF mutation status. A total of 639 patients whose tumours lacked KRAS exon 2 mutations had results for at least one of KRAS exon 3 or 4, NRAS exon 2, 3 or 4, or BRAF exon 15, with 90% overall ascertainment. Among 512 patients with no RAS mutation, progression-free survival was 10.1 months with panitumumab-FOLFOX4 against 7.9 with FOLFOX4 alone (hazard ratio 0.72) and overall survival 26.0 against 20.2 months (hazard ratio 0.78). A total of 108 patients (17%) with non-mutated KRAS exon 2 had other RAS mutations, and those mutations were associated with inferior progression-free and overall survival on panitumumab-FOLFOX4, consistent with the findings in KRAS exon 2 mutants. BRAF mutations were a negative prognostic factor.

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Journal: New England Journal of Medicine
- Year: 2013
- DOI: 10.1056/NEJMoa1305275
- Authors: Douillard JY, Oliner KS, Siena S, et al.
- Findings: 108 of 639 KRAS exon 2 wild-type patients (17%) carried another RAS mutation.; RAS wild-type: overall survival 26.0 against 20.2 months (hazard ratio 0.78).; Other RAS mutations predicted lack of benefit, exactly as KRAS exon 2 mutations do.
- What it means: It moved the label and every guideline from KRAS exon 2 testing to extended RAS testing of KRAS and NRAS exons 2, 3 and 4, which is the threshold in use today.
- Caveats: Prospective-retrospective; 10% of patients had no extended RAS result.; BRAF was prognostic rather than clearly predictive in this analysis.; Sidedness was analysed later.

## Sources

- Douillard et al., N Engl J Med 2013: PRIME, extended RAS testing and panitumumab-FOLFOX4: https://doi.org/10.1056/NEJMoa1305275
- PubMed: https://pubmed.ncbi.nlm.nih.gov/24024839/

## Connected records

- cancers: [Colorectal cancer](https://onco.cc/cancers/colorectal/)
- targets: [BRAF](https://onco.cc/targets/braf/), [EGFR](https://onco.cc/targets/egfr/), [KRAS](https://onco.cc/targets/kras/), [NRAS](https://onco.cc/targets/nras/)
- drugs: [Panitumumab](https://onco.cc/drugs/panitumumab/), [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: [Next-generation sequencing (NGS)](https://onco.cc/terms/ngs/), [Wild-type (WT)](https://onco.cc/terms/wild-type/)
- people: [Salvatore Siena](https://onco.cc/people/salvatore-siena/)
- journals: [New England Journal of Medicine](https://onco.cc/journals/nejm/)
- trials: [PARADIGM](https://onco.cc/trials/paradigm/)
- biomarkers: [KRAS G12D (and other non-G12C KRAS mutations)](https://onco.cc/biomarkers/kras-g12d/)

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