Aflibercept: Indications and Uses
Aflibercept is a recombinant fusion protein VEGF inhibitor approved for two distinct clinical contexts: (1) second-line treatment of metastatic colorectal cancer in combination with FOLFIRI after oxaliplatin failure, and (2) intravitreal treatment of retinal vascular diseases including diabetic retinopathy, diabetic macular edema, age-related macular degeneration, and retinal vein occlusion. 1
Mechanism of Action
Aflibercept functions as a soluble decoy receptor that binds with high affinity to VEGF-A, VEGF-B, and placental growth factor (PlGF), thereby preventing activation of VEGF receptors 1 and 2 on endothelial cells. 1 This blockade inhibits neovascularization and vascular permeability, which are pathological processes in both cancer angiogenesis and retinal diseases. 1
Oncology Indications
Metastatic Colorectal Cancer (mCRC)
Aflibercept combined with FOLFIRI is indicated specifically for second-line treatment in patients with mCRC that has progressed after oxaliplatin-containing regimens. 2
The VELOUR phase III trial demonstrated that aflibercept plus FOLFIRI improved overall survival by 1.44 months compared to FOLFIRI alone (13.5 vs 12.06 months; HR 0.817, p=0.0032), with additional improvements in progression-free survival and response rates. 2, 3
This benefit was observed regardless of whether patients received prior bevacizumab in first-line treatment. 2
Aflibercept is particularly considered in RAS-mutated tumors with rapid progression on first-line bevacizumab, as the VELOUR trial specifically included such patients. 2
Current guidelines prefer bevacizumab over aflibercept in second-line treatment due to superior tolerability and cost considerations, positioning aflibercept as an alternative when bevacizumab is contraindicated or has failed. 2
Toxicity Profile in Oncology
Aflibercept carries both VEGF-class toxicities and amplifies chemotherapy-related adverse events. 2
VEGF-related toxicities include hypertension, proteinuria, arterial thrombosis, mucosal bleeding, gastrointestinal perforation, and wound healing complications. 2
Chemotherapy-related toxicities are increased compared to chemotherapy alone, particularly diarrhea, neutropenia, asthenia, and stomatitis. 2
In the VELOUR trial, 83% of aflibercept patients experienced serious adverse events versus 62% in the placebo group. 4
Ophthalmology Indications
Diabetic Retinopathy and Diabetic Macular Edema
The FDA has approved aflibercept for treatment of diabetic retinopathy, administered as 2 mg (0.05 mL) intravitreal injection. 2, 5
Initial dosing consists of monthly injections for the first 5 doses, followed by every 8 weeks. 5
For proliferative diabetic retinopathy (PDR), aflibercept represents an alternative to traditional panretinal photocoagulation, with evidence supporting safety and efficacy through at least 2 years. 5
Anti-VEGF therapy requires more frequent visits and injections compared to laser photocoagulation, which may impact treatment adherence. 2
For center-involved diabetic macular edema with moderate visual impairment (20/50 or worse), aflibercept provides superior vision outcomes compared to bevacizumab. 2
Age-Related Macular Degeneration and Retinal Vein Occlusion
Aflibercept is effective for neovascular age-related macular degeneration (nAMD) and macular edema secondary to retinal vein occlusion. 2, 6
The COPERNICUS and GALILEO studies demonstrated 15-letter gains in 56% of aflibercept-treated eyes with central retinal vein occlusion versus 12% with sham injections. 2
The SCORE2 trial showed aflibercept was similar to bevacizumab for macular edema from central retinal vein occlusion at 6 months. 2
For branch retinal vein occlusion, anti-VEGF agents including aflibercept are preferred initial therapy due to favorable risk-benefit profiles compared to corticosteroids or laser. 2
Intravitreal Administration Considerations
The 8 mg intravitreal formulation (EYLEA HD) achieves peak plasma concentrations of free aflibercept at median 2.9 days, with minimal systemic accumulation. 1
Systemic exposure following intravitreal administration is substantially lower than oncologic dosing, with median time to non-quantifiable plasma concentrations of 3.5 weeks. 1
No dose adjustment is required for renal or hepatic impairment in ophthalmic use. 1
Common ocular adverse events include endophthalmitis, cataract formation, retinal detachment, and elevated intraocular pressure, though meta-analyses show no increased arterial thromboembolic events. 2
Clinical Caveats
Aflibercept is contraindicated in pregnancy due to embryofetal toxicity, with fetal malformations observed at all doses in animal studies. 1 Females of reproductive potential require effective contraception during treatment and for 4 months after the last dose. 1
In oncology, there are no validated predictive molecular markers for aflibercept response. 2
Aflibercept should not be used in first-line mCRC, as the AFFIRM study showed no benefit with increased toxicity. 2
For ophthalmic use, ongoing treatment may be necessary even after resolution of macular edema in patients with active proliferative disease. 5
Regular monitoring with follow-up intervals less than 1 month is essential for active proliferative diabetic retinopathy. 5