Lung Cancer: Avastin Dosing and Usage

The overall survival (OS) results seen in Study E4599 in first-line advanced non-squamous non-small cell lung cancer (nsNSCLC) were achieved with Avastin® (bevacizumab) given at the approved dose until disease progression or unacceptable toxicity. [1]

Avastin dosing in first-line advanced nsNSCLC

In advanced nsNSCLC, Avastin is administered as a solution for intravenous (IV) infusion at the following dose and schedule [1]:

Tumor type

Chemotherapy

Avastin dose

Avastin schedule

NSCLC*

PC

15 mg/kg IV

Every 3 weeks

*15 mg/kg IV dose evaluated in first-line locally advanced or metastatic nsNSCLC in combination with paclitaxel/carboplatin (PC). Avastin plus PC was given for up to 6 cycles, after which Avastin was continued alone until disease progression or unacceptable toxicity. [1]

  • 15 mg/kg IV every 3 weeks is the only dose of Avastin to demonstrate significantly increased OS in first-line advanced nsNSCLC [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 nsNSCLC

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

Survival benefits were seen with Avastin continued until disease progression or unacceptable toxicity [1]

  • The OS results seen in Study E4599 were achieved with Avastin given until disease progression or unacceptable toxicity [1]
Avastin for NSCLC Treatment Duration Chart
  • 60% of patients receiving Avastin plus PC in Study E4599 completed 6 cycles of therapy (vs 44% in the PC alone arm), thereby making those patients eligible to continue Avastin alone until disease progression or unacceptable toxicity [41]
  • In Study E4599, patients in the Avastin plus PC arm received an average of 8.9 cycles of study treatment [3]
    • Study treatment consisted of either Avastin plus PC or Avastin alone after PC was discontinued

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

Bevacizumab plus PC is a standard of care for first-line nsNSCLC

Bevacizumab plus PC holds an NCCN category 1 recommendation per NCCN Clinical Practice Guidelines In Oncology (NCCN Guidelines®) for NSCLC V.8.2017[38]

NCCN Guidelines® include bevacizumab plus PC as a treatment option for first-line nsNSCLC patients using the following criteria

  • No history of hemoptysis   
  • ECOG PS 0–1

Bevacizumab has an NCCN category 1 recommendation for continuation maintenance* (based on high-level evidence and uniform consensus)[38]

NCCN Guidelines® 

Bevacizumab should be given until progression.

Bevacizumab should not be given as a single agent, unless as maintenance if initially used with chemotherapy.

*Maintenance therapy as defined by the NCCN

Continuation maintenance Use of at least 1 of the agents given in first line, beyond 4-6 cycles, in the absence of disease progression

Use of bevacizumab (Avastin) in the first line increases availability of second-line therapeutic options in the treatment of nsNSCLC [38]

In nsNSCLC, Avastin's approval is only in first line and as treatment to progression or unacceptable toxicity [1]

Metastatic NSCLC Treatment Algorithm Chart

Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.8.2017. ©2017 National Comprehensive Cancer Network, Inc. The National Comprehensive Cancer Network makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application in any way. All rights reserved. The NCCN Guidelines® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. The NCCN Guidelines are a work in progress that may be refined as often as new significant data becomes available. [38]

*Chemotherapy given for up to 6 cycles. [1,6]
PS 0-1 non-squamous NSCLC and no recent history of hemoptysis. Bevacizumab should not be given as a single agent unless as   maintenance if initially used with chemotherapy. Any regimen with a high risk of thrombocytopenia and the potential risk of bleeding should be used with caution in combination with bevacizumab. [38]

Indications

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.

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 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%)

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.