Background
Phase III randomized open-label trial. 508 patients with unresectable metastatic colorectal cancer, ECOG PS 0–2, no prior chemotherapy for metastatic disease. Evaluated whether first-line FOLFOXIRI (triplet) + bevacizumab is superior to standard FOLFIRI (doublet) + bevacizumab.
Interventions and follow up
Arm A: FOLFOXIRI + bevacizumab 5 mg/kg q2wk × up to 12 cycles, then maintenance bevacizumab ± 5-FU/LV
Arm B: FOLFIRI + bevacizumab 5 mg/kg q2wk × up to 12 cycles, then maintenance bevacizumab ± 5-FU/LV
Primary endpoint: Progression-free survival (PFS)
Median follow-up: 48.1 months
Arm B: FOLFIRI + bevacizumab 5 mg/kg q2wk × up to 12 cycles, then maintenance bevacizumab ± 5-FU/LV
Primary endpoint: Progression-free survival (PFS)
Median follow-up: 48.1 months
Results
mPFS: 12.1 vs 9.7 months, HR 0.75 (95% CI 0.62–0.90), P=.003
mOS: 29.8 vs 25.8 months, HR 0.80 (95% CI 0.65–0.98), P=.054
ORR: 65% vs 53%, P=.006
R0 resection rate: 15% vs 12%, P=.33
Early tumor shrinkage (≥20% at 8 wks): 62% vs 46%, P=.001
mOS: 29.8 vs 25.8 months, HR 0.80 (95% CI 0.65–0.98), P=.054
ORR: 65% vs 53%, P=.006
R0 resection rate: 15% vs 12%, P=.33
Early tumor shrinkage (≥20% at 8 wks): 62% vs 46%, P=.001
Adverse events
Hematologic grade ≥3: neutropenia 50% vs 28%, febrile neutropenia 18% vs 8%
Non-hematologic grade ≥3: diarrhea 19% vs 11%, stomatitis 9% vs 4%, peripheral neuropathy 5% vs 3%
Discontinuation due to toxicity: 11% vs 9%
Non-hematologic grade ≥3: diarrhea 19% vs 11%, stomatitis 9% vs 4%, peripheral neuropathy 5% vs 3%
Discontinuation due to toxicity: 11% vs 9%
Conclusions
FOLFOXIRI + bevacizumab significantly improved PFS (12.1 vs 9.7 months, HR 0.75) and ORR (65% vs 53%) vs FOLFIRI + bevacizumab in first-line mCRC. A trend toward improved OS (HR 0.80, P=.054) was observed, with significantly higher rates of early tumor shrinkage, at the cost of increased grade ≥3 neutropenia and diarrhea.
Key Limitations
OS improvement did not reach statistical significance (P=.054). Conducted in Italy at centers experienced in FOLFOXIRI delivery — real-world tolerability may differ. ECOG PS 0–2 enrolled but optimal patients are fit PS 0–1. No RAS/BRAF stratification — the trial preceded routine molecular profiling. Triplet + bevacizumab is not universally accessible due to toxicity and logistical complexity.
Clinical Context
TRIBE established FOLFOXIRI + bevacizumab as a first-line option for fit mCRC patients with unresectable or borderline resectable disease where maximum tumor shrinkage is desired. Long-term OS data (Cremolini C et al, JCO 2018) confirmed 5-year OS benefit (13% vs 8%). TRIBE2 demonstrated maintained benefit with rechallenge. ESMO recommends FOLFOXIRI+bevacizumab for fit patients (PS 0–1) aiming for conversion to resectability or maximum response. ESMO-MCBS score: 3.