TRIBE2: Latest data for patients with mCRC

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Published: 15 Jul 2019
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Dr Chiara Cremolini - Università di Pisa, Pisa, Italy

Dr Chiara Cremolini speaks to ecancer at ESMO 21st World Congress on Gastrointestinal Cancer about the TRIBE2 updated results.

She reports that the trial met its primary endpoint of prolonged second progression-free survival in the arm of unresectable metastatic colorectal cancer (mCRC) patients treated with upfront FOLFOXIRI plus bevacizumab followed by the pre-planned reintroduction of the same agents after disease progression.

Dr Cremolini outlines how the toxicity profiles varied and what these latest results mean for clinical practice in the future.


The TRIBE2 study is a non-profit, academic trial conducted in Italy. 56 oncology units throughout Italy took part in the study. It was conceived in order to answer some frequently asked questions with regard to the use of the triplet FOLFOXIRI plus bevacizumab as an up-front option for metastatic colorectal cancer. In particular some concerns with regards to the adoption of this regimen in daily clinical practice deal with the efficacy and the feasibility of treatment after progression and the actual superiority of exposing the patients to the three cytotoxics in first line instead of in a pre-planned sequence of doublets.

The TRIBE2 study was designed and conducted to answer this question. In order to properly assess the whole efficacy of the first and second line treatment strategy patients were randomised to receive a standard TML-like treatment, FOLFOX/bevacizumab, then followed after progression by FOLFIRI/bevacizumab, or an experimental strategy – FOLFOXIRI/bevacizumab and then after progression the reintroduction of the same agents. In order to assess the efficacy of the whole strategy PFS2, progression free survival 2, was identified as the primary endpoint of the study, that is the time from randomisation until the second evidence of disease progression on any treatment given after first progression.

The trial met its primary endpoint. A preliminary interim analysis was already presented at the last ESMO Congress , now we have the final analysis with regards to the primary endpoint clearly showing an advantage in the arm treated with a triplet as up-front regimen. We also have a preliminary overall survival analysis which is quite interesting, it includes the 60% of death events and patients in the experimental arm achieved a significant benefit also in terms of overall survival with a median difference as an absolute value of 5 months between the two treatment strategies in favour of starting the therapeutic route with FOLFOXIRI plus bevacizumab.

How did the toxicity profiles vary in this latest set of results?

Data with regard to the toxicity profile confirmed that the triplet is associated with an increased risk of experiencing some chemotherapy-related adverse events. This is well-known, well-established also in the previous trials conducted not only in Italy but worldwide with this kind of regimen. Now we have another piece of information, that when in the second line treatment we want to reintroduce the triplet, and we will be keen to reintroduce the triplet in those patients who had a good tolerance in first line, then the toxicity profile is quite manageable. In fact, in the second line analysis of patients treated with the pre-protocol planned treatment, which is FOLFIRI/bevacizumab in the control arm and FOLFOXIRI/bevacizumab in the experimental arm, the triplet is not associated with an increase in adverse events except for neurotoxicity. Clearly this does not mean that the triplet is not more toxic than a doublet in second line but that if we properly identify those patients who experienced good tolerance and probably also good efficacy of this therapeutic regimen as first line then it is also feasible to reintroduce FOLFOXIRI/bevacizumab in second line and there is also a modest advantage in terms of second progression free survival.

What did you do about the patients who didn’t respond particularly well to first-line treatment?

Those patients who do not achieve any kind of benefit, they are the so-called early progressors and they are luckily a small amount of patients, just a small percentage, less than 10%, then probably they would not have achieved benefit also from one doublet in first line and the other doublet in second line. For these patients the best choice is enrolment in clinical trials and trying to exploit such an aggressive disease with such an aggressive behaviour with a targeted strategy based on deeper molecular characterisation of the tumour profile. We also have advanced line options such as regorafenib or trifluridine-tipiracil, although honestly I do not expect so much benefit from these kinds of options for patients with primary refractory to the triplet plus bevacizumab.

What will the latest results mean for clinical practice in the next year or two?

These results that actually confirm the safety and efficacy of FOLFOXIRI/bevacizumab as an up-front option, there will be a wider use of this first line treatment regimen especially in those patients with a right-sided and/or a RAS or BRAF mutant tumour. We know that today, to make it very simple, patients with left-sided tumours and RAS and BRAF wildtype are probably the best candidates for first line doublet plus anti-EGFR. For all the other patients who have more aggressive disease based on the primary tumour location and the RAS and BRAF mutational status probably trying to counteract the biological aggressiveness of this disease with a triplet plus bevacizumab may be a good option. Clearly we have to carefully select the patients to use this kind of first line option based on their general conditions and their comorbidities, expectations. So this is not a regimen for everyone but 80% of patients included in the TRIBE2 study had a right-sided and/or a RAS or BRAF mutant tumour. So in this population we will recognise the best candidates to receive first line FOLFOXIRI plus bevacizumab.