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; I2 = 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.

Colon Cancer, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology

“…Other phase II trials, including CHARTA and STEAM, have also reported improved outcomes for FOL-FOXIRI plus bevacizumab when compared with a chemotherapy doublet plus bevacizumab for first-line treatment of mCRC. 187,188 A pooled analysis of TRIBE and TRIBE2 189 and a meta-analysis of individual patient data from CHARTA, OLIVIA, STEAM, TRIBE, and TRIBE2 190 reached similar conclusions as the clinical trials. These analyses concluded that first-line treatment with FOLFOXIRI plus bevacizumab yields significantly better outcomes, albeit at the expense of higher toxicity, compared with sequential treatment with chemotherapy doublets in combination with bevacizumab.…”

The Evolutionary Landscape of Treatment for BRAFV600E Mutant Metastatic Colorectal Cancer

“…In contrast, the TRIBE 2 study did not confirmed the advantage of FOLFOXIRI plus bevacizumab versus the doublet regimens plus bevacizumab in the BRAF V600E mutant mCRC patients [ 52 ]. This has been recently confirmed by a meta-analysis from the same group, demonstrating no benefit from FOLFOXIRI plus bevacizumab if compared to standard doublet cytotoxic combinations [ 53 ]. These data relight the debate on current clinical guidelines recommendation, making FOLFOXIRI plus bevacizumab no longer the treatment of choice in first line for BRAF V600E mutant mCRC patients [ 3 , 4 , 53 ].…”

“…This has been recently confirmed by a meta-analysis from the same group, demonstrating no benefit from FOLFOXIRI plus bevacizumab if compared to standard doublet cytotoxic combinations [ 53 ]. These data relight the debate on current clinical guidelines recommendation, making FOLFOXIRI plus bevacizumab no longer the treatment of choice in first line for BRAF V600E mutant mCRC patients [ 3 , 4 , 53 ]. In addition to FOLFOXIRI plus bevacizumab, in the randomized phase II VOLFI trial FOLFOXIRI plus panitumumab has also been studied in first-line, showing a high ORR improvement (85% versus 22%) in BRAF V600E mutant mCRC [ 54 ], requiring confirmation in larger studies and possibly leading to reconsider the role anti-EGFR in this setting.…”

“…Among these, the exploitation of agents targeting the MAPK pathway and intensive chemotherapy regimens appear as the most promising based on previous results derived from published clinical trials [ 25 , 28 ]. However, a recent meta-analysis, showing no benefit from FOLFOXIRI plus bevacizumab if compared to standard cytotoxic doublets plus bevacizumab in BRAF V600E mutant mCRC, will lead to reconsider current clinical guidelines recommendations [ 3 , 4 , 53 ]. Moreover, the combination of targeted agents plus CPIs is of great interest, particularly for MSS tumors, even if there are only initial data in mCRC [ 73 ].…”

Is it necessary to add anti-angiogenic therapy to chemotherapy in patients with metastatic colorectal cancer and BRAF mutation? The systematic review and meta-analysis results

“…Исследования, результаты которых послужили в качестве рекомендации по применению режима FOLFOXIRI с бевацизумабом в первой линии при мутации в гене BRAF, не включали контрольную группу без бевацизумаба [11,12]. В 2020 году были доложены результаты двух мета-анализов, показавших, что комбинация FOLFOXIRI с бевацизумабом не улучшает ни частоту объективных эффектов, ни ВБП, ни ОВ в сравнении с двойными комбинациями с бевацизумабом [13,14].…”