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The trials that established EGFR antibodies in bowel cancer and discovered they only work when the RAS gene is normal.
CRYSTAL (NEJM 2009) showed cetuximab + FOLFIRI improved PFS and, in KRAS wild-type tumours, OS (23.5 vs 20.0 months). Retrospective RAS analyses defined the first negative predictive biomarker in CRC. FIRE-3 (Lancet Oncology 2014) showed longer OS with cetuximab than bevacizumab in KRAS wild-type disease (28.7 vs 25.0 months), later shown to be driven by left-sided tumours.
Numbers are from the trial as recorded here; see the source links in the table below. This is orientation, not medical advice: ask your team how closely the trial population matches you.
1,198 randomised.
| Endpoint | Arm | n | Value | HR (95% CI) | p | Source |
|---|---|---|---|---|---|---|
| Overall survival, KRAS wild-type (CRYSTAL) | FOLFIRI + cetuximab | - | 23.5 months | 0.8 | - | link |
| FOLFIRI | - | 20 months | ||||
| CRYSTAL: progression-free survival (KRAS wild-type) | FOLFIRI plus cetuximab | - | 0.68 hazard ratio | 0.68 (0.5 to 0.94) | - | link |
| FOLFIRI | - | 1 hazard ratio | ||||
| FIRE-3: overall survival (KRAS exon 2 wild-type) | FOLFIRI plus cetuximab | 297 | 28.7 months | 0.77 (0.62 to 0.96) | 0.017 | link |
| FOLFIRI plus bevacizumab | 295 | 25 months | ||||
| FIRE-3: objective response (primary endpoint)primary | FOLFIRI plus cetuximab | 297 | 62 percent | - | 0.18 | link |
| FOLFIRI plus bevacizumab | 295 | 58 percent |
The full inclusion and exclusion criteria are on the registry record. Read 2026-10-07. Recruiting overall does not mean a particular site is open; ask the study team.
The full inclusion and exclusion criteria are on the registry record. Read 2026-10-07. Recruiting overall does not mean a particular site is open; ask the study team.
ClinicalTrials.gov data courtesy of the US National Library of Medicine.
It showed the sidedness effect is not an artefact of pooling and survives adjustment for BRAF, which is what made guideline committees act on it.
The analysis that put 'left-sided, RAS and BRAF wild-type' into every guideline as the anti-EGFR population, and made an anatomical fact into a treatment-selection biomarker.
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.
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.
Shares Anti-EGFR antibody + chemotherapy in left-sided RAS/BRAF wild-type mCRC, OPUS, CALGB/SWOG 80405, PRIME.
Shares FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3), 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, Sidedness (left vs right colon), FOLFIRI (5-FU, leucovorin, irinotecan).
Shares Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer (CRYSTAL), 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, Sidedness (left vs right colon), 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.
Shares Eric Van Cutsem, Sidedness (left vs right colon), FOLFIRI (5-FU, leucovorin, irinotecan), Cetuximab.
Shares Sidedness (left vs right colon), Cetuximab, EGFR, KRAS.
Shares Sidedness (left vs right colon), FOLFIRI (5-FU, leucovorin, irinotecan), Bevacizumab, EGFR.
Shares RAS wild-type (extended KRAS and NRAS testing), Sidedness (left vs right colon), EGFR, KRAS.
Shares Cetuximab, EGFR, KRAS, Monoclonal antibodies.
Every source this page cites, grouped by who published it. Grouping is read from the web address, not assigned by hand.
A source that has moved or gone is reported by the weekly link check. /audit/