• cetuximab
• first-line induction
• FOLFOXIRI
• maintenance.
• metastatic colorectal cancer
• RAS and BRAF

Background: The combination of triple chemotherapy regimens with an anti-EGFR monoclonal antibody (moAb) reported promising activity with some safety concerns in phase II trials. MACBETH trial aimed at evaluating the activity and safety of first-line modified FOLFOXIRI (mFOLFOXIRI) plus cetuximab and at exploring the role of maintenance with cetuximab or bevacizumab in metastatic colorectal (mCRC) patients. The study initially enrolled KRAS wild-type patients and after an amendment in October 2013 only RAS and BRAF wild-type.
Patients and methods: Eligibility criteria included measurable, unresectable, RAS and BRAF wild-type mCRC, age 18-75 years. Patients were randomized 1:1 to receive up to 8 cycles of first-line induction with mFOLFOXIRI plus cetuximab repeated every 2 weeks, followed by maintenance with cetuximab (arm A) or bevacizumab (arm B) until progression. MACBETH was a phase II randomized non-comparative study, with primary endpoint 10 months-Progression Free Rate (10m-PFR).
Results: Between October 2011 and March 2015, 323 patients from 21 Italian centers were screened. Out of 143 randomized patients, 116 were RAS and BRAF wild-type and were included in the modified ITT (mITT) population, evaluable for primary and secondary endpoints. At a median follow-up of 40.0 months, 10m-PFR were 50.9% and 40.4% in arm A and B, respectively. Objective response rate was 71.6%; 45 patients (38.8%) underwent secondary surgery of metastases, and R0 resection was achieved in 33 cases (28.4%). Among patients with liver-only disease, the R0 resection rate was 51.9%. Main grade 3-4 adverse events during induction treatment were neutropenia (31.0%), diarrhea (18.1%), skin toxicity (15.5%), asthenia (9.5%), stomatitis (6.0%), and febrile neutropenia (2.6%).
Conclusions: Neither of the two arms met the primary endpoint. However, four months-induction with mFOLFOXIRI plus cetuximab is feasible and has relevant activity, leading to high conversion rate. Continuing cetuximab as maintenance until progression seems to affect positively progression-free survival.