As such, http://www.selleckchem.com/products/Tipifarnib(R115777).html aflibercept 4 mg/kg dose level was selected as for further development in combination with irinotecan, 5-FU and

leucovorin (41,42,44). The pharmacokinetic studies showed that aflibercept’s elimination half-life ranged from less than 1-3 days for free aflibercept and was approximately 18 days for VEGF-bound aflibercept (41,48). The benefit of aflibercept in combination with FOLFIRI was confirmed in the pivotal phase III VELOUR trial. In the study, patients with metastatic CRC previously Inhibitors,research,lifescience,medical treated with oxaliplatin-containing regimen, irregardless of prior bevacizumab treatment, were randomly assigned to received aflibercept 4 mg/kg IV every 2 weeks or placebo combination with FOLFIRI. Overall response rate was 19.8% in the aflibercept arm compared to 11.1% in the placebo (P=0.0001).

Compared to the control group, the aflibercept-containing arm had better PFS (6.9 vs. 4.67 months; HR 0.758; P<0.0001) and OS (13.5 vs. 12.06 months; HR 0.817; P=0.0032). Pre-planned subgroup Inhibitors,research,lifescience,medical analysis showed that prior bevacizumab use did not influence aflibercept’s effect on PFS and OS though the study was not powered to show a treatment difference between arms (9,18). Toxicities related to aflibercept Inhibitors,research,lifescience,medical were consistent with those expected from the anti-VEGF drug class (49). When compared to the bevacizumab-related toxicity profile reported in the phase III trial of IFL with or without bevacizumab, the frequency of grade 3 or 4 proteinuria seemed to be higher for aflibercept Inhibitors,research,lifescience,medical than bevacizumab (7.5% vs. 0.8%) though risks for Grade 3 or 4 bleeding (2.8% vs. 3.1%) and hypertension (11% vs. 11%) seemed similar (9,21). Together with the results from ML18147 study, clinicians now have the option of using aflibercept or bevacizumab with FOLFIRI in mCRC patients who

progressed following oxaliplatin containing regimen. The benefit achieved by aflibercept and bevacizumab in second-line setting seemed comparable: in ML18147 study, continuing bevacizumab into second-line Inhibitors,research,lifescience,medical while switching the cytotoxic chemotherapy achieved a median OS improvement of 1.4 Afatinib months (HR 0.81, 95% CI: 0.69-0.94; P=0.0062) (25) whilst the addition of aflibercept to FOLFIRI in the VELOUR trial achieved a comparable median OS survival improvement of 1.4 months (HR 0.817, 95.34% CI: 0.713-0.937; P=0.0032) (9). The frequency of vascular-related GSK-3 adverse events seemed to be higher with aflibercept than bevacizumab treatment when comparing across trials. Cost is another consideration: aflibercept treatment costs, in average, $11,063 per month, which is more than twice as high as bevacizumab therapy. As such, aflibercept is not recommended routinely in metastatic CRC patients who progressed on oxaliplatin-containing treatment until more evidence available.