According to the results of TRIBE2, a phase 3 trial (NCT02339116), the triplet treatment FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) in combination with bevacizumab has been shown to be more effective in treating patients with metastatic colorectal cancer before and after disease progression compared with sequential administration of chemotherapy doublets plus bevacizumab.
Patients aged 18 to 75 years with an Eastern Cooperative Oncology Group (ECOG) performance status of 2, with unresectable, previously untreated metastatic colorectal cancer were enrolled in this study, results of which are published in The Lancet Oncology. In a 1:1 ratio, 679 patients were randomly assigned to either receive an experimental or control treatment. The control treatment consisted of mFOLFOX6 (oxaliplatin/leucovorin/fluorouracil/bevacizumab) followed by FOLFIRI (irinotecan/leucovorin/fluorouracil/bevacizumab) after disease progression. For the experimental treatment, patients were administered FOLFOXIRI (irinotecan/oxaliplatin/leucovorin/fluorouracil/bevacizumab) followed by reintroduction of the same regimen once disease progression occurred. Every 14 days, combination treatments were repeated for up to eight cycles. After, fluorouracil and leucovorin were administered at the same dose as the last induction cycle in combination with bevacizumab maintenance. Treatment continued unless disease progression, unacceptable adverse events, or consent withdrawal occurred. Progression-free survival 2 (PFS2), defined as the time from randomization to disease progression on any treatment given after first disease progression or death, was the primary endpoint.
After a median follow-up of 35.9 months, median PFS2 was higher in the experimental group compared with the control group (19.2 months vs 16.4 months). Grade 3/4 treatment-related events included diarrhea (17% vs 5%), neutropenia (50% vs 21%), and arterial hypertension (7% vs 10%) in the experimental versus control group. Death occurred in 8 patients in the experimental group including two intestinal occlusions, two intestinal perforations, two sepsis, one myocardial infarction, and one bleeding. Four deaths occurred in the control group which involved two occlusions, one perforation, and one pulmonary embolism. No significant differences were found in the incidence of grade 3/4 side effects between the experimental and control groups, except for neurotoxicity (5%), which was reported solely in the experimental group after disease progression. In 15% of patients in the experimental group and 12% in the control group, serious adverse events occurred after disease progression, and three treatment-related deaths happened in the experimental group (two intestinal occlusions and one sepsis), while four occurred in the control group (one intestinal occlusion, one intestinal perforation, one cerebrovascular event, and one sepsis).
The study authors conclude, "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."
For More Information
Cremolini C, Antoniotti C, Rossini D, et al (2020). 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 multicenter, open-label, phase 3, randomized, controlled trial. Lancet Oncol. [Epub ahead of print] DOI:10.1016/S1470-2045(19)30862-9
Image Courtesy of Mikael Haggstrom, MD. Licensed under CC0