Original ResearchTreatment sequence with either irinotecan/cetuximab followed by FOLFOX-4 or the reverse strategy in metastatic colorectal cancer patients progressing after first-line FOLFIRI/bevacizumab: An Italian Group for the Study of Gastrointestinal

•The effect of introducing in second or third-line cetuximab after a progression to FOLFIRI/bevacizumab.•No difference in progression-free survival among the two sequences.•A trend for a better overall survival for cetuximab third-line.•An observed reduced activity of cetuximab after a first-line bevacizumab-based therapy.•This reduced activity may have relevant therapeutic consequences in patients with left tumours.

IntroductionThe optimal treatment strategy for RAS wild type (WT) mCRC is controversial. Our phase III study investigated the effect of introducing earlier (second-line) or later (third-line) cetuximab in patients progressed after FOLFIRI/bevacizumab first-line.Patients and methodsmCRC patients progressing after FOLFIRI/bevacizumab first-line were randomised to receive second-line irinotecan/cetuximab followed by third-line FOLFOX-4 (arm A) or the reverse sequence (arm B). Primary end-point was progression-free survival (PFS).ResultsAbout 54 and 56 patients were randomised in arm A and in arm B, respectively. After a median follow-up of 37.5 months, 100 PFS events were recorded. Median PFS was 9.9 months in arm A and 11.3 months in arm B (Hazard ratio [HR] 1.04, 95% confidence interval [CI]: 0.69-1.56, p = 0.854), while median overall survival was 12.3 months in arm A and 18.6 months in arm B (HR 0.84, 95% CI: 0.55-1.28; p = 0.411). No overall difference in side-effects were observed between the two treatment arms.ConclusionsThis trial did not meet the primary end-point (PFS). Like other preclinical and clinical evidences, our study seems to suggest a reduced activity of cetuximab after a first-line bevacizumab-based therapy.