In the Italian phase III TRIBE2 trial reported in The Lancet Oncology, Cremolini et al found that reintroduction of FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab after progression on upfront treatment with the regimen was associated with improved progression-free survival 2—the time from randomization to disease progression on any treatment given after first disease progression or death—vs the sequence of modified (m) FOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) and FOLFIRI (fluorouracil, leucovorin, and irinotecan) doublets in combination with bevacizumab in patients with previously untreated metastatic colorectal cancer.
As stated by the investigators, “The triplet FOLFOXIRI plus bevacizumab showed improved outcomes for patients with metastatic colorectal cancer, compared with FOLFIRI 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.”
Study Details
In the open-label multicenter trial, 679 patients were randomly assigned between February 2015 and May 2017 to a control group (n = 340) or an experimental group (n = 339). The control group received mFOLFOX6 plus bevacizumab followed by FOLFIRI plus bevacizumab after disease progression. The experimental group received FOLFOXIRI plus bevacizumab followed by 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 plus bevacizumab maintenance until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival 2.
Progression-Free Survival 2
At data cutoff (July 2019), the median follow-up was 35·9 months. Median progression-free survival 2 was 19.2 months in the experimental group vs 16.4 months in the control group (hazard ratio [HR] = 0.74, P = .0005). Median progression-free survival 1 was 12.0 months vs 9.8 months (HR = 0.74, P = .0002).
Objective response to first-line treatment was observed in 62% of patients in the experimental group vs 50% in the control group (odds ratio = 1.61, P = .0023). Median overall survival was 27.4 months in the experimental group vs 22.5 months in the control group (HR = 0.82, P = .032).
Toxicity
For the experimental vs control group, the most common grade 3 or 4 adverse events during first-line treatment were diarrhea (17% vs 5%), neutropenia (50% vs 21%), and arterial hypertension (7% vs 10%). Serious adverse events occurred in 25% vs 17% of patients. Treatment-related death occurred in eight patients in the experimental group (two each due to intestinal occlusion, intestinal perforation, and sepsis; and one each due to myocardial infarction bleeding) and in four patients in the control group (two due to intestinal occlusion and one each due to intestinal perforation and pulmonary embolism).
After first disease progression, there were no substantial differences in frequency of grade 3 or 4 adverse events, except for a higher incidence of neurotoxicity in the experimental group (5% vs 0%). Serious adverse events occurred in 15% vs 12% of patients after first disease progression. Treatment-related death occurred in three patients in the experimental group (two due to intestinal occlusion and one due to sepsis) and in four patients in the control group (one each due to intestinal occlusion, intestinal perforation, cerebrovascular event, and sepsis).
The investigators concluded: “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.”
Alfredo Falcone, MD, of Azienda Ospedaliera-Universitaria Pisana, Pisa, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by the GONO Cooperative Group, the ARCO Foundation, and F. Hoffmann-La Roche. For full disclosures of the study authors, visit thelancet.com.
