FOLFOXIRI/bevacizumab versus doublets/bevacizumab as initial therapy of unresectable liver-only, right-sided and/or RAS or BRAF mutated metastatic colorectal cancer: An individual patient data-based pooled analysis of randomized trials

Background: Upfront FOLFOXIRI/bevacizumab is associated with better outcome over doublets/bevacizumab in metastatic colorectal cancer (mCRC), independently of the presence of liver-only disease and the secondary resection of metastatic lesions. Limited data are available about the comparison of these two regimens in patients with initially unresectable liver-only mCRC who represent the optimal candidates according to primary tumour sidedness and/or RAS and BRAF mutational status. Methods: We performed an individual patient data pooled analysis of four phase II or III randomized trials (TRIBE [NCT00719797], TRIBE2 [NCT02339116], CHARTA [NCT01321957], STEAM [NCT01765582]) to compare efficacy, activity and safety of first-line FOLFOXIRI/bevacizumab versus doublets/bevacizumab in patients with initially unresectable liver-only, right-sided and/or RAS or BRAFV600E mutated mCRC. Results: Among 300 eligible patients, 130 (43 %) and 170 (57 %) received doublets/bevacizumab and FOLFOXIRI/bevacizumab, respectively. Median follow-up was 40.1 months (IQR: 32.7–50.0). Patients receiving FOLFOXIRI/bevacizumab showed longer PFS (median, 12.3 vs 10.3 months, HR:0.75, P = 0.019) with a non-significant OS advantage (median, 29.1 vs 23.3 months, HR:0.85, P = 0.253), than those treated with doublets/bevacizumab. FOLFOXIRI/bevacizumab was also associated with numerically higher ORR (64 % vs 53 %, OR:1.54, P = 0.076) and higher rates of grade 3–4 neutropenia (44 % versus 22 %, P < 0.0001) and diarrhoea (19 % versus 4 %, P < 0.0001), while no difference in R0 resection rate (27 % vs 24 %, OR:1.15, P = 0.696) was reported. No significant interaction was found between treatment effect and the achievement of R0 resection (PFS Pinteraction=0.808, OS Pinteraction= 0.530). Conclusions: As compared to doublets/bevacizumab, FOLFOXIRI/bevacizumab provides a meaningful PFS and ORR advantage among patients with initially unresectable, liver-only, right-sided and/or RAS or BRAFV600E mut mCRC, independently of achieving R0 resection or not, thus corroborating the choice of this regimen as upfront treatment for these patients.