Individual Patient Data Meta-Analysis of FOLFOXIRI Plus Bevacizumab Versus Doublets Plus Bevacizumab as Initial Therapy of Unresectable Metastatic Colorectal Cancer

Abstract

PURPOSE: A proper estimation of the magnitude of the overall survival (OS) benefit from infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) plus bevacizumab versus doublets + bevacizumab is lacking because all trials that have investigated this regimen had primary end points other than OS. To test OS with higher power and to explore the interaction of treatment effect with main patient and disease characteristics, we performed an individual patient data (IPD) meta-analysis. PATIENTS AND METHODS: IPD from 5 eligible trials were collected: CHARTA (ClinicalTrials.gov identifier: NCT01321957 ), OLIVIA (ClinicalTrials.gov identifier: NCT00778102 ), STEAM (ClinicalTrials.gov identifier: NCT01765582 ), TRIBE (ClinicalTrials.gov identifier: NCT00719797 ), and TRIBE2 (ClinicalTrials.gov identifier: NCT02339116 ). The primary end point was OS. Secondary end points were progression-free survival (PFS), objective response rate (ORR), R0 resection rate, grade 3/4 adverse events, and subgroup analyses according to clinical and molecular characteristics. RESULTS: A total of 1,697 patients were randomly assigned to FOLFOXIRI + bevacizumab (n = 846) or doublets + bevacizumab (n = 851). Most (78%) had an Eastern Cooperative Oncology Group performance status of 0, and the median age was 61 years. After a median follow-up of 39.9 months, patients assigned to FOLFOXIRI + bevacizumab had significantly longer OS than those assigned to doublets + bevacizumab (median, 28.9 v 24.5 months; hazard ratio [HR], 0.81; 95% CI, 0.72 to 0.91; P < .001), with no significant heterogeneity among trials ( P = .39; I 2 = 2%). No significant interaction effect between treatment arm and investigated characteristics was demonstrated. Patients assigned to FOLFOXIRI + bevacizumab had longer PFS (median, 12.2 v 9.9 months; HR, 0.74; 95% CI, 0.67 to 0.82; P < .001), higher ORR (64.5% v 53.6%; P < .001), higher R0 resection rate (16.4% v 11.8%; P = .007), and higher rates of grade 3/4 neutropenia (45.8% v 21.5%; P < .001), febrile neutropenia (6.3% v 3.7%; P = .019), and diarrhea (17.8% v 8.4%; P < .001). CONCLUSION: FOLFOXIRI + bevacizumab significantly and meaningfully improves survival of patients with metastatic colorectal cancer compared with doublets + bevacizumab and provides advantage in PFS, ORR, and R0 resection rate at the price of a moderate increase in toxicity. No increased benefit is observed among patients with BRAF-mutant tumors.