Kidney Cancer: Avastin Dosage and Usage


Clinical benefits in patients with metastatic renal cell carcinoma (mRCC) were observed with Avastin® (bevacizumab) given at the approved dose until disease progression or unacceptable toxicity—even if interferon alfa (IFN) was reduced or discontinued. [1,3,7]

Avastin dosing in metastatic renal cell carcinoma

In mRCC, Avastin is administered as a solution for intravenous (IV) infusion at the following dosage [1]:

Tumor type Combination regimen Avastin dose Avastin schedule
mRCC* IFN 10 mg/kg IV Every 2 weeks

*10 mg/kg IV dose evaluated in mRCC in combination with IFN. AVOREN protocol allowed for IFN dose escalation (attaining a dose of 9 million international units [MIU] within the first 2 weeks), reduction, or discontinuation. IFN was discontinued after 52 weeks or earlier. [3,7]

  • 10 mg/kg IV every 2 weeks is the only dose of Avastin proven to increase progression-free survival and objective response rate in mRCC [1]

Important treatment considerations—Women of childbearing potential

  • Avastin increases the risk of ovarian failure and may impair fertility. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin
  • Long-term effects of Avastin exposure on fertility are unknown
  • Counsel patients about the possible risks, including hazard to the fetus and/or loss of pregnancy, of both continued treatment and prolonged exposure following discontinuation, keeping in mind the approximate half-life of Avastin (20 days; range 11–50 days). Patients should also be counseled to continue adequate contraception for 6 months following the last dose of Avastin 
  • Nursing mothers should be advised to discontinue nursing or Avastin, taking into account the half-life of the product and the importance of Avastin to the mother

Duration of Avastin in metastatic renal cell carcinoma

The FDA-approved Prescribing Information addresses the duration of Avastin treatment [1]:
Patients should continue treatment until disease progression or unacceptable toxicity.

Clinical benefits have been observed with Avastin given until disease progression or unacceptable toxicity [1,7]

  • Avastin was continued until disease progression or unacceptable toxicity in AVOREN, even if IFN was reduced or discontinued [1,7]
Avastin Duration in Metastatic Renal Cell Carcinoma Versus IFM

q2w=every 2 weeks.
An initial dose of less than 9 MIU was permitted as long as the recommended dose was reached within the first 2 weeks of treatment.
[7]

  • IFN was discontinued after a maximum of 52 weeks, but Avastin was continued until disease progression or unacceptable toxicity [1,7]
  • In AVOREN, 31% (105/337) of patients in the Avastin plus IFN arm discontinued IFN after 52 weeks and received Avastin alone thereafter [1,7]
  • 49% (165/337) of patients in the Avastin plus IFN group received IFN dose reduction and 21% (71/337) discontinued IFN prior to 52 weeks [3]
  • Avastin was not dose reduced but was discontinued in 21% (71/337) of patients vs 6% (17/304) discontinuation of placebo in the placebo plus IFN group [3,7]

AVOREN protocol allowed for IFN dose escalation, reduction, or discontinuation [3,7]

AVOREN Protocol Allowed for IFN Does Escalation, Reduction, or Discontinuation

An initial dose of less than 9 MIU was permitted as long as the recommended dose was reached within the first 2 weeks of treatment. [7]
After IFN held per protocol.

IFN was discontinued in any patient with [3,7]

  • Grade 4 toxicity
  • Grade 3 toxicity that did not resolve to grade ≤1 within 4 weeks while IFN was held
  • Grade 3 toxicity after 2 dose modifications
  • 52 weeks of treatment

Important treatment considerations—Dose modifications

  • There are no recommended dose reductions 
  • Discontinue Avastin in patients with 
    • Gastrointestinal (GI) perforations (GI perforations, fistula formation in the GI tract, intra-abdominal abscess) 
    • Fistula formation involving an internal organ 
    • Wound dehiscence and wound healing complications requiring medical intervention
    • Serious hemorrhage (ie, requiring medical intervention)
    • Severe arterial thromboembolic event (ATE)
    • Life-threatening (grade 4) venous thromboembolic events, including pulmonary embolism
    • Hypertensive crisis or hypertensive encephalopathy 
    • Posterior reversible encephalopathy syndrome (PRES)
    • Nephrotic syndrome
  • Temporarily suspend Avastin for: at least 4 weeks prior to elective surgery, severe hypertension not controlled with medical management, moderate to severe proteinuria, and severe infusion reactions 
  • The safety of resumption of Avastin therapy in patients that experienced PRES or ATE is unknown

Inclusion of bevacizumab in National Comprehensive Cancer Network® (NCCN®) recommendations [42]

  • NCCN Clinical Practice Guidelines In Oncology (NCCN Guidelines®) for Kidney Cancer include bevacizumab plus IFN as a first-line treatment option for patients with predominantly clear cell histology

Indications

Metastatic renal cell carcinoma (mRCC)
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 3.2% 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 0.4% to 6.9% 
    • 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
    • GI fistulae (up to 2% in metastatic colorectal cancer and ovarian cancer patients)
    • Non-GI fistulae (<1% in trials across various indications; 1.8% in a cervical cancer trial) 
    • Arterial thromboembolic events (grade ≥3, 2.6%)
    • Proteinuria (nephrotic syndrome, <1%)
  • Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included 
    • GI-vaginal fistulae occurred in 8.3% of patients in a cervical cancer trial
    • Hypertension (grade 3–4, 5%–18%)
    • Posterior reversible encephalopathy syndrome (PRES) (<0.5%)
  • 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

Pregnancy warning

  • Based on the mechanism of action and animal studies, Avastin may cause fetal harm
  • Advise female patients that Avastin may cause fetal harm, and to inform their healthcare provider of a known or suspected pregnancy 
  • Advise females of reproductive potential to use effective contraception during treatment with Avastin and for 6 months after the last dose of Avastin
  • Advise nursing women that breastfeeding is not recommended during treatment with Avastin
  • Avastin may impair fertility

Most common adverse events

  • Across indications, the 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

Indication-specific adverse events

  • 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%)

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch.
You may also report side effects to Genentech at (888) 835-2555.

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