• maintenance
• FOLFOXIRI plus bevacizumab
• metronomic chemotherapy

Background: Alternating induction and maintenance phases is a common strategy in the treatment of metastatic colorectal cancer (mCRC) patients. The repeated and protracted administration of low doses of cytotoxic agents with no free intervals, defined as metronomic chemotherapy (metroCT), may represent a well-tolerated chemotherapy backbone for maximizing bevacizumab effect. The MOMA study investigated whether the addition of metroCT to bevacizumab as maintenance treatment following 4 months of upfront therapy with FOLFOXIRI plus bevacizumab could improve PFS of mCRC patients.
Patients and methods: In this phase II study, patients with unresectable mCRC were randomized to receive up to 8 cycles of FOLFOXIRI plus bevacizumab, followed by bevacizumab (arm A), or the same induction followed by bevacizumab plus metroCT (capecitabine 500 mg/three times per day and cyclophosphamide 50 mg/die, arm B) until disease progression. The primary endpoint was progression-free survival (PFS).
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.
Results: Between May 2012 and March 2015, 232 patients, mostly with RAS (65%) or BRAF (9%) mutant tumours, were randomized in 16 Italian centers.
At a median follow up of 47.8 months (IQR 36.2-55.3), 210 and 164 progression and death events were registered. The primary endpoint was not met: median PFS arm B/A: 10.3 / 9.4 months, (HR: 0.94, [70%CI: 0.82-1.09], p=0.680). No significant differences were reported in terms of overall survival (OS) (median OS arm B/A: 22.5 / 28 months; HR: 1.16 [95%CI: 0.99-1.37], p=0.336).
No interaction effect between treatment arm and RAS/BRAF status or tumour sidedness was associated in PFS or OS.
The proportion of patients who achieved objective response with FOLFOXIRI plus bevacizumab was 63% in the overall population (arm B/A: 58%/68%). In terms of secondary surgery on metastatic sites with curative intent, the resection rate was 49% in the liver only subgroup, with no differences between the two arms.
Main grade 3/4 adverse events were manageable and similar between arms during induction; the incidence of hand&foot syndrome was significantly higher in the arm B during maintenance.
Conclusions; The addition of metroCT to maintenance with bevacizumab 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 bevacizumab are confirmed with a shorter treatment duration (4-months).