2015 Antineoplastics

Signal Transduction Inhibitors of VEGF-R: PAZOPANIB, SORAFENIB, SUNITINIB

  • the receptors for VEGF and PDGF are receptor tyrosine kinases (RTKs)

  • 3 of the FDA-approved signal transduction inhibitors are antagonists of VEGF-R and PDGF-R

  • PAZOPANIB, SORAFENIB, and SUNITINIB are much less specific than IMATINIB (i.e., they block multiple kinases)

  • in addition to blocking VEGF-R and PDGF-R, they also inhibit:
    • SORAFENIB: Raf

  • these drugs are approved as 1st line treatment for renal cell carcinoma and several other cancers
    • these drugs are highlighted in the controversy over the high cost of new cancer treatments
      • SUNITINIB is one of the most expensive drugs ever marketed, especially since it is a drug that doesn't cure cancer but "only" prolongs life
      • the estimated cost is $85,000/life year added --- and usually it only extends life by a matter of weeks
      • in a recent survey on the impact of cost on treatment, approximately 25% of patients with insurance said that they postponed or declined treatment because of cost

  • pharmacokinetics are the same as for STIs that block Bcr-Abl and HER2:
    • oral administration; good bioavailability
    • highly plasma protein bound
    • metabolized in the liver (CYP 3A4), and excreted in the feces (hepatobiliary excretion)

  • they exhibit the same general toxicities as STIs that block Bcr-Abl and HER2:
    • relatively minor side effects (esp. compared to conventional therapies that work by preventing rapid cell growth): nausea, vomiting, fatigue, myalgia, diarrhea, skin rashes and acne, drug interactions
    • can cause congestive heart failure and decreased left ventricular ejection fraction (causing shortness of breath, palpitations, fatigue) and/or myocardial infarction
      • incidence and severity vary widely within STIs; less severe for these agents
    • teratogenic

  • in addition, FOR THESE STIs, specific side effects include:
    • PAZOPANIB: severe (fatal) hepatotoxicity, hemorrhage, QT prolongation and torsades de points, GI perforation and hypertension
    • SORAFENIB: increased risk of hemorrhage, hypertension
    • SUNITINIB: skin discolouration, hand-foot syndrome (palmar-plantar erythrodysesthesia)
Email: Dr. Janet Fitzakerley | ©2015 University of Minnesota Medical School Duluth | Last modified: 11-apr-15 9:39 AM