The starting point of the TRIBE-2 study was the first TRIBE study that was conducted by the GONO group where metastatic colorectal cancer patients previously untreated for their metastatic disease were randomised to receive FOLFOXIRI/bevacizumab or FOLFIRI/bevacizumab as up front option. The study met its primary endpoint demonstrating a better response rate, PFS and OS with the triplet, however, some concerns still exist in the scientific community with regard to the adoption of this up front regimen that is a more intensified regimen than conventional doublet. These concerns include the feasibility and the efficacy of treatments after progression as well as the actual superiority of administering the three cytotoxics up front instead of in a pre-planned sequential strategy of first and second line.
Meanwhile, some important achievements were reported with regard to the efficacy of the inhibition of angiogenesis in colorectal cancer, the role of maintenance and the efficacy of anti-angiogenics beyond progression. Drawing from these considerations we designed the TRIBE-2 study that is a strategy trial, always from the GONO group, by the GONO group in Italy, who are untreated metastatic colorectal cancer patients randomised to two different strategies – a standard strategy TML like, first line doublet FOLFOX/bevacizumab followed after progression by FOLFIRI/bevacizumab or an experimental strategy, up front FOLFOXIRI/bevacizumab followed after progression by the reintroduction of the same agents. The primary endpoint is PFS2, the time from randomisation until the second evidence of disease progression in order to properly assess the efficacy of the whole first and second line strategy.
How was the management of adverse events in the experimental arm?
Actually we confirm in this study that FOLFOXIRI plus bevacizumab is associated with a higher incidence of some specific chemotherapy related adverse events especially in terms of diarrhoea and neutropenia. However, the management of these adverse events is not different than what we are able to do in our daily clinical practice with doublets. There is a higher incidence but not a higher seriousness of diarrhoea or neutropenia. Actually also the incidence of febrile neutropenia is around 7%, that is much below the threshold for the use of prophylactic GCSF.
When it comes to the endpoints, they were met and everyone came away happy?
Yes, the study was positive and the primary endpoint, PFS2, was met. Actually patients in the experimental strategy derived a significant benefit when compared with those in the standard strategy. Also results in terms of first line, response rate and first PFS with FOLFOXIRI plus bevacizumab are highly consistent with those already achieved in the previous TRIBE study, thus confirming the magnitude of benefit of the intensification of the up-front chemotherapy backbone.
So based on these results the take home message is that actually starting the therapeutic route of metastatic colorectal cancer patients with FOLFOXIRI plus bevacizumab is able to provide a long-term benefit and that the concern with regard to the superiority of the triplet when compared to the pre-planned sequential strategy of exposure to the same agents is a winning strategy. So the up-front intensified regimen has a good impact on metastatic colorectal cancer patients’ outcome.
