Upfront FOLFOXIRI plus bevacizumab and reintroduction after progression versus mFOLFOX6 plus bevacizumab followed by FOLFIRI plus bevacizumab in the treatment of patients with metastatic colorectal cancer (TRIBE2): a multicentre, open-label, phase 3, randomised, controlled trial

Summary

Background

The triplet FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab showed improved outcomes for patients with metastatic colorectal cancer, compared with FOLFIRI (fluorouracil, leucovorin, and irinotecan) plus bevacizumab. However, the actual benefit of the upfront exposure to the three cytotoxic drugs compared with a preplanned sequential strategy of doublets was not clear, and neither was the feasibility or efficacy of therapies after disease progression. We aimed to compare a preplanned strategy of upfront FOLFOXIRI followed by the reintroduction of the same regimen after disease progression versus a sequence of mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) and FOLFIRI doublets, in combination with bevacizumab.

Methods

TRIBE2 was an open-label, phase 3, randomised study of patients aged 18–75 years with an Eastern Cooperative Oncology Group (ECOG) performance status of 2, with unresectable, previously untreated metastatic colorectal cancer, recruited from 58 Italian oncology units. Patients were stratified according to centre, ECOG performance status, primary tumour location, and previous adjuvant chemotherapy. A randomisation system incorporating a minimisation algorithm was used to randomly assign patients (1:1) via a masked web-based allocation procedure to two different treatment strategies. In the control group, patients received first-line mFOLFOX6 (85 mg/m² of intravenous oxaliplatin concurrently with 200 mg/m² of leucovorin over 120 min; 400 mg/m² intravenous bolus of fluorouracil; 2400 mg/m² continuous infusion of fluorouracil for 48 h) plus bevacizumab (5 mg/kg intravenously over 30 min) followed by FOLFIRI (180 mg/m² of intravenous irinotecan over 120 min concurrently with 200 mg/m² of leucovorin; 400 mg/m² intravenous bolus of fluorouracil; 2400 mg/m² continuous infusion of fluorouracil for 48 h) plus bevacizumab after disease progression. In the experimental group, patients received FOLFOXIRI (165 mg/m² of intravenous irinotecan over 60 min; 85 mg/m² intravenous oxaliplatin concurrently with 200 mg/m² of leucovorin over 120 min; 3200 mg/m² continuous infusion of fluorouracil for 48 h) plus bevacizumab followed by the reintroduction of the same regimen after disease progression. Combination treatments were repeated every 14 days for up to eight cycles followed by fluorouracil and leucovorin (at the same dose administered at the last induction cycle) plus bevacizumab maintenance until disease progression, unacceptable adverse events, or consent withdrawal. Patients and investigators were not masked. The primary endpoint was progression-free survival 2, defined as the time from randomisation to disease progression on any treatment given after first disease progression, or death, analysed by intention to treat. Safety was assessed in patients who received at least one dose of their assigned treatment. Study recruitment is complete and follow-up is ongoing. This trial is registered with Clinicaltrials.gov, NCT02339116.

Findings

Between Feb 26, 2015, and May 15, 2017, 679 patients were randomly assigned and received treatment (340 in the control group and 339 in the experimental group). At data cut-off (July 30, 2019) median follow-up was 35·9 months (IQR 30·1–41·4). Median progression-free survival 2 was 19·2 months (95% CI 17·3–21·4) in the experimental group and 16·4 months (15·1–17·5) in the control group (hazard ratio [HR] 0·74, 95% CI 0·63–0·88; p=0·0005). During the first-line treatment, the most frequent of all-cause grade 3–4 events were diarrhoea (57 [17%] vs 18 [5%]), neutropenia (168 [50%] vs 71 [21%]), and arterial hypertension (25 [7%] vs 35 [10%]) in the experimental group compared with the control group. Serious adverse events occurred in 84 (25%) patients in the experimental group and in 56 (17%) patients in the control group. Eight treatment-related deaths were reported in the experimental group (two intestinal occlusions, two intestinal perforations, two sepsis, one myocardial infarction, and one bleeding) and four in the control group (two occlusions, one perforation, and one pulmonary embolism). After first disease progression, no substantial differences in the incidence of grade 3 or 4 adverse events were reported between the control and experimental groups, with the exception of neurotoxicity, which was only reported in the experimental group (six [5%] of 132 patients). Serious adverse events after disease progression occurred in 20 (15%) patients in the experimental group and 25 (12%) in the control group. Three treatment-related deaths after first disease progression were reported in the experimental group (two intestinal occlusions and one sepsis) and four in the control group (one intestinal occlusion, one intestinal perforation, one cerebrovascular event, and one sepsis).

Interpretation

Upfront FOLFOXIRI plus bevacizumab followed by the reintroduction of the same regimen after disease progression seems to be a preferable therapeutic strategy to sequential administration of chemotherapy doublets, in combination with bevacizumab, for patients with metastatic colorectal cancer selected according to the study criteria.

