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The Role of VEGF in Angiogenesis and Prognosis

As demonstrated in preclinical models:

The VEGF ligand is one of the first pro-angiogenic factors and is present throughout the tumor life cycle1-4

The VEGF ligand is the only angiogenic factor present throughout the entire tumor life cycle
  • Adapted from Folkman 2005.

  • VEGF is a ligand that binds to receptors on endothelial cells to help drive angiogenesis1,2,4
  • As secondary pathways emerge over time, VEGF continues to be expressed and remains a primary anti-angiogenic target1
  • In addition, VEGF is genetically stable, making continued targeting of this pathway a viable and important antitumor strategy5
  • While expressed in normal tissues, VEGF also is present at physiologically relevant levels in the majority of tumors6,7
  • High VEGF expression may be associated with
    • Reduced overall survival8-12
    • Disease progression8
    • Risk of relapse10,13
    • Lymph node involvement14-16
    • Malignant pleural effusion17

In retrospective analyses:

High VEGF expression was implicated in poorer prognosis6,12,13,16

High VEGF expression was implicated in poorer prognosis High VEGF expression was implicated in poorer prognosis
  • CRC=colorectal cancer; NSCLC=non-small cell lung cancer.

The mechanism of action of Avastin has been elucidated primarily in preclinical models. Its clinical significance is unknown.

Indications

Metastatic Renal Cell Carcinoma (mRCC)
Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.

Non–Squamous Non–Small Cell Lung Cancer (NSCLC)
Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.

Metastatic Colorectal Cancer (MCRC)
Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy.

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%)
  • In NSCLC, grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a ≥2% higher incidence in Avastin-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thrombus/embolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%)
  • In first-line MCRC, the most common grade 3–4 events in Study 2107, which occurred at a ≥2% higher incidence in the Avastin plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%)
  • In second-line MCRC, the most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E3200, which occurred at a higher incidence (≥2%) in the Avastin plus FOLFOX4 vs FOLFOX4 groups, were diarrhea (18% vs 13%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), ileus (4% vs 1%), neuropathy–sensory (17% vs 9%), neurologic–other (5% vs 3%), fatigue (19% vs 13%), abdominal pain (8% vs 5%), headache (3% vs 0%), hypertension (9% vs 2%), and hemorrhage (5% vs 1%)

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

Next: Inhibiting Angiogenesis

References:
  1. Folkman J. In: DeVita VT Jr. Hellman S, Rosenberg SA, eds. Cancer: Principles & Practice of Oncology. Vol 2. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:2865-2882.
  2. Hanrahan V, Currie MJ, Gunningham SP, et al. J Pathol. 2003;200:183-194.
  3. Fontanini G, Vignati S, Boldrini L, et al. Clin Cancer Res. 1997;3:861-865.
  4. Rini BI, Small EJ. J Clin Oncol. 2005;23:1028-1043.
  5. Mukhopadhyay D, Datta K. Semin Cancer Biol. 2004;14:123-130.
  6. Hicklin DJ, Ellis LM. J Clin Oncol. 2005;23:1011-1027.
  7. Bergers G, Benjamin LE. Nat Rev Cancer. 2003;3:401-410.
  8. Imoto H, Osaki T, Taga S, et al. J Thorac Cardiovasc Surg. 1998;115:1007-1014.
  9. Kaya A, Ciledag A, Gulbay BE, et al. Respir Med. 2004;98:632-636.
  10. Des Guetz G, Uzzan B, Nicolas P, et al. Br J Cancer. 2006;94:1823-1832.
  11. O’Byrne KJ, Koukourakis MI, Giatromanolaki A, et al. Br J Cancer. 2000;82:1427-1432.
  12. Jacobsen J, Grankvist K, Rasmuson T, et al. BJU Int. 2004;93:297-302.
  13. Yuan A, Yu CJ, Chen WJ, et al. Int J Cancer (Pred Oncol). 2000;89:475-483.
  14. Saad RS, Kordunsky L, Liu YL, et al. Mod Pathol. 2006;19:1317-1323.
  15. Ottaiano A, Franco R, Talamanca AA, et al. Clin Cancer Res. 2006;12:2795-2803.
  16. Ishigami SI, Arii S, Furutani M, et al. Br J Cancer. 1998;78:1379-1384.
  17. Yeh HH, Lai WW, Chen HHW, et al. Oncogene. 2006;25:4300-4309.