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VEGF Inhibitor

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VEGF Inhibitor, VEGFR Inhibitor, Small Molecule VEGF Inhibitor, Vascular Endothelial Growth Factor Receptor Antagonist, Axitinib, Inlyta, Cabozantinib, Cometrig, Lenvatinib, Lenvima, Pazopanib, Votrient, Regorafenib, Stivarga, Sunitinib, Sutent, Sorafenib, Nexavar, Vandetanib, Capreisa

  • See Also
  1. Small Molecule Inhibitor-Mediated Chemotherapy
  2. Chemotherapy
  3. Ponatinib
  4. Decoy VEGF Receptor
  • Indications
  1. Renal Cell Cancer (advanced)
    1. Axitinib
    2. Cabozantinib (Cometrig)
    3. Lenvatinib (Lenvima)
    4. Sunitinib (Sutent)
    5. Sorafenib (Nexavar)
  2. Medullary Thyroid Cancer (metastatic)
    1. Cabozantinib (Cometrig)
  3. Differentiated Thyroid Cancer (refractory)
    1. Lenvatinib (Lenvima)
    2. Sorafenib (Nexavar)
  4. Hepatocellular Carcinoma (unresectable)
    1. Cabozantinib (Cometrig)
    2. Lenvatinib (Lenvima)
    3. Regorafenib
    4. Sorafenib (Nexavar)
  5. Colorectal Cancer (metastatic)
    1. Regorafenib
  6. Gastrointestinal stromal tumors
    1. Regorafenib
    2. Sunitinib (Sutent)
  7. Pancreatic Neuroendocrine Tumor
    1. Sunitinib (Sutent)
  • Mechanism
  1. Vascular Endothelial Growth Factor Receptor (VEGF, VEGFR)
    1. Angiogenesis signaling Protein
      1. Binds to VEGF receptors on Tyrosine Kinases to initiate Angiogenesis
      2. Target in some Targeted Cancer Therapy (e.g. Avastin)
    2. Other functions
      1. Monocyte activation and differentiation (VEGFR 1)
      2. Also used in Age-Related Macular Degeneration as a VEGF Inhibitor Intravitreal Injection
  2. VEGFR Inhibitors
    1. Broad group of small molecule inhibitors of VEGFR (specifically VEGFR2 with or without VEGFR 1 and/or 3)
    2. Most VEGFR blocking agents, also block multiple other Tyrosine Kinases
  • Medications
  1. Axitinib (Inlyta)
    1. Oral small molecule agent inhibits proangiogenic Cytokines (VEGFR, PDGFR)
    2. Risk of Severe Hypertension including PRES, thrombosis, bleeding, GI perforation, Hypothyroidism, hepatotoxicity
    3. Avoid with strong CYP3A4/5 Inhibitors and Inducers
  2. Cabozantinib (Cometrig)
    1. Oral agent blocks multiple small molecule receptor Tyrosine Kinases affecting tumor growth and Angiogenesis
    2. In addition to VEGFR 1-3, blocks MET, RET, KIT, FLT-3, TIE-2, TRKB and AXL
    3. Risk of Severe Hypertension, thrombosis, bleeding, GI perforation, Diarrhea, hepatotoxicity, palmar-plantar erythrodysesthesia
  3. Lenvatinib (Lenvima)
    1. Oral small molecule agent blocking VEGFR2
    2. Risk of Hypertension, arterial thrombosis, bleeding, GI perforation, Prolonged QT, hepatotoxicity, Renal Failure, Hypocalcemia, Cardiomyopathy
  4. Pazopanib (Votrient)
    1. Oral small molecule agent blocks VEGFR 1-3, c-Kit, and PDGF-R
    2. Risk of arterial thrombosis, bleeding, Prolonged QT, hepatotoxicity, Retinal Detachment, polycythemia, Interstitial Lung Disease
    3. Avoid with Antacids (decreased absorption)
  5. Ponatinib (Iclusig)
    1. Oral small molecule agent blocks VEGFR, as well as BCR-ABL (see BCR-ABL Inhibitor), FGFR, FLT3 and TIE2
    2. Ponatinib inhibits both unmutated and mutated forms of Bcr-Abl, including highly drug resistant mutations
    3. Ponatinib is associated with serious cardiovascular events (CVA, MI, PVD) in 20-30%, mortality in 1% (black box warning)
    4. Ponatinib also has a black box warning for hepatotoxicity
  6. Regorafenib (Stivarga)
    1. Oral small molecule agent blocks VEGFR 2-3, as well as Ret, c-Kit, PDGFR and Raf kinases
    2. Risk of hepatotoxicity (black box)
    3. Does not require dose adjustments in hepatic Impairment (mild-moderate) or renal Impairment (moderate-severe)
    4. Avoid with strong CYP3A4 Inhibitors and Inducers
  7. Sunitinib (Sutent)
    1. Oral small molecule agent blocks VEGFR2 and PDGFRb, as well as c-kit and FLT3
    2. Risk of hepatotoxicity, Prolonged QT, bleeding, Cardiomyopathy, adrenal toxicity, GI Perforation, myelosuppression, Hypertension, Thyroid dysfunction
    3. Also may cause Tumor Lysis Syndrome
  8. Sorafenib (Nexavar)
    1. Oral small molecule agent blocks VEGFR2 and PDGFRb, as well as RAF
    2. Risk of bleeding, Cardiomyopathy, GI perforation, hepatotoxicity, severe rash (SJ/TEN), Hypertension
    3. Take 1 hour before or 2 hours after a meal (best absorption)
