Background
Phase 3 RCT in patients aged 18–75 with unresectable, previously untreated metastatic colorectal cancer (mCRC). Left-sided RAS/BRAF wild-type tumors comprised 16% (arm A) vs 17% (arm B); ~74% had RAS/BRAF-mutated tumors and ~38% right-sided primaries. Tested upfront FOLFOXIRI + bevacizumab with planned reintroduction vs sequential doublets.
Interventions and follow up
Arm A: Induction FOLFOXIRI (irinotecan 165, oxaliplatin 85, leucovorin 200 mg/m², 5-FU 3200 mg/m² 48-h infusion) + bevacizumab 5 mg/kg Q2W ×8 cycles, then 5-FU/bevacizumab maintenance, with reintroduction of induction regimen at progression
Arm B: First-line mFOLFOX6 + bevacizumab, then FOLFIRI + bevacizumab at progression
Primary endpoint: PFS2 (randomization to progression on second-line therapy)
Median follow-up: 35.9 mo (IQR 30.1–41.4)
Arm B: First-line mFOLFOX6 + bevacizumab, then FOLFIRI + bevacizumab at progression
Primary endpoint: PFS2 (randomization to progression on second-line therapy)
Median follow-up: 35.9 mo (IQR 30.1–41.4)
Results
PFS2: 19.2 mo (arm A) vs 16.4 mo (arm B); HR 0.74, 95% CI 0.63–0.88, P=.0005
First-line PFS: 12.0 vs 9.8 mo; HR 0.74, P=.002
Second PFS: 6.2 vs 5.6 mo; HR 0.87, P=.11
ORR: 62% vs 50%
R0 resection: 17% vs 12%
First-line PFS: 12.0 vs 9.8 mo; HR 0.74, P=.002
Second PFS: 6.2 vs 5.6 mo; HR 0.87, P=.11
ORR: 62% vs 50%
R0 resection: 17% vs 12%
Adverse events
Hematologic: Grade 3–4 neutropenia 50% (arm A) vs 21% (arm B) during first-line treatment
GI: Grade 3–4 diarrhea 17% vs 5%; stomatitis more frequent with FOLFOXIRI+bevacizumab
Vascular/overall: Arterial hypertension 7% vs 10%; any grade 3–4 events 68% vs 46%; serious AEs 25% vs 17%
GI: Grade 3–4 diarrhea 17% vs 5%; stomatitis more frequent with FOLFOXIRI+bevacizumab
Vascular/overall: Arterial hypertension 7% vs 10%; any grade 3–4 events 68% vs 46%; serious AEs 25% vs 17%
Conclusions
Upfront FOLFOXIRI + bevacizumab with reintroduction at progression improved PFS2 versus sequential doublets with bevacizumab and is a preferred strategy for eligible patients with mCRC, at the cost of greater toxicity.
Key Limitations
PFS2 is a less established endpoint than OS. The triplet's toxicity restricts use to fit, younger patients (≤75). Roughly 78% of arm B vs 59% of arm A received planned post-progression therapy, complicating sequence interpretation. Right-sided/RAS-mutant predominance limits extrapolation to left-sided RAS wild-type disease where anti-EGFR doublets are competitive.
Clinical Context
TRIBE2 reinforced TRIBE in supporting FOLFOXIRI + bevacizumab as an intensive first-line option for fit mCRC patients, particularly those with right-sided or RAS/BRAF-mutated tumors. ESMO endorses triplet + bevacizumab as a first-line option in selected patients; doublet + anti-EGFR remains preferred for left-sided RAS/BRAF wild-type disease.