FIRE-3
Multicenter Randomized Trial Evaluating FOLFIRI Plus Cetuximab Versus FOLFIRI Plus Bevacizumab in First Line Treatment of Metastatic Colorectal Cancer.
Phase 3N = 592NCT00433927
- Population
- Previously untreated stage IV colorectal cancer with KRAS exon 2 wild-type tumours
- Design
- Open-label randomised phase 3 trial in Germany and Austria: patients aged 18 to 75 years with stage IV colorectal cancer, ECOG performance status 0 to 2 and KRAS exon 2 codon 12/13 wild-type tumours were centrally randomised (1:1) to FOLFIRI plus cetuximab or FOLFIRI plus bevacizumab. The primary endpoint was objective response analysed by intention to treat. 592 patients with KRAS exon 2 wild-type tumours were randomly assigned and received treatment (297 and 295). The 2016 report analyses the final RAS (KRAS and NRAS exons 2 to 4) wild-type subgroup (n=400) in a post hoc analysis.
- Primary endpoint
- ORR
- Arms
- FOLFIRI plus bevacizumab (control, n = 295): FOLFIRI (fluorouracil, folinic acid, irinotecan) plus bevacizumab
- FOLFIRI plus cetuximab (experimental, n = 297): FOLFIRI (fluorouracil, folinic acid, irinotecan) plus cetuximab
- People
- Heinemann V
Δ ORR+4 pointsPFSHR 1.06 (95% CI 0.88–1.26)Δ median PFS−0.3 monthsOSHR 0.77 (95% CI 0.62–0.96)Δ median OS+3.7 monthsOSHR 0.70 (95% CI 0.54–0.90)
Show the numbers
| Endpoint | Analysis | FOLFIRI plus cetuximab | FOLFIRI plus bevacizumab | Effect |
|---|---|---|---|---|
| ORRITT (stated in the abstract for the primary endpoint), KRAS exon 2 wild-type | primaryHeinemann 2014 | 62% (56.2–67.5%) | 58% (52.1–63.7%) | P=0.18Primary endpoint. Odds ratio 1.18 (95% CI 0.85-1.64), cetuximab versus bevacizumab; 184 and 171 patients responded. |
| PFSAll randomised KRAS exon 2 wild-type patients (analysis population not stated in the abstract for this endpoint) | primaryHeinemann 2014 | median 10 months (8.8–10.8) | median 10.3 months (9.8–11.3) | HR 1.06 (95% CI 0.88–1.26)P=0.55Not the primary endpoint (the primary endpoint was objective response). |
| OSAll randomised KRAS exon 2 wild-type patients (analysis population not stated in the abstract for this endpoint) | primaryHeinemann 2014 | median 28.7 months (24.0–36.6) | median 25 months (22.7–27.6) | HR 0.77 (95% CI 0.62–0.96)P=0.017Not the primary endpoint (the primary endpoint was objective response); reported in the primary publication. |
| OSFinal RAS (KRAS and NRAS exons 2-4) wild-type subgroup (n=400); post hoc analysis | exploratoryStintzing 2016 | median 33.1 months (24.5–39.4) | median 25 months (23.0–28.1) | HR 0.70 (95% CI 0.54–0.90)P=0.0059Post hoc subgroup of FIRE-3; the same abstract states that investigator-assessed objective response and progression-free survival were comparable between the groups in this subgroup. |
| Endpoint | Analysis | FOLFIRI plus cetuximab | FOLFIRI plus bevacizumab | Effect |
|---|---|---|---|---|
| ORRITT (stated in the abstract for the primary endpoint), KRAS exon 2 wild-type | primaryHeinemann 2014 | 62% (56.2–67.5%) | 58% (52.1–63.7%) | P=0.18Primary endpoint. Odds ratio 1.18 (95% CI 0.85-1.64), cetuximab versus bevacizumab; 184 and 171 patients responded. |
| PFSAll randomised KRAS exon 2 wild-type patients (analysis population not stated in the abstract for this endpoint) | primaryHeinemann 2014 | median 10 months (8.8–10.8) | median 10.3 months (9.8–11.3) | HR 1.06 (95% CI 0.88–1.26)P=0.55Not the primary endpoint (the primary endpoint was objective response). |
| OSAll randomised KRAS exon 2 wild-type patients (analysis population not stated in the abstract for this endpoint) | primaryHeinemann 2014 | median 28.7 months (24.0–36.6) | median 25 months (22.7–27.6) | HR 0.77 (95% CI 0.62–0.96)P=0.017Not the primary endpoint (the primary endpoint was objective response); reported in the primary publication. |
| OSFinal RAS (KRAS and NRAS exons 2-4) wild-type subgroup (n=400); post hoc analysis | exploratoryStintzing 2016 | median 33.1 months (24.5–39.4) | median 25 months (23.0–28.1) | HR 0.70 (95% CI 0.54–0.90)P=0.0059Post hoc subgroup of FIRE-3; the same abstract states that investigator-assessed objective response and progression-free survival were comparable between the groups in this subgroup. |
Data table
| Endpoint | HR | 95% CI |
|---|---|---|
| PFS | 1.06 | 0.88–1.26 |
| OS | 0.77 | 0.62–0.96 |
| OS | 0.7 | 0.54–0.9 |
- FOLFIRI plus cetuximab (experimental)
- FOLFIRI plus bevacizumab (control)
Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.
Data table (modelled values)
| Months | FOLFIRI plus cetuximab | FOLFIRI plus bevacizumab |
|---|---|---|
| 0 | 100.0% | 100.0% |
| 6 | 66.0% | 66.8% |
| 13 | 40.6% | 41.7% |
| 19 | 26.8% | 27.8% |
| 26 | 16.5% | 17.4% |
- FOLFIRI plus cetuximab (experimental)
- FOLFIRI plus bevacizumab (control)
Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.
Data table (modelled values)
| Months | FOLFIRI plus cetuximab | FOLFIRI plus bevacizumab |
|---|---|---|
| 0 | 100.0% | 100.0% |
| 18 | 64.7% | 60.7% |
| 36 | 41.9% | 36.9% |
| 54 | 27.1% | 22.4% |
| 72 | 17.6% | 13.6% |
Appears in
Sources
Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15(10):1065-75.
Stintzing S, Modest DP, Rossius L, Lerch MM, von Weikersthal LF, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic colorectal cancer (FIRE-3): a post-hoc analysis of tumour dynamics in the final RAS wild-type subgroup of this randomised open-label phase 3 trial. Lancet Oncol. 2016;17(10):1426-1434.