# Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer (PRIME)

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

## TL;DR

Looking beyond the one KRAS exon everyone tested found that a further 17 percent of patients carried a RAS mutation and were harmed rather than helped by the antibody. Testing widened overnight.

## Summary

Douillard, Oliner, Siena and colleagues assessed the efficacy and safety of panitumumab plus FOLFOX4 against FOLFOX4 alone by RAS (KRAS or NRAS) and BRAF mutation status, in a prospective-retrospective analysis of PRIME. Six hundred and thirty-nine patients whose tumours had no KRAS exon 2 mutation had results for at least one of KRAS exon 3 or 4, NRAS exon 2, 3 or 4, or BRAF exon 15; the overall rate of RAS status ascertainment was 90 percent.

No new safety signals were identified, and BRAF mutation was a negative prognostic factor rather than a predictor of antibody benefit.

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Tags: colorectal-evidence
- Journal: New England Journal of Medicine
- Year: 2013
- DOI: 10.1056/NEJMoa1305275
- Authors: Douillard JY, Oliner KS, Siena S, et al.
- Findings: Among 512 patients without any RAS mutation, progression-free survival 10.1 against 7.9 months (hazard ratio 0.72, 95 percent CI 0.58 to 0.90, p=0.004).; Overall survival 26.0 against 20.2 months (hazard ratio 0.78, 0.62 to 0.99, p=0.04).; 108 of 639 patients (17 percent) with non-mutated KRAS exon 2 had other RAS mutations, and these were associated with inferior outcomes on panitumumab-FOLFOX4.; BRAF mutation was a negative prognostic factor.
- What it means: Extended RAS testing (KRAS and NRAS exons 2, 3 and 4) became the standard before any EGFR antibody, and about one in six patients who would previously have been treated is now spared a drug that would have made things worse.
- Caveats: Prospective-retrospective: the RAS analysis was planned but performed after the trial read out, on 90 percent of samples.; The harm signal in the additional RAS-mutant group rests on 108 patients.; Sidedness was analysed only later, in the pooled analysis of six trials.

## Sources

- N Engl J Med 2013: https://doi.org/10.1056/NEJMoa1305275
- PubMed: https://pubmed.ncbi.nlm.nih.gov/24024839/

## Connected records

- 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/), [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/), [Sotorasib plus panitumumab in refractory colorectal cancer with mutated KRAS G12C (CodeBreaK 300)](https://onco.cc/key-papers/paper-fakih-codebreak-300-sotorasib-panitumumab-nejm-2023/), [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: [BRAF](https://onco.cc/targets/braf/), [EGFR](https://onco.cc/targets/egfr/), [KRAS](https://onco.cc/targets/kras/)
- drugs: [FOLFOX (5-FU, leucovorin, oxaliplatin)](https://onco.cc/drugs/folfox/), [Oxaliplatin](https://onco.cc/drugs/oxaliplatin/), [Panitumumab](https://onco.cc/drugs/panitumumab/)
- companies: [Amgen](https://onco.cc/companies/amgen/)
- pathways: [RAS / RAF / MEK / ERK (MAPK)](https://onco.cc/pathways/ras-mapk/)
- terms: [Sidedness (left vs right colon)](https://onco.cc/terms/sidedness/)
- people: [Josep Tabernero](https://onco.cc/people/josep-tabernero/), [Salvatore Siena](https://onco.cc/people/salvatore-siena/)
- 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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