Exploratory pooled analysis evaluating the effect of sequence of biological therapies on overall survival in patients with RAS wild-type metastatic colorectal carcinoma

Background The aim of this study was to evaluate the optimal sequence of targeted therapies (epidermal growth factor receptor inhibitors (EGFRi) and vascular endothelial growth factor inhibitors (VEGFi)), combined with chemotherapy, in patients with RAS wild-type (WT) metastatic colorectal carcinoma (mCRC). Exploratory analyses of overall survival (OS) for patients treated with either first-line panitumumab (EGFRi) and second-line VEGFi therapy, or first-line bevacizumab (VEGFi) and second-line EGFRi, were conducted. Methods Patients from PEAK (NCT00819780), PRIME (NCT00364013) and Study 181 (NCT00339183), with RAS WT or RAS WT/ BRAF WT tumours, were included in the analyses. OS data were pooled for patients receiving first-line panitumumab (PEAK and PRIME) or first-line bevacizumab (PEAK and 181), followed by second-line VEGFi or EGFRi, respectively. Results Overall, 104 RAS WT patients were included (n=66 panitumumab→VEGFi, n=38 bevacizumab→EGFRi). At the time of final data analysis, 63.6% versus 92.1% of patients in the panitumumab→VEGFi versus bevacizumab→EGFRi arms had died; median OS was 36.8 versus 27.8 months, respectively (HR 0.65; 95% CI 0.42 to 1.03). The OS HR for patients with RAS WT/ BRAF WT mCRC overall was 0.58 (95% CI 0.36 to 0.95) and was 0.56 (95% CI 0.30 to 1.04) in those with left-sided tumours. Conclusion Although numbers are small, these exploratory analyses suggest a trend towards improved OS for first-line panitumumab plus chemotherapy followed by second-line VEGFi, compared with first-line bevacizumab followed by second-line EGFRi in patients with RAS WT and RAS WT/ BRAF WT mCRC. Large prospective randomised trials are needed to further evaluate the optimum sequence of EGFRi/VEGFi in mCRC.