  9. Vandetanib (Capreisa)
    1. Oral small molecule agent blocks VEGFR2, as well as EGFR
    2. Risk of GI perforation, Prolonged QT (black box), Interstitial Lung Disease, impaired Wound Healing
    3. Also risk of Hypertension, CVA, Cardiomyopathy, severe rash (SJ/TEN)
  10. Ziv-Aflibercept (Zaltrap)
    1. Ziv-Aflibercept has a unique mechanism of VEGF Inhibitors
    2. Recombinant fusion Protein that acts as a decoy for Vascular Endothelial Growth Factor (VEGF) receptors
  • Dosing
  1. See other references for disease specific dosing protocols
  • Adverse Effects
  1. Cardiovascular
    1. Severe Hypertension including PRES (Axitinib, Cabozantinib, Lenvatinib, Sorafenib, Vandetanib)
    2. Venous Thromboembolism (Axitinib, Cabozantinib)
    3. Arterial occlusive events (Axitinib, Cabozantinib,Lenvatinib, Pazopanib, and ACS with Sorafenib, CVA with Vandetanib)
    4. Cardiomyopathy or cardiac failure (Lenvatinib, Sunitinib, Vandetanib)
    5. Prolonged QTc (Lenvatinib, Pazopanib, Sunitinib, Vandetanib)
  2. Pulmonary
    1. Interstitial Lung Disease (Pazopanib, Vandetanib)
  3. Hematologic
    1. Bleeding risk and Hemorrhage (Axitinib, Cabozantinib, Lenvatinib, Sunitinib, Sorafenib)
    2. Polycythemia (Pazopanib)
    3. Neutropenia (Pazopanib with east asian descent)
    4. Thrombocytopenia (Pazopanib with east asian descent)
    5. Tumor Lysis Syndrome (Sunitinib)
  4. Endocrine
    1. Adrenal Toxicity (Sunitinib)
    2. Hypothyroidism (Axitinib, Sunitinib)
    3. Hypocalcemia (Lenvatinib)
  5. Eye
    1. Retinal Detachment (Pazopanib)
  6. Dermatologic
    1. Palmar-plantar erythrodysesthesia or PPES (Cabozantinib, Pazopanib with east asian descent)
    2. Hair or skin depigmentation (Sunitinib)
    3. Yellow Skin Discoloration (Sunitinib)
    4. Impaired Wound Healing (Axitinib, Vandetanib)
    5. Severe dermatologic reaction (Vandetanib, Sorafenib)
      1. Steven Johnson Syndrome (SJS)
      2. Toxic Epidermal Necrolysis (TEN)
  7. Gastrointestinal
    1. Gastrointestinal perforation (Axitinib, Cabozantinib, Lenvatinib, Sunitinib, Sorafenib, Vandetanib)
    2. Hepatotoxicity (Axitinib, Cabozantinib, Pazopanib, Regorafenib, Sunitinib, Sorafenib)
    3. Severe Diarrhea (Cabozantinib)
  8. Renal
    1. Proteinuria (Axitinib, Cabozantinib, Lenvatinib)
    2. Acute Renal Failure (Cabozantinib)
  • Safety
  1. Avoid in Lactation
  2. Avoid in pregnancy (all trimesters, pregnancy category X)
    1. Use reliable Contraception
    2. Continue Contraception for at least 4 months after Vandetanib
  3. Monitoring
    1. Complete Blood Count
    2. Liver Function Tests (Cabozantinib)
    3. Electrocardiogram for Prolonged QT (Lenvatinib, Pazopanib, Sunitinib, Vandetanib)
    4. INR (Sunitinib, Sorafenib)
    5. Blood Pressure (Axitinib, Cabozantinib, Lenvatinib, Sorafenib)
  • Drug Interactions
  1. Strong CYP3A4/5 Inhibitors and Inducers
    1. Avoid with Axitinib, Regorafenib
    2. Avoid strong CYP3A4 inducers with Vandetanib
    3. Increased Sunitinib levels with inihibitors, decreased levels with inducers
  2. Antacids
    1. Avoid with Pazopanib
  3. Medication Causes of QTc Prolongation
    1. Avoid with Lenvatinib, Pazopanib, Sunitinib
  4. BCRP Substrates
    1. Regorafenib may increase levels
  5. INR
    1. Increased with Sunitinib, Sorafenib
  • Resources
  1. Axitinib (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=84137882-e000-47da-bd5b-fa76ab3c76f9
  2. Cabozantinib (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3850cce2-6137-42e5-a792-d318c4a4b3b5
  3. Lenvatinib (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f4bedd21-efde-44c6-9d9c-b48b78d7ed1e
  4. Pazopanib (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=eeaaaf38-fb86-4d9f-a19d-0f61daac2fd7
  5. Ponatinib (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=16d804b6-4957-43ee-b18c-3b36ec37c5ac
  6. Regorafenib (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=824f19c9-0546-4a8a-8d8f-c4055c04f7c7
  7. Sunitinib (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=43a4d7f8-48ae-4a63-9108-2fa8e3ea9d9c
  8. Sorafenib (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=b50667e4-5ebc-4968-a646-d605058dbef0
  9. Vandetanib (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e5721cb8-4185-47b9-bbb3-1c587e558a03
  • References
  1. Melincovici (2018) Rom J Morphol Embryol 59(2):455-67 +PMID: 30173249 [PubMed]