A phase III multicenter trial comparing two different sequences of second/third line therapy (irinotecan/cetuximab followed by FOLFOX-4 vs. FOLFOX-4 followed by irinotecan/cetuximab in K-RAS wt metastatic colorectal cancer (mCC) patients refractory to FOLFIRI/Bevacizumab

Background: Improvements in survival have been reported in mCC with the addition of bevacizumab or cetuximab to chemotherapy. However, their efficacy in different therapy lines and the optimal sequence are still controversial. While bevacizumab seems to lose its efficacy along the course of treatment lines, cetuximab is active even in 2degree and 3degree line therapy. We designed a randomised, phase III study to compare efficacy and safety of two different sequences of Cetuximab or FOLFOX to optimize the treatment of mCC pts refractory to FOLFIRI/bevacizumab. Methods: Pts were randomised in a 1:1 ratio to receive as 2degree or 3degree line cetuximab/irinotecan followed by FOLFOX‐4 (Arm A) or FOLFOX‐4 followed by cetuximab/irinotecan (Arm B). Primary end point was progression free survival (PFS); secondary end points were overall survival and toxicity. Results: 109 mCC pts were enrolled and 108 were evaluable for analysis. 63 patients were males and 45 females, with a median age of 61 years. Efficacy results are reported in the table. Treatments were well tolerated with a low number of serious adverse reactions in both arms (8 and 4, respectively), even if grade 3‐4 toxicity was overall higher in cetuximab treatment.Conclusions: While the primary end point was not met (PFS was not statistically different), FOLFOX seems to be more effective than cetuximab (overall survival: 18.6 months vs 12.4 months) as 2degree line treatment in patients receiving bevacizumab/FOLFIRI. This seems to confirm preclinical and clinical (FIRE‐3) data suggesting that a prior anti‐VEGF therapy may determine a lower sensitivity to a subsequent anti‐EGFR treatment.