Study rationale

The association of FOLFOX (5-fluoruracil, folinic acid, and oxaliplatin) and panitumumab is a standard option for the first-line treatment of unresectable RAS and BRAF wt mCRC patients. The phase III TRIBE trial demonstrated that FOLFOXIRI (5-fluoruracil, folinic acid, oxaliplatin and irinotecan) plus bevavizumab significantly prolongs PFS and OS and increases RECIST response rate, ETS and DoR, as compared to FOLFIRI (5-fluoruracil folinic acid, and irinotecan) plus bev. The advantage provided by the intensification of the upfront chemotherapy backbone is independent of RAS and BRAF mutational status. Some phase II trials recently assessed the safety and activity of the combination of three-drugs chemotherapy regimens with an anti-EGFR monoclonal antibody. Promising activity results in terms of RECIST response rate and R0 resection rate have been achieved, with some safety concerns with special regards to gastrointestinal toxicity. In the phase II randomized MACBETH study the combination of a modified schedule of FOLFOXIRI with cetuximab determined remarkable activity results, with an acceptable and manageable safety profile. Activity parameters (RECIST response rate, ETS, DoR) are clinically relevant endpoints, associated with longer survival, in particular with anti-EGFR moAb-based treatment. On the basis of these considerations, we designed the present phase III randomized trial of first-line mFOLFOXIRI plus pan versus mFOLFOX6 plus pan in RAS and BRAF wt unresectable mCRC patients.

Study objective

The primary objective of this trial is to compare the activity of pan in combination with mFOLFOX6 or with mFOLFOXIRI in RAS and BRAF wt mCRC patients in terms of Overall Response Rate according to RECIST version 1.1 (ORR).