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Wednesday, July 30, 2025

VEGF/VEGFR inhibitors


Vascular Endothelial Growth Factor and VEGF Receptor Inhibitors

VEGF/VEGFR inhibitors are a class of targeted anticancer and anti-angiogenic agents that inhibit the vascular endothelial growth factor (VEGF) or its receptors (VEGFR). VEGF is a key signaling protein involved in angiogenesis, the process of new blood vessel formation. Tumors exploit this pathway to promote vascular supply, enabling continued growth, invasion, and metastasis. Inhibiting the VEGF-VEGFR axis starves tumors of nutrients and oxygen, leading to growth arrest and apoptosis.

This drug class includes monoclonal antibodies, soluble decoy receptors, and small-molecule tyrosine kinase inhibitors (TKIs). These agents are widely used in the treatment of solid tumors, hematologic malignancies, and ocular diseases such as age-related macular degeneration (AMD).

Biological Basis of VEGF and VEGFR

  • VEGF Ligands: Include VEGF-A (main mediator), VEGF-B, VEGF-C, VEGF-D, and placental growth factor (PlGF)

  • VEGFRs: Three primary receptors—VEGFR-1 (Flt-1), VEGFR-2 (KDR/Flk-1), and VEGFR-3—located on endothelial cells

  • VEGF-A and VEGFR-2 interaction: Primary driver of pathological angiogenesis in cancer

Mechanism of Action
VEGF/VEGFR inhibitors block this pathway through one or more of the following:

  1. Ligand inhibition: Monoclonal antibodies that bind VEGF ligands and prevent receptor activation

  2. Receptor blockade: Antibodies or soluble receptors that prevent VEGF from binding to VEGFR

  3. Intracellular inhibition: TKIs that inhibit VEGFR-associated tyrosine kinase activity, blocking downstream signaling cascades (e.g., PI3K/Akt, MAPK/ERK)

Therapeutic Applications

  1. Solid Tumors

    • Metastatic colorectal cancer (mCRC)

    • Non-small cell lung cancer (NSCLC)

    • Renal cell carcinoma (RCC)

    • Hepatocellular carcinoma (HCC)

    • Glioblastoma multiforme (GBM)

    • Cervical and ovarian cancers

    • Pancreatic neuroendocrine tumors

    • Differentiated thyroid cancer

  2. Hematologic Malignancies

    • Some subtypes of lymphoma, leukemia (less common)

  3. Ophthalmology (VEGF-A-specific agents)

    • Wet age-related macular degeneration (wAMD)

    • Diabetic macular edema (DME)

    • Retinal vein occlusion (RVO)

    • Myopic choroidal neovascularization

Approved Generic Drugs in VEGF/VEGFR Inhibitor Class

1. Monoclonal Antibodies (mAbs)

  • Bevacizumab

    • Generic: Bevacizumab

    • Brand: Avastin® (and biosimilars: Mvasi®, Zirabev®)

    • Mechanism: Binds VEGF-A, preventing receptor activation

    • Indications: mCRC, NSCLC, GBM, RCC, cervical cancer, ovarian cancer

    • Route: Intravenous infusion

  • Ramucirumab

    • Generic: Ramucirumab

    • Brand: Cyramza®

    • Mechanism: Fully human IgG1 mAb that targets VEGFR-2

    • Indications: Gastric cancer, NSCLC, HCC, colorectal cancer

    • Route: Intravenous

  • Faricimab

    • Generic: Faricimab-svoa

    • Brand: Vabysmo®

    • Mechanism: Dual inhibitor of VEGF-A and Angiopoietin-2 (Ang-2)

    • Indications: wAMD, DME (ophthalmic use)

    • Route: Intravitreal injection

  • Ranibizumab

    • Generic: Ranibizumab

    • Brand: Lucentis®, Byooviz® (biosimilar)

    • Mechanism: Inhibits VEGF-A (fragment of bevacizumab, ophthalmic only)

    • Indications: wAMD, DME, RVO, myopic CNV

    • Route: Intravitreal injection

2. VEGF-Trap / Fusion Protein

  • Aflibercept

    • Generic: Aflibercept

    • Brand: Eylea® (Zaltrap® in oncology)

    • Mechanism: Fusion protein of VEGFR-1 and VEGFR-2 extracellular domains with IgG1 Fc—acts as a decoy receptor

    • Indications:

      • Eylea®: wAMD, DME, RVO

      • Zaltrap®: mCRC (combined with FOLFIRI)

    • Route: Intravitreal (Eylea), IV (Zaltrap)

3. Small-Molecule Tyrosine Kinase Inhibitors (TKIs)

These orally administered agents inhibit VEGFR tyrosine kinase activity (often multi-targeted):

a. Sunitinib

  • Generic: Sunitinib malate

  • Brand: Sutent®

  • Targets: VEGFR-1/2/3, PDGFR, c-Kit

  • Indications: RCC, GIST, pNET

  • Route: Oral

b. Sorafenib

  • Generic: Sorafenib tosylate

  • Brand: Nexavar®

  • Targets: VEGFR-2/3, PDGFR, Raf kinase

  • Indications: HCC, RCC, DTC

  • Route: Oral

c. Pazopanib

  • Generic: Pazopanib hydrochloride

  • Brand: Votrient®

  • Targets: VEGFR-1/2/3, PDGFR, c-Kit

  • Indications: RCC, soft tissue sarcoma

  • Route: Oral

d. Axitinib

  • Generic: Axitinib

  • Brand: Inlyta®

  • Targets: Potent VEGFR-1/2/3 inhibition

  • Indications: RCC (second-line)

