Lung Cancer: Avastin Dosing and Usage

First-line non-squamous non-small cell lung cancer (NSCLC)
Avastin, in combination with carboplatin and paclitaxel, is indicated for the first‑line treatment of patients with unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer.

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*	Paclitaxel/carboplatin	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 overall survival (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 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 not breastfeed during treatment and for 6 months following their last dose of treatment

Duration of Avastin in nsNSCLC

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

Survival benefits were seen with Avastin when 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® (bevacizumab) for 1L metastatic non-squamous NSCLC Treatment Duration

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^[12]
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^[1]

No dose reductions for Avastin are recommended.

Dose Modifications for Adverse Reactions

Adverse reaction	Severity	Dosage 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	Any	Withhold Avastin until adequate wound healing. The safety of resumption of Avastin after resolution of wound healing complications has not been established.
Wound healing complications	Necrotizing fasciitis	Discontinue Avastin
Hemorrhage	Grade 3 or 4	Discontinue Avastin
Hemorrhage	Recent history of hemoptysis of ½ teaspoon (2.5 mL) or more	Withhold Avastin
Thromboembolic events	Arterial thromboembolism, severe Venous thromboembolism, Grade 4	Discontinue Avastin
Hypertension	Hypertensive crisis Hypertensive encephalopathy	Discontinue Avastin
Hypertension	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
Renal toxicity and proteinuria	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-related reaction	Severe	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

Select NCCN Guidelines

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.5.2019^[9]

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

ECOG PS=Eastern Cooperