aflibercept

**Mechanism:** Aflibercept is a soluble decoy receptor. It combines VEGFR-1 (Flt-1) domain 2 and VEGFR-2 (KDR/Flk-1) domain 3 with the Fc region of IgG1. It binds VEGF-A, VEGF-B, and PlGF with higher affinity than native receptors, so these ligands can't activate endogenous VEGFR-1/2. This reduces angiogenesis, vascular permeability, and neovascularization. By contrast, bevacizumab and ranibizumab bind only VEGF-A.

**Indications:** - Ophthalmology (intravitreal, Eylea): wet AMD (choroidal neovascularization), diabetic macular edema, diabetic retinopathy, macular edema after retinal vein occlusion, and retinopathy of prematurity (in some regions). Higher-dose formulations (8 mg) allow longer dosing intervals. Biosimilars are now available. - Oncology (IV, Zaltrap): metastatic colorectal cancer, resistant to or progressed after an oxaliplatin-containing regimen, given with FOLFIRI (5-FU, leucovorin, irinotecan).

**Adverse effects:** - Intravitreal: endophthalmitis, retinal detachment or tear, increased intraocular pressure, conjunctival hemorrhage, cataract, and a theoretical risk of arterial thromboembolic events. - IV (anti-VEGF class effects): hypertension, proteinuria/nephrotic syndrome, hemorrhage, GI perforation, impaired wound healing, arterial thromboembolism, and reversible posterior leukoencephalopathy syndrome (RPLS/PRES). Also neutropenia and diarrhea when combined with FOLFIRI.

**Clinical pearls and board associations:** - Wet AMD involves choroidal neovascularization driven by VEGF. Dry AMD (drusen, geographic atrophy) is more common and has no anti-VEGF therapy. - Anti-VEGF class drugs: bevacizumab (anti-VEGF-A mAb; colorectal cancer, NSCLC non-squamous, glioblastoma, RCC, cervical and ovarian cancer), ranibizumab and brolucizumab (intravitreal fragments), and aflibercept (fusion "trap"). Ramucirumab targets VEGFR-2. Tyrosine kinase inhibitors such as sunitinib, sorafenib, and pazopanib also act on VEGFR. - Stop IV anti-VEGF agents before elective surgery because of impaired wound healing, and avoid them in patients with recent hemorrhage, an unhealed wound, or GI perforation. - Classic stem: an elderly patient with sudden central vision loss and metamorphopsia (distorted straight lines on an Amsler grid), with subretinal fluid or hemorrhage. The treatment is intravitreal anti-VEGF. - Pharmacology categories: biologic, recombinant fusion protein, angiogenesis inhibitor.