Updated results from TRIBE, a phase III study performed by the Italian research group, Gruppo Oncologico Nord Ovest (GONO), in patients with metastatic colorectal cancer (mCRC), indicate that FOLFOXIRI in combination with bevacizumab is superior to FOLFIRI/bevacizumab. Compared to the FOLFIRI combination regimen with bevacizumab, the FOLFOXIRI/bevacizumab extended overall survival (OS) by 4 months and doubled the 5-year OS rate. The study was presented at 2015 Gastrointestinal Cancers Symposium (15-17 January 2015, San Francisco, USA).
The study confirms findings from a previous, smaller phase III GONO study which showed that FOLFOXIRI alone improved survival compared with FOLFIRI alone in the first-line treatment of mCRC.
The TRIBE trial met its primary endpoint by demonstrating that first-line FOLFOXIRI/bevacizumab significantly prolongs progression-free survival, as compared to FOLFIRI/bevacizumab. Also response rate according RECIST, early response rate and depth of response were significantly increased. At the first statistical analysis, with a median follow-up of 32.2 months, OS results were considered preliminary.
In the study, 508 patients with mCRC were randomly assigned between July 2008 and May 2011 to induction therapy consisting of FOLFIRI/bevacizumab or FOLFOXIRI/bevacizumab. Up to 12 cycles of induction therapy were planned, followed by maintenance treatment with bevacizumab in combination with 5-fluorouracil, until disease progression. In about 80% of the patients, the cancer was not confined to the liver, and surgery was not feasible in most of them. Similar numbers of patients in both groups (15% in the FOLFOXIRI/bevacizumab group, 12% in the FOLFIRI/bevacizumab group) were able to undergo radical resection after the induction therapy.
The results presented at 2015 Gastrointestinal Cancers Symposium considered follow-up of included patients for a median period of 48.1 months. The median OS was significantly improved in the FOLFOXIRI/bevacizumab group compared to the FOLFIRI/bevacizumab group (29.8 vs. 25.8 months, p = 0.030). The estimated 5-years OS rate of patients treated with FOLFOXIRI/bevacizumab was equal to 24.9%, with an absolute benefit of 12.5% compared to controls.
Among clinical variables, ECOG performance status of 1 or 2, right-sided primary tumour, synchronous metastases, disease not confined to the liver, unresected primary tumour, high Kohne score negatively affected prognosis at univariate analyses. At an exploratory model accounting for these variables, adjusted hazard ratio for treatment effect on OS was 0.77 (p=0.020).
“This new approach offers a substantial survival improvement, even for patients with a rather unfavorable prognosis. This is a remarkable step forward in the treatment of this disease,” said in accompanied press release presenting author Dr. Chiara Cremolini, a medical oncologist at the Azienda Ospedaliero-Universitaria Pisana Istituto Toscano Tumori in Pisa, Italy. “We believe that our results will encourage clinicians to adopt the FOLFOXIRI regimen with bevacizumab as an upfront therapy option for patients in otherwise good health.”
While FOLFOXIRI increased the risks of diarrhoea and neutropenia compared to FOLFIRI, serious adverse events were not increased. Dr. Cremolini noted that, while many patients are able to tolerate FOLFOXIRI, it is an intensive regimen and should not be given to all patients, such as those older than 75 and those between 70 and 75 who are not in good general condition.
TRIBE-2, the follow-on phase III trial to the current study, is being launched in Italy by the GONO group. In this study, 654 patients will be randomised to receive first-line FOLFOXIRI plus bevacizumab followed by either reintroduction of FOLFOXIRI plus bevacizumab at disease progression or FOLFOX plus bevacizumab followed by FOLFIRI plus bevacizumab at progression.
Ongoing phase II trials, MACBETH and MOMA, are exploring strategies to shorten the duration of initial chemotherapy (from 6 to 4 months) and improve efficacy of the maintenance treatment. In the MACBETH study FOLFOXIRI is being tested in combination with cetuximab.
The study was supported by the GONO and the ARCO Foundation. A research grant was provided by F. Hoffmann–La Roche.