  • Route: Oral

e. Lenvatinib

  • Generic: Lenvatinib mesylate

  • Brand: Lenvima®

  • Targets: VEGFR-1/2/3, FGFR, PDGFRα, RET, KIT

  • Indications: DTC, RCC, HCC, endometrial carcinoma

  • Route: Oral

f. Cabozantinib

  • Generic: Cabozantinib

  • Brand: Cabometyx®, Cometriq®

  • Targets: VEGFRs, MET, AXL

  • Indications: RCC, HCC, medullary thyroid carcinoma

  • Route: Oral

g. Regorafenib

  • Generic: Regorafenib

  • Brand: Stivarga®

  • Targets: VEGFRs, PDGFR, FGFR, BRAF, KIT

  • Indications: mCRC, GIST, HCC

  • Route: Oral

h. Vandetanib

  • Generic: Vandetanib

  • Brand: Caprelsa®

  • Targets: VEGFR-2, RET, EGFR

  • Indications: Medullary thyroid cancer

  • Route: Oral

Formulations and Administration

  • Monoclonal antibodies: Administered via intravenous infusion (e.g., bevacizumab, ramucirumab)

  • Fusion proteins (e.g., aflibercept): Intravenous (oncology) or intravitreal (ophthalmology)

  • TKIs: Oral tablets/capsules, usually taken daily with/without food

  • Ophthalmic formulations: Intravitreal injection every 4–12 weeks depending on agent and indication

Contraindications

  • Hypersensitivity to the active substance or excipients

  • Recent history of arterial thromboembolism (for bevacizumab and some TKIs)

  • Poorly controlled hypertension

  • Active or recent gastrointestinal perforation or fistula (particularly with bevacizumab)

  • Pregnancy (teratogenicity risk)

Warnings and Precautions

  • Hemorrhage and bleeding risk: Especially GI and CNS hemorrhage

  • Hypertension: Requires monitoring and management during therapy

  • Wound healing complications: Delay surgery; do not administer perioperatively

  • Proteinuria: Monitor renal function regularly

  • Arterial thromboembolic events: Stroke, myocardial infarction

  • QT prolongation: Especially with vandetanib

  • Hand-foot syndrome (palmar-plantar erythrodysesthesia): Common with TKIs

  • Thyroid dysfunction: Hypothyroidism with sunitinib and others

Adverse Effects

CategoryExamples
CardiovascularHypertension, thromboembolism, heart failure
GastrointestinalDiarrhea, stomatitis, perforation, hemorrhage
DermatologicRash, hand-foot syndrome, dry skin
RenalProteinuria, nephrotic syndrome
HematologicLeukopenia, thrombocytopenia, bleeding
EndocrineHypothyroidism, adrenal insufficiency
Ocular (for ophthalmic use)Conjunctivitis, eye pain, increased IOP



Drug Interactions

  • CYP3A4 Inhibitors/Inducers (for TKIs)

    • Inhibitors (e.g., ketoconazole): Increase TKI plasma concentration → toxicity

    • Inducers (e.g., rifampin): Reduce efficacy

  • Antihypertensives: May be required concurrently; monitor BP

  • Anticoagulants/NSAIDs: Increase bleeding risk when combined

  • Other anti-angiogenics: Combined toxicity risk

  • QT-prolonging drugs: Avoid with vandetanib and others with cardiac risk

Special Populations

  • Elderly: Increased risk of toxicity (bleeding, hypertension)

  • Hepatic impairment: TKIs require dose adjustment or avoidance

  • Pregnancy: Category D/X – contraindicated due to fetal developmental effects

  • Breastfeeding: Discontinue due to risk of infant exposure

  • Renal impairment: Adjustments needed for some agents (e.g., sunitinib)

Monitoring Parameters

  • Blood pressure (before and during treatment)

  • Proteinuria (urinalysis)

  • Thyroid function (TSH)

  • Liver enzymes and renal function

  • ECG (QT prolongation with some agents)

  • CBC (myelosuppression with TKIs)

  • Imaging (tumor response, hemorrhage, GI perforation risk)

Emerging Agents and Ongoing Trials

  • Tivozanib: Potent VEGFR-1/2/3 TKI with favorable safety in RCC

  • Combinations: VEGF inhibitors with immune checkpoint inhibitors (e.g., atezolizumab + bevacizumab for HCC)

  • Next-generation bispecific antibodies and VEGF trap variants

  • Biomarker-driven therapy: Identification of predictive biomarkers for VEGF-inhibitor efficacy (e.g., VEGF-A levels, tumor perfusion metrics)



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