Funding

The GONO Cooperative Group, the ARCO Foundation, and F Hoffmann–La Roche.

Introduction

Several options are available for the upfront treatment of patients with metastatic colorectal cancer. On the basis of the results from the phase 3 TRIBE study1, 2 by the Gruppo Oncologico del Nord Ovest (GONO) and other phase 2 randomised trials,3, 4, 5, 6 the combination of the three-cytotoxic drug regimen FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) with the antiangiogenic bevacizumab is regarded as a valuable first-line option by most guidelines.7, 8

The previous TRIBE study² showed significantly longer progression-free survival (the primary endpoint of the study; hazard ratio [HR] 0·77 [95% CI 0·65–0·93]; p=0·006), increased response rate (odds ratio [OR] 1·59 [95% CI 1·10–2·28]; p=0·013), and longer overall survival (HR 0·80 [95% CI 0·65–0·98]; p=0·030) with the triplet FOLFOXIRI plus bevacizumab compared with the doublet FOLFIRI (fluorouracil, leucovorin, irinotecan) plus bevacizumab; however, an increased incidence of specific grade 3 and 4 adverse events (diarrhoea, stomatitis, and neutropenia) was reported following FOLFOXIRI.1, 2 Notably, because the treatment used after progression was left to the investigators' choice and collected as post-study treatments in the TRIBE study,1, 2 the efficacy of the triplet compared with exposure to the same drugs in a sequential strategy of less toxic doublets was not shown.⁹ Furthermore, despite the significant improvement in overall survival with the intensified chemotherapy backbone, some concerns have been raised regarding the feasibility and efficacy of treatments after progression following the upfront exposure to the three cytotoxic drugs.

Research in context

Evidence before this study

A previous phase 3 trial (TRIBE study) by the Italian GONO Foundation suggested the superiority of the first-line triplet regimen FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) over the doublet FOLFIRI (fluorouracil, leucovorin, and irinotecan) when bevacizumab was added to both regimens in patients with unresectable metastatic colorectal cancer. On the basis of these results, FOLFOXIRI plus bevacizumab is supported by all major clinical guidelines as a valuable first-line option for patients with metastatic colorectal cancer patients, selected according to the pivotal TRIBE study criteria. However, some concerns have been raised about the use of FOLFOXIRI in daily practice, including the actual benefit of the exposure to all the three cytotoxic agents compared with the preplanned sequential administration of the same drugs in oxaliplatin-based doublets and irinotecan-based doublets, and the feasibility and the efficacy of treatments after progression. We searched PubMed from inception until July 30, 2019, with the terms “FOLFOXIRI”, “triplet”, “doublets”, “FOLFOX”, “XELOX”, “FOLFIRI”, “XELIRI”, “bevacizumab”, “reintroduction”, “second-line”, “strategy trial”. Only publications in English were considered. We found only a few reports that retrospectively described a favourable outcome of second-line therapies, including the reintroduction of the triplet, given following disease progression after first-line FOLFOXIRI in non-randomly assigned subgroups, and no trials that prospectively compared the efficacy of the upfront use of FOLFOXIRI versus a standard sequential strategy of oxaliplatin-based doublets and irinotecan-based doublets.

Added value of this study

We provide additional evidence of the effect of the upfront use of FOLFOXIRI plus bevacizumab on the survival of patients with unresectable metastatic colorectal cancer, showing its superiority compared with a sequential strategy of doublets plus bevacizumab. The efficacy of treatments after progression to FOLFOXIRI plus bevacizumab is clear, and the beneficial effect of the reintroduction of the triplet in selected patients is suggested, to our knowledge, for the first time.

Implications of all the available evidence

On the basis of these results, upfront FOLFOXIRI plus bevacizumab followed by the reintroduction of the same regimen in case of disease progression seems to be an optimal therapeutic option for patients with metastatic colorectal cancer who meet the study inclusion criteria.

Over the past few years, new recommendations were formulated on the basis of results from clinical trials of maintenance strategies and treatments after progression: following a 4–6 month first-line treatment with a combination chemotherapy regimen plus bevacizumab, maintenance with a fluoropyrimidine plus bevacizumab until disease progression is recommended,10, 11, 12, 13 and the continuation of angiogenesis inhibition beyond disease progression is a valuable option supported by evidence from phase 3 trials.14, 15

From these considerations, the TRIBE2 study was designed to verify whether the upfront exposure to the three cytotoxic drugs in the FOLFOXIRI regimen was superior to a preplanned sequence of doublets (first-line mFOLFOX6 [fluorouracil, leucovorin, and oxaliplatin], followed by FOLFIRI after disease progression), with a sustained inhibition of angiogenesis with bevacizumab in both groups. Therefore, upfront FOLFOXIRI plus bevacizumab is compared with an oxaliplatin-based doublet instead of an irinotecan-based doublet plus bevacizumab as done in the previous TRIBE study.1, 2