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.
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 / Antoniotti C., Marmorino F., Rossini D., Schmoll H.J., Lonardi S., Tonini G., Borelli B., Cupini S., Stein A., Moretto R., Bergamo F., Ronzoni M., Germani M.M., Zaniboni A., Fazio R., De Grandis M.C., Ongaro E., Masi G., Cremolini C.. - In: EUROPEAN JOURNAL OF CANCER. - ISSN 0959-8049. - ELETTRONICO. - 228:(2025), pp. 115713.0-115713.0. [10.1016/j.ejca.2025.115713]
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
Rossini D.;
2025
Abstract
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.
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