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The role of VEGF in RCC

VEGF is highly expressed in RCC, and RCC is a VEGF-driven disease early and throughout tumor development.1-6 The majority of clear cell RCC tumors are driven by dysfunction of the von Hippel-Lindau (VHL) gene.2,3 Loss of VHL function causes upregulation of hypoxia inducible factor (HIF), which results in increased VEGF.2-5 This dysfunction of the VHL gene is thought to be a very early event in clear cell RCC tumor development.6 Due to the role of VHL gene dysfunction, VEGF is a primary disease driver in RCC.2

Avastin: Direct VEGF ligand inhibition for a VEGF-driven disease

  • Avastin binds directly to the VEGF ligand (which is expressed by both normal and tumor cells) to prevent its interaction with receptors on the surface of endothelial cells, thereby inhibiting the biologic activity of VEGF as observed in in vitro and in vivo assay systems7,8

Avastin is designed to directly bind the VEGF ligand to specifically inhibit angiogenesis7

Angiogenic cascade in RCC2-6, 8-10

Angiogenic cascade in RCC2-8

  • VEGF-2=vascular endotheliall growth factor receptor-2.

Avastin is designed to bind the VEGF ligand extracellularly.8,9

The mechanism of action of anti-VEGF agents has been elucidated primarily in preclinical models. Its clinical significance is unknown.

Indication

Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.

Boxed WARNINGS
  • Gastrointestinal (GI) perforation
    • Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls
    • The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies
    • Discontinue Avastin in patients with GI perforation
  • Surgery and wound healing complications
    • The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients
    • Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined
    • Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound healing complications requiring medical intervention
  • Hemorrhage
    • Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6%
    • Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood)
    • Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)
Additional serious adverse events
  • Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs control included
    • Non-GI fistula formation (≤0.3%)
    • Arterial thromboembolic events (grade ≥3, 2.4%)
    • Proteinuria including nephrotic syndrome (<1%)
  • Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included
    • Hypertension (grade 3–4, 5%–18%)
    • Reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%)
  • Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients
  • Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin
Most common adverse events
  • Most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were
    – Epistaxis
    – Headache
    – Hypertension
    – Rhinitis
    – Proteinuria
    – Taste alteration
    – Dry skin
    – Rectal hemorrhage
    – Lacrimation disorder
    – Back pain
    – Exfoliative dermatitis
  • Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions
Pregnancy warning
  • Avastin may impair fertility
  • Based on animal data, Avastin may cause fetal harm
  • Advise patients of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following the last dose of Avastin
  • For nursing mothers, discontinue nursing or Avastin, taking into account the importance of Avastin to the mother
  • In mRCC, the most common grade 3–5 adverse events in AVOREN, occurring at a ≥2% higher incidence in Avastin-treated patients vs controls, were fatigue (13% vs 8%), asthenia (10% vs 7%), proteinuria (7% vs 0%), hypertension (6% vs 1%), and hemorrhage (3% vs 0.3%)

Please see full Prescribing Information, including Boxed WARNINGS, for additional important safety information.

Next: Benefit-risk Ratio

References:
  1. Escudier B, Pluzanska A, Koralewski P, et al. Lancet. 2007;370:2103-2111.
  2. Rini BI, Small EJ. J Clin Oncol. 2005;23:1028-1043.
  3. Haase VH. Kidney Int. 2006;69:1302-1307.
  4. George DJ, Kaelin WG Jr. N Engl J Med. 2003;349:419-421.
  5. Iliopoulos O, Levy AP, Kiang C, et al. Proc Natl Acad Sci USA. 1996;93:10595-10599.
  6. Hemminki K, Jiang Y, Ma X, et al. Carcinogenesis. 2002;23:809-815.
  7. Avastin Prescribing Information. Genentech, Inc. September 2011.
  8. Hicklin DJ, Ellis LM. J Clin Oncol. 2005;23:1011-1027.
  9. Presta LG, Chen H, O’Connor SJ, et al. Cancer Res. 1997;57:4593-4599.
  10. Jain RK, Duda DG, Clark JW, Loeffler JS. Nat Clin Pract Oncol. 2006;3:24-40.