Kidney Cancer: Avastin Dosage and Usage

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

Avastin dosing in metastatic renal cell carcinoma

In mRCC, Avastin is administered as a solution for intravenous (IV) infusion at the following dose and schedule [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]

Boxed WARNINGS

  • Gastrointestinal (GI) perforation
    • Discontinue for gastrointestinal perforation
  • Surgery and wound healing complications
    • Withhold Avastin for at least 28 days prior to elective surgery. Do not administer Avastin for at least 28 days after surgery and until the wound is fully healed
    • Discontinue in patients with wound healing complications requiring medical intervention
  • Hemorrhage
    • Severe or fatal hemorrhage have occurred
    • Do not administer Avastin to patients with serious hemorrhage or recent history of hemoptysis
    • Discontinue for Grade 3-4 hemorrhage

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 the first dose of Avastin
  • Long-term effects of Avastin exposure on fertility are unknown
  • Patients should also use effective contraception during treatment and for 6 months following the last dose of Avastin
  • Nursing mothers should be advised to discontinue nursing during treatment and for 6 months following their last dose of treatment

Duration of Avastin in metastatic renal cell carcinoma

Patients were treated 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® (bevacizumab) 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

No dose reductions for Avastin are recommended.

Dose Modifications for Adverse Reactions

 

Adverse Reaction

Severity

Dose Modification

Gastrointestinal Perforation and Fistulae

  • Gastrointestinal perforation, any grade
  • Tracheoesophageal fistula, any grade
  • Fistula, Grade 4
  • Fistula formation involving any internal organ

Discontinue Avastin

Wound Healing Complications

  • Wound healing complications requiring medical intervention
  • Necrotizing fasciitis

Discontinue Avastin

Hemorrhage

  • Grade 3 or 4

Discontinue Avastin

  • Recent history of hemoptysis of 1/2 teaspoon (2.5 mL) or more

Withhold Avastin

Thromboembolic Events

  • Arterial thromboembolism, severe

Discontinue Avastin

  • Venous thromboembolism, Grade 4

Discontinue Avastin

Hypertension

  • Hypertensive crisis
  • Hypertensive encephalopathy

Discontinue Avastin

  • Hypertension, severe

Withhold Avastin if not controlled with medical management; resume once controlled

Posterior Reversible Encephalopathy Syndrome (PRES)

Any

Discontinue Avastin

Renal Toxicity and Proteinuria

  • Nephrotic syndrome

Discontinue Avastin

  • Proteinuria greater than or equal to 2 grams per 24 hours in absence of nephrotic syndrome

Withhold Avastin until proteinuria less than 2 grams per 24 hours

Infusion Reaction

  • Severe infusion reaction

Discontinue Avastin

  • Clinically significant

Interrupt infusion; resume at a decreased rate of infusion after symptoms resolve

 

  • Mild, clinically insignificant

Decrease infusion rate

Congestive Heart Failure

Any

Discontinue Avastin

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 Category 1 first-line treatment option for patients with predominantly clear cell histology

Indications

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

Boxed WARNINGS

  • Gastrointestinal (GI) perforation
    • Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to patients treated with chemotherapy
    • The incidence of GI perforation ranged from 0.3% to 3% 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
    • Withhold Avastin for at least 28 days prior to elective surgery. Do not administer Avastin for at least 28 days after surgery and until the wound is fully healed
    • Discontinue 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. In clinical studies, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 0.4% to 7%
    • Do not administer Avastin to patients with serious hemorrhage or a recent history of hemoptysis (≥1/2 tsp of red blood)
    • Discontinue Avastin in patients who develop grade 3-4 hemorrhage

Additional serious adverse events

  • Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs chemotherapy arm included:
    • Non-GI fistulae (<1% to 1.8%, highest in patients with cervical cancer)
    • Arterial thromboembolic events (grade ≥3, 5%, highest in patients with GBM)
    • Renal injury and proteinuria
      • Grade 3–4 proteinuria ranged from 0.7% to 7% in clinical studies
      • Nephrotic syndrome (<1%)
  • Additional serious adverse events with increased incidence in the Avastin-treated arm vs chemotherapy arm included:
    • Venous thromboembolism (grade ≥3, 11% seen in GOG-0240)
    • Hypertension (grade 3–4, 5%–18%)
    • Posterior reversible encephalopathy syndrome (PRES) (<0.5%)
    • Congestive heart failure (CHF) (1%)
  • Infusion reactions with the first dose of Avastin occurred in <3% of patients, 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 and for 6 months following their last dose of treatment
  • Avastin may impair fertility

Most common adverse events

  • Across studies, the most common adverse reactions observed in Avastin patients at a rate >10% 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% to 22% 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%, including hypertension and hypertensive crisis), and hemorrhage (3% vs 0.3%;, including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, hemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma)

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.