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 by GONO

Background: The triplet FOLFOXIRI (fluorouracil, L-leucovorin, oxaliplatin, and irinotecan) plus bevacizumab showed improved outcomes of patients with metastatic colorectal cancer, when compared to FOLFIRI (fluorouracil, Lleucovorin, and irinotecan) plus bevacizumab. However, the actual benefit of the upfront exposure to the three cytotoxics when compared with a preplanned sequential strategy of doublets was not clear, as well as the feasibility and efficacy of therapies after progression. To this purpose, we aimed at comparing a pre-planned strategy of upfront FOLFOXIRI followed by the reintroduction of the same regimen after disease progression to a sequence of mFOLFOX6 (fluorouracil, L-leucovorin, and oxaliplatin) and FOLFIRI doublets, in combination with bevacizumab. Methods: TRIBE2 was an open-label, prospective, phase 3 randomised study of patients (aged 18-70 years with Eastern Cooperative Oncology Group [ECOG] performance status of 2 or less and aged 71-75 years with an ECOG performance status of 0), with unresectable, previously untreated metastatic colorectal cancer, who were recruited from 58 Italian Oncology Units. Patients were stratified according to center, ECOG performance status, primary tumour location and previous adjuvant chemotherapy, and randomly assigned (1:1) via a web-based procedure to two different strategies: first-line mFOLFOX6 plus bevacizumab followed by FOLFIRI plus bevacizumab after disease progression (control group) or FOLFOXIRI plus bevacizumab followed by the reintroduction of the same regimen after disease progression (experimental group). Combination treatments were administered up to 8 cycles followed by fluorouracil/L-leucovorin plus bevacizumab maintenance until disease progression, unacceptable adverse events, or consent withdrawal. Both patients and investigators were aware of treatment assignment. The primary endpoint was progression-free survival 2, defined as the time from randomization to disease progression on any treatment given after first disease progression or death, analysed by intention to treat. Safety was assessed in the population of patients who received at least one dose of their assigned treatment. The study recruitment was completed, and follow-up of participants is still ongoing. Findings: Between February 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). 81% of enrolled patients had a right-sided and/or RAS or BRAF mutated tumour. At data cut-off (July 30, 2019) the 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 (95% CI 15·1-17·5) in the control group (hazard ratio [HR] 0·74, 95% CI 0·63-0·88; p<0·001). Median 1st progression-free survival was 12·0 months (95% CI 11·1-12·9) with FOLFOXIRI plus bevacizumab and 9·8 months (95% CI 9·0-10·5) with mFOLFOX6 plus bevacizumab (HR 0·74, 95% CI 0·63-0·86, p<0·001). Higher incidences of grade 3 or 4 diarrhoea (17% vs 5%, p<0·001), neutropenia (50% vs 21%, p<0·001) and febrile neutropenia (7% vs 3%, p=0·045) were reported in the experimental group. Out of 570 patients alive at the time of disease progression, 82% and 88% received a treatment after progression in the experimental and in the control group, respectively. Median 2nd progression-free survival was 6·2 months (95% CI 5·6-6·6) in the experimental group and 5·6 months (95% CI 4·9-6·4) in the control group, (HR 0·87, 95% CI 0·73-1·04; p=0·116). Median overall survival was 27·4 months (95% CI 23·7-30·0) in the experimental group and 22·5 months (95% CI 20·7-24·8) in the control group (HR 0·82, 95% CI 0·68-0·98; p=0·032). Interpretation: Upfront FOLFOXIRI plus bevacizumab followed by the reintroduction of the same regimen in case of disease progression is the best therapeutic strategy for patients with metastatic colorectal cancer selected according to the study criteria and particularly for those with rightsided and/or a RAS or BRAF mutated tumours. Trial Registration: The trial is registered at Clinicaltrials.gov: NCT02339116. Funding Statement: Supported by the GONO and the ARCO Foundations. A research grant was provided by F. Hoffmann-La Roche. Declaration of Interests: CCr received personal fees from Roche, Amgen, Bayer, Servier, research funding from Merck Serono, and has a consulting or advisory role with Roche, Bayer, Amgen. DR received personal fees from Takeda. SL received personal fees from Roche, Lilly, Bristol-Myers Squibb, Servier, Merck Serono, research funding from Amgen, Merck Serono, and has a consulting or advisory role with Amgen, Merck Serono, Lilly, Servier. FL received personal fees from Roche, Sanofi, Bayer, Amgen, research funding from Roche, Merck Serono, Amgen, Bayer, and has a consulting or advisory role with Amgen, Sanofi, Bayer, Amal. FP received personal fees from Amgen, Merck Serono, Roche, Sanofi, Bayer, Servier, Lilly, research funding from Bristol-Myers Squibb, and has a consulting or advisory role with Amgen, Merck Serono, Bayer, Lilly, Sanofi, Roche, Servier. RB received personal fees from and has a consulting or advisory role with Bayer, AstraZeneca, Sanofi, Novartis, Amgen, Roche, Pfizer, Jansen, Bristol-Myers Squibb. GA received personal fees from and has consulting or advisory role with Merck Serono, Amgen, Roche, Servier. AZ received personal fees from and has consulting or advisory role with Amgen, Bayer, Lilly, Merck Serono, Servier, Sanofi. SCo received personal fees from Roche, Sanofi, Servier, Merck Serono, Lilly, research funding from Roche, Merck Serono, Amgen, Servier, Lilly, has a consulting or advisory role with Amgen, Sanofi, Bayer, Servier, Merck Serono, Ipsen. VZ received personal fees from Bayer, Roche, Bristol-Myers Squibb, Astellas Pharma, Servier, AstraZeneca, Lilly, research funding from Bayer (Inst), Roche (Inst), Lilly (Inst), Bristol-Myers Squibb (Inst), Ipsen (inst), Astellas Pharma (Inst) has a consulting or advisory role with Bristol-Myers Squibb, Merck Serono. AF received personal fees from Roche, Amgen, Merck Serono, Celgene, Bayer, Sanofi, research funding from Roche (Inst), Amgen (Inst), Merck Serono (inst). CA, TPL, ET, DS, AP, FM, RG, SMu, CG, AB, RM, SC, LA, GT, GM, MR, SDD, CCa, MC, GR, AM, MR, SCu, SMa, EF, EC, GF, CU, LB report no competing interests. Ethics Approval Statement: The study was conducted in accordance with the Declaration of Helsinki and adhered to Good Clinical Practice guidelines. Approval for the protocol was obtained from local ethics committees of participating sites. All patients provided written informed consent to study procedures before enrollment.