• mCRC

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, L-leucovorin, and irinotecan) plus bevacizumab. However, the actual benefit of the upfront exposure to the three cytotoxics when compared with a pre-planned 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 an unmasked web-based allocation procedure to two different strategies: first-line mFOLFOX6 (85 mg/m² of intravenous oxaliplatin concurrently with 200 mg/m² of L-leucovorin over 120 minutes; 400 mg/m² intravenous bolus of fluorouracil; 2400 mg/m² continuous infusion of fluorouracil for 48 hours) plus bevacizumab (5 mg/kg intravenously over 30 minutes) followed by FOLFIRI (180 mg/m² of intravenous irinotecan over 120 minutes concurrently with 200 mg/m² of L-leucovorin; 400 mg/m² intravenous bolus of fluorouracil; 2400 mg/m² continuous infusion of fluorouracil for 48 hours) plus bevacizumab (5 mg/kg intravenously over 30 minutes) after disease progression (control group) or FOLFOXIRI (165 mg/m² of intravenous irinotecan over 60 minutes; 85 mg/m² intravenous oxaliplatin concurrently with 200 mg/m² of L-leucovorin over 120 minutes; 3200 mg/m² continuous infusion of fluorouracil for 48 hours) plus bevacizumab (5 mg/kg intravenously over 30 min) followed by the reintroduction of the same regimen after disease progression (experimental group). Combination treatments were administered up to 8 bi-weekly cycles followed by fluorouracil/L-leucovorin (same dose administered at the last induction cycle) 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. The trial is registered at Clinicaltrials.gov: NCT02339116.

Results
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). Most patients had ECOG Performance Status 0 (582 [86%] of 679), presented with synchronous metastases (604 [89%] of 679), and had a RAS (436 [64%] of 679) or BRAF mutated (66 [10%] of 679) tumour, while only a minority (109 [16%] of 679) had a left-sided and RAS and BRAF wild-type 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). During the first-line treatment, grade 3–4 adverse events were reported in 229 (68%) of 336 patients in the experimental group, and 155 (46%) of 336 in the control group (p<0·001). Higher incidences of all-cause grade 3-4 diarrhoea (57 [17%] of 336 vs 18 [5%] of 336, p<0·001), neutropenia (168 [50%] of 336 vs 71 [21%] of 336, p<0·001) and febrile neutropenia (22 [7%] of 336 vs 10 [3%] of 336, p=0·045) were reported in the experimental group. Serious adverse events occurred in 84 (25%) of 336 patients in the experimental group and in 56 (17%) of 336 patients in the control group. Eight treatment-related deaths were reported in the experimental group (two intestinal occlusions, two perforations, two sepsis, one myocardial infarction and one bleeding) and four in the control group (two occlusions, one perforation, one pulmonary embolism).

Conclusions
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.