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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 |
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.