Bevacizumab is a humanized anti-vascular endothelial growth factor (VEGF) monoclonal antibody, approved in combination with chemotherapy in the treatment of mCRC. It is proposed that the schedule of administration might be critical and that anticipating bevacizumab to chemotherapy, might improve treatment efficacy.
mCRC patients, ≤ 75 years old, ECOG PS ≤ 1, having received no more than one previous treatment, with at least one measurable lesion according to RECIST, were randomized (1:1) to receive standard administration of bevacizumab (5mg/kg d1 Q14) with chemotherapy (mFOLFOX/OXXEL regimen for 12 cycles) vs experimental bevacizumab given 4 days before chemotherapy (same dose), at each cycle. Patients could receive maintenance bevacizumab (7.5 mg/kg d1 Q21) until disease progression or unacceptable toxicity in both arms. Primary end point was the objective response rate (ORR). With 80% power and 2-tailed alpha 0.05, an expected 20% increase in response rate, 230 patients were planned. With 163 events, the study also had 80% power to detect a hazard ratio (HR) 0.64 of progression-free survival. Analyses were based on intention to treat.
From May 2012 to Dec 2015, 230 patients were randomly assigned to experimental (n = 115) and standard (n = 115) arm. Median age was 62 (IQ range 53-68), 79% were PS 0, 93% were not pretreated, 53% had a single metastatic site, 54% were RAS-mutant (47% and 62% in the standard and experimental arm, respectively). ORR was 54% in both arms (p = 0.89). With a median follow-up of 32.4 months, 204 PFS events and 131 deaths were reported. Median PFS was 10.5 and 11.7 months (HR 0.79, 95% CI: 0.60-1.05; multivariate adjusted p = 0.10) and median OS was 23.7 and 29.9 months (HR 0.73, 95% CI: 0.52-1.04; multivariate adjusted p = 0.08), in the standard and experimental arm, respectively. 57.4% and 59.1% of the patient received a following treatment in the standard and experimental arm, respectively.
Anticipating bevacizumab to chemotherapy does not improve ORR. A not statistically significant prolongation of PFS and OS was reported in this study. Supported by the Italian Ministry of Health. CT.gov NCT01718873.
Clinical trial identification
EudraCT Number: 2011-004997-27
Legal entity responsible for the study
Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale
Italian Ministry of Health
A. Avallone: Travel, accommodation: Roche and Amgen; honoraria for consulting: Bayer, Roche and Amgen. F. Perrone: Travel, accommodation: Roche, Lilly, Bayer, Daiichi Sankyo; honoraria: Amgen, Novartis, Lilly, Roche, Bayer, Daiichi Sankyo; research funding to institution: Roche and Bayer. M.C. Piccirillo: Travel, accommodation: Roche and Bayer; honoraria for consulting: Bayer. All other authors have declared no conflicts of interest.