FOLFOXIRI plus bevacizumab (bev) followed by maintenance with bev alone or bev plus metronomic chemotherapy (metroCT) in mCRC: Final results of the phase II randomized MOMA trial by GONO
Authors: F. Marmorino, C. Cremolini, F. Bergamo, N. Pella, C. Antoniotti, D. Rossini, E. Dell'Aquila, G. Masi, L. Salvatore, F. Loupakis, L. Marcucci, D. Gemma, G. Cardellino, B. Borelli, V. Ricci, S. Delfanti, E. Mori, G. Tonini, S. Lonardi, G. Fontanini, L. Boni, A. Falcone
Journal: Annals of Oncology (2018)

Introduction: The MOMA study investigated whether the addition of metroCT to bev as maintenance treatment following 4 months of upfront therapy with FOLFOXIRI plus bev could improve PFS of mCRC patients. From May 2012 to March 2015, 232 patients, mostly RAS (65%) or BRAF (9%) mutant, were randomized in 16 Italian centers. The primary endpoint was not met. Here we provide final clinical results of the study including OS findings, subgroup analyses and treatments after progression. Methods: Patients with unresectable mCRC were randomized 1:1 to receive up to 8 cycles of FOLFOXIRI plus bev, followed by bev (arm A), or the same induction followed by bev plus metroCT (capecitabine 500 mg/tid and cyclophosphamide 50 mg/die per os, arm B) until disease progression (PD). According to the comparative Rubinstein and Korn's design, estimating a first-line PFS of 11 months, to detect a HR of 0.75 favoring arm B, with 1 sided-alpha and beta errors of 15% and 80%, 173 events were required. In the case of PD during maintenance, the re-introduction of FOLFOXIRI plus bev or of a modified FOLFOXIRI plus bev regimen (i.e. FOLFOXIRI/FOLFOX or FOLFIRI plus bev) was recommended up to 4 cycles, followed by maintenance, according to randomization arm. Results: At a median follow up of 43.9 months, 210 and 164 progression and death events were registered. No significant differences between arms were reported in terms of PFS (median PFS arm A/B: 9.4 / 10.3 months; HR: 0.94 [70%CI: 0.82-1.09], p = 0.680) and OS (median OS arm A/B: 28 / 22.5 months; HR: 1.16 [70%CI: 0.99-1.37], p = 0.336). Response rate with FOLFOXIRI plus bev was 63% (arm A/B: 68%/57%). No interaction effect between treatment arm and RAS/BRAF status or tumour sidedness was reported in PFS or OS. In the overall study population median PFS among RAS/BRAF wt (N = 36), RAS mutant (N = 150) and BRAF mutant (N = 20) patients were 10.2, 10.1 and 9.4 months (log-rank test, p = 0.759) and median OS were 31.3, 24.9 and 19.2 months, respectively (log-rank test, p = 0.457). 152 (72%) out of 210 patients with progression event received a treatment after PD. In 87 (57%) and 44 (29%) cases FOLFOXIRI plus bev or modified FOLFOXIRI plus bev were re-introduced, respectively. Main grade 3/4 adverse events occurring during the reintroduction of FOLFOXIRI plus bev were neutropenia (20%), diarrhea (9%), stomatitis (3%), vomiting (2%), hypertension (1%), and venous thrombosis (1%). Conclusion: The addition of metroCT to maintenance with bev does not significantly improve PFS or OS of mCRC patients irrespective of their RAS/BRAF mutational status and tumour sidedness. Activity results of FOLFOXIRI plus bev are confirmed with a shorter treatment duration (4-months). Outcome results in the BRAF mutant subgroup are consistent with previous findings with the triplet plus bev. Re-introduction of FOLFOXIRI plus bev was feasible and associated with a favourable safety profile.