VEGF inhibitors

Mechanism & Class Overview

• Class mechanism: Target VEGF-A or VEGF receptors (VEGFR1/2/3) → inhibit angiogenesis, ↓ vascular permeability (transient vascular normalization, improving perfusion), ↓ endothelial integrity.
• Resistance: ↑ other VEGF isoforms (B, C, D), ↑ HGF, ↑ FGF, ↑ alternative angiogenic pathways.

VEGF-Pathway Class Adverse Effects

• Whether the agent is an antibody, a ligand trap, or a VEGFR-TKI, the shared "AEs due to VEGF inhibition" recur: hypertension (control BP before and during treatment), arterial thromboembolism (MI, stroke/TIA; arterial > venous), proteinuria (agent-specific thresholds: bevacizumab hold at ≥2 g/24h; VEGFR-TKIs per their own labels, e.g. pazopanib ≥3 g/24h; discontinue for nephrotic syndrome), hemorrhage (agent/indication-specific: avoid after recent serious hemoptysis; pazopanib not studied if hemoptysis/cerebral/clinically significant GI hemorrhage within 6 months), GI perforation, impaired wound healing (hold around surgery), and RPLS/PRES (AMS, headache, vision changes, seizures).

Anti-VEGF Monoclonal Antibody

Bevacizumab (Avastin)

• Mechanism: mAb against VEGF-A → ↓ angiogenesis, ↓ vascular permeability (transient vascular normalization, improving perfusion).
• Indications: CRC, NSCLC (nonsquamous), ovarian, cervical, renal cell cancer, recurrent glioblastoma, HCC (with atezolizumab). The breast cancer indication was revoked by FDA in 2011.
• Pharmacokinetics: Half-life 15 to 20 days; metabolism not well characterized.
• Toxicities: Withhold ≥28 days (4 wks) before elective surgery; do not resume for ≥28 days after major surgery and until adequate wound healing (↓ wound healing). Bleeding (minor, most commonly grade 1 epistaxis; serious/fatal hemorrhage is pulmonary, GI, or CNS, discontinue for grade 3 to 4; ↑ risk of fatal hemoptysis in squamous NSCLC so avoid (phase 2, Johnson JCO 2004; squamous then excluded from E4599, Sandler NEJM 2006)), ↑↑↑ HTN (20 to 30% of patients; control BP pre-treatment), GI perforation, hold for proteinuria ≥ 2 g/24h; discontinue for nephrotic syndrome, doubled arterial thromboembolic events (CAD, CVA/TIA; ↑ risk age >65, history of CVD), ↑ VTE (arterial > venous), RPLS/PRES (AMS, headache, vision changes/loss, seizures).

VEGF Receptor Tyrosine Kinase Inhibitors

Sunitinib (Sutent)

• Mechanism: Multi-targeted TKI; inhibits VEGFR (1, 2, 3), PDGFR (α and β), c-KIT, FLT3, RET, CSF1R.
• Indications: Renal cell cancer (metastatic or adjuvant), GIST (after imatinib progression), pancreatic neuroendocrine tumors.
• Pharmacokinetics: Hepatic metabolism (CYP3A4, ~60% hepatic elimination; no starting-dose adjustment for Child-Pugh A or B; not studied in Child-Pugh C); half-life 2 to 3 days; may take with food. Interactions: azoles, protease inhibitors, grapefruit/starfruit/pomelo ↑ toxicity; rifampin, phenytoin, St. John's Wort ↓ levels. RCC/GIST: 50 mg daily, 4 weeks on / 2 weeks off. Pancreatic NET: 37.5 mg daily continuously (no scheduled break).
• Toxicities: Myelosuppression, cardiotoxicity (↓ EF; baseline and follow-up TTE; caution within 12 months of CAD/MI/unstable angina/CABG, do not start in symptomatic CHF), hepatotoxicity/jaundice, ↑ QT, HTN, hand-foot syndrome, diarrhea, adrenal and thyroid dysfunction (check cortisol and TSH).

Pazopanib (Votrient)

• Mechanism: Multi-targeted TKI; inhibits VEGFR (1, 2, 3), PDGFR-α/β, FGFR-3, c-KIT, ITK, LCK, cFms.
• Indications: Renal cell cancer, soft tissue sarcoma.
• Pharmacokinetics: Hepatic metabolism (CYP3A4); inhibits UGT1A1 (↑ irinotecan toxicity). Half-life ~30h.
• Toxicities: ↑↑ LFTs (boxed warning; mainly ALT elevation; monitor frequently early on; hold if ALT >8× ULN), ↑ QT (periodic EKG; monitor electrolytes), hypothyroidism (monitor TSH), mild myelosuppression. VEGF-related: HTN, arterial thrombosis (MI, stroke/TIA), proteinuria, hemorrhagic events (avoid if hemoptysis/GI bleed within 6 months).

Axitinib (Inlyta)

• Mechanism: VEGFR-selective TKI; inhibits VEGFR 1, 2, 3 (more selective than sunitinib/pazopanib).
• Indications: Renal cell cancer (advanced).
• Toxicities: HTN (monitor BP regularly; dose adjust for uncontrolled HTN), diarrhea, fatigue, dysphonia, proteinuria, hand-foot syndrome.

Cabozantinib (Cometriq, Cabometyx)

• Mechanism: Multi-targeted TKI; inhibits VEGFR (1, 2, 3), MET, AXL, RET.
• Indications: Renal cell cancer, medullary thyroid cancer, hepatocellular carcinoma.
• Toxicities: Hand-foot syndrome (major; often dose-limiting), diarrhea, HTN, ↑ LFTs, fatigue, proteinuria, appetite suppression.

Lenvatinib (Lenvima)

• Mechanism: Multi-targeted TKI; inhibits VEGFR (1, 2, 3), FGFR (1, 2, 3, 4), RET, KIT, PDGFR.
• Indications: Thyroid cancer (refractory), renal cell cancer (with everolimus), hepatocellular carcinoma, endometrial cancer.
• Toxicities: ↑↑↑ HTN (often severe; check BP weekly initially), diarrhea, fatigue, hand-foot syndrome, appetite suppression, proteinuria, ↑ LFTs, thyroid dysfunction.

Regorafenib (Stivarga)

• Mechanism: Multi-targeted TKI; inhibits VEGFR 1 to 3, FGFR, RET, KIT, PDGFR, BRAF.
• Indications: CRC (refractory), hepatocellular carcinoma, GIST.
• Toxicities: Hand-foot syndrome (severe, often dose-limiting), diarrhea, fatigue, HTN, ↑ LFTs, rash.

Sorafenib (Nexavar)

• Mechanism: Multi-targeted TKI; inhibits VEGFR 1/2/3, PDGFR-β, c-KIT, FLT3, RET, RAF kinase (wt- and mutant-BRAF, c-RAF).
• Indications: Hepatocellular carcinoma, renal cell cancer, differentiated thyroid cancer.
• Pharmacokinetics: Hepatic metabolism (CYP3A4, UGT1A9); take without food (fatty food ↓ absorption); avoid grapefruit; ↑ INR if on warfarin.
• Toxicities: Hand-foot syndrome, diarrhea, rash (limit sun exposure), HTN, fatigue, ↑ LFTs, ↓ phosphate (hypophosphatemia), bleeding (epistaxis), wound dehiscence (hold around surgery), cardiac ischemia (monitor).

VEGF Ligand Trap

Ziv-aflibercept (Zaltrap); aflibercept (Eylea)

• Mechanism: Recombinant fusion protein (VEGFR1 + VEGFR2 ectodomains fused to Fc) that acts as a VEGF "trap," binding VEGF-A with higher affinity than bevacizumab → ↓ angiogenesis. Resistance via ↑ IL-6/STAT3, ↑ HGF, ↑ FGF. Half-life ~6 days.
• Indications: Metastatic CRC in combination with FOLFIRI after progression on an oxaliplatin regimen (IV; Zaltrap). Intravitreal aflibercept (Eylea) is used for wet AMD.
• Toxicities: Similar to bevacizumab: wound dehiscence, HTN, arterial thrombosis, VTE, GI perforation, bleeding, diarrhea, RPLS.

VEGFR2 Antibody

Ramucirumab (Cyramza)

• Mechanism: IgG1 mAb against VEGFR2 that prevents ligand (VEGF-A/C/D) binding → ↓ angiogenesis and ↓ tumor vascular permeability. Resistance via ↑ HGF, ↑ FGF.
• Indications: Gastric cancer, CRC, lung cancer (in combination therapies).
• Pharmacokinetics/monitoring: No dose adjustment for mild to moderate hepatic impairment; in Child-Pugh B/C cirrhosis, new or worsening encephalopathy, ascites, or hepatorenal syndrome reported (use only if benefit outweighs risk).
• Toxicities: HTN, GI perforation, proteinuria, bleeding, arterial thrombosis (> VTE), infusion reactions (especially early cycles); monitor thyroid function.

2026 update: new VEGF-targeting agents

Fruquintinib (Fruzaqla)

• Mechanism: highly selective VEGFR-1/2/3 TKI (fewer off-target kinases → better tolerability profile).
• Indications: refractory metastatic CRC after fluoropyrimidine, oxaliplatin, irinotecan, and anti-VEGF therapy, plus anti-EGFR if RAS wild-type and medically appropriate. FDA Nov 8, 2023 based on FRESCO-2 (Dasari Lancet 2023): mOS 7.4 vs 4.8 mo (HR 0.66).
• Toxicities: HTN, hand-foot syndrome, proteinuria, hypothyroidism, fatigue; class VEGFR-TKI AEs.

Tivozanib (Fotivda)

• Mechanism: highly selective VEGFR-1/2/3 TKI.
• Indications: relapsed/refractory advanced RCC after ≥2 prior systemic therapies (FDA Mar 10, 2021) based on TIVO-3 (Rini Lancet Oncol 2020). Selected for its lower off-target profile.

Cabozantinib: new NET indication

• CABINET (Chan NEJM 2024): cabozantinib vs placebo in previously-treated advanced pan-NET (pancreatic and extra-pancreatic). Extra-pNET mPFS 8.4 vs 3.9 mo; pNET mPFS 13.8 vs 4.4 mo. Halted early for efficacy. FDA Mar 26, 2025 approval for advanced pretreated pan-NET, the first multikinase TKI approved across the full NET spectrum.

Ivonescimab: PD-1 × VEGF bispecific

• Mechanism: first-in-class bispecific, an anti-PD-1 arm plus an anti-VEGF-A arm, with enhanced avidity in the VEGF-rich TME.
• HARMONi-2 (Zhou WCLC 2024): ivonescimab vs pembrolizumab monotherapy 1L PD-L1+ advanced NSCLC (Chinese phase 3, Summit/Akeso). mPFS 11.14 vs 5.82 mo (HR 0.51); doubled PFS vs pembro. First trial to beat pembrolizumab head-to-head in 1L NSCLC. Chinese NMPA approved 2024; FDA under review.
• HARMONi-6: ivonescimab + chemo vs tislelizumab + chemo 1L squamous NSCLC; positive PFS (Chen Lancet 2025).

Class overlaps

• Atezolizumab + bevacizumab (IMbrave150, 1L HCC; IMpower150 with carboplatin/paclitaxel, nonsquamous NSCLC) not changed; but in HR+ MBC bevacizumab is no longer standard. VEGF-TKIs were displaced in RCC 1L by IO + VEGFi combinations (see RCC section).