Sequential cetuximab/bevacizumab therapy is associated with improved outcomes in patients with wild‐type KRAS exon 2 metastatic colorectal cancer

PURPOSE: Combination of biological therapy and chemotherapy improves the survival of patients with metastatic colorectal cancer (mCRC). However, the optimal biological therapy sequence remains unclear. In this retrospective study, we evaluated the clinical outcomes of patients with mCRC treated with different sequences of biological therapies as first‐ and third‐line therapy. METHODS: We only included patients with wild‐type KRAS exon 2 mCRC who had received cetuximab, bevacizumab, and standard chemotherapy. The patients were treated with cetuximab or bevacizumab as first‐ or third‐line therapy combined with a similar chemotherapy backbone. RESULTS: In total, 102 patients were included. Forty‐six patients received first‐line cetuximab therapy followed by third‐line bevacizumab therapy (cetuximab → bevacizumab group) and 56 patients received first‐line bevacizumab therapy followed by third‐line cetuximab therapy (bevacizumab → cetuximab group). The cetuximab → bevacizumab group was associated with increased survival (OS) compared with the bevacizumab → cetuximab group (median OS: 30.4 months vs 25.7 months, hazard ratio (HR): 0.55, 95% confidence interval (CI): 0.36‐0.86). When calculated from the start of second‐ and third‐line therapies, OS was also higher in the cetuximab → bevacizumab group (second‐line: 20.6 months vs 14.8 months, HR: 0.54, 95% CI: 0.34‐0.81; third‐line: 12.5 months vs 9.9 months, HR: 0.53, 95% CI: 0.35‐0.83). The cetuximab → bevacizumab group was also associated with better progression‐free survival than the bevacizumab → cetuximab group (8.8 vs 4.5 months, HR: 0.43, 95% CI: 0.25‐0.58) in the third‐line setting, but not in the first‐ or second‐line settings. CONCLUSIONS: Our study demonstrated that first‐line cetuximab therapy followed by third‐line bevacizumab therapy was associated with favorable clinical outcomes as compared to the reverse sequence.