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Evidence-based dosing and duration

15 mg/kg as a solution for IV infusion q3w is the only dose of Avastin demonstrated to significantly increase OS in first-line metastatic non-squamous NSCLC

ECOG Study E4599 was a large, multicenter, randomized, Phase III trial1,2
  • *Included patients with locally advanced, metastatic, or recurrent NSCLC.
Results from Study AVF0757g† (Phase II) determined 15 mg/kg as a solution for IV infusion q3w until disease progression or unacceptable toxicity as the Avastin dose in Study E45992,3
  • NS=nonsignificant.
  • †Study AVA0757g was not powered to make any definitive conclusions regarding a relationship between dose and treatment effect.
  • ‡Patients in the PC alone arm could cross over to the Avastin 15 mg/kg arm upon progression.
  • §Vs control arm.

Important safety information—Study AVF0757g

  • The most common events of any severity (≥10% incidence) in the Avastin plus PC group in Study AVF0757g were nausea, leukopenia, neuropathy, peripheral neuritis, infection, paresthesia, vomiting, diarrhea, thrombocytopenia, and fever. In this trial, the incidence of serious or fatal pulmonary hemorrhage was 31% (4 of 13) in Avastin-treated patients with squamous cell histology and 4% (2 of 53) in Avastin-treated patients with histology other than squamous cell. As a result, patients with squamous cell histology were excluded from Study E4599

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
  • Prior to initiation of therapy, advise patients of the potential risk of Avastin to the developing fetus
  • Counsel patients who become pregnant 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 at least 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

Avastin plus PC has demonstrated an increase in OS with Avastin given until disease progression or unacceptable toxicity

Avastin was continued until disease progression or unacceptable toxicity in Study E45991

In Study E4599, patients who were responding or had stable disease after 6 cycles of Avastin plus PC continued on Avastin alone until disease progression or unacceptable toxicity1,4

Based on its significant first-line survival data, bevacizumab plus chemotherapy [PC] is FDA approved and NCCN recommended for first-line metastatic non-squamous NSCLC1,5

Bevacizumab is the only FDA-approved agent for first-line metastatic non-squamous NSCLC that has an NCCN category 1 recommendation for continuation maintenance (based on high-level evidence and uniform consensus)5

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)
    • Hypertensive crisis or hypertensive encephalopathy
    • Reversible posterior leukoencephalopathy syndrome (RPLS) (symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae)
    • 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 pending further evaluation, and severe infusion reactions
  • The safety of resumption of Avastin therapy in patients that experienced RPLS, ATE, and moderate to severe proteinuria is unknown

Preparing and administering the infusion

The necessary amount of Avastin should be withdrawn and diluted in a total volume of 100 mL of 0.9% Sodium Chloride Injection, USP. Discard any unused portion left in the vial, as the product contains no preservatives. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Avastin infusions should not be administered or mixed with dextrose solutions. Diluted Avastin solutions for infusion may be stored at 2°C–8°C (36°F–46°F) for up to 8 hours. DO NOT ADMINISTER AS AN IV PUSH OR BOLUS.1

Avastin infusion times may be reduced over the course of treatment if tolerated. The initial Avastin dose should be delivered over 90 minutes as an IV infusion following chemotherapy. If the first infusion is tolerated, the second infusion may be administered over 60 minutes. If the 60-minute infusion is tolerated, all subsequent infusions may be administered over 30 minutes.1

Infusion times1

Avastin Administration

In clinical studies, infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients. Adequate information on rechallenge is not available. Avastin infusion should be interrupted in all patients with severe infusion reactions and appropriate medical therapy administered.1

Indication

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.

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 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%)

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

Next: NSCLC Resources

References:
  1. Avastin Prescribing Information. Genentech, Inc. September 2011.
  2. Sandler A, Gray R, Perry MC, et al. N Engl J Med. 2006;355:2542-2550.
  3. Johnson DH, Fehrenbacher L, Novotny WF, et al. J Clin Oncol. 2004;22:2184-2191.
  4. Data on file. Genentech, Inc.
  5. The NCCN Non-Small Cell Lung Cancer Clinical Practice Guidelines in Oncology (Version 3.2011). ©2011 National Comprehensive Cancer Network, Inc. http://www.nccn.org. Accessed February 22, 2011. To view the most recent and complete version of the guidelines, go online to www.nccn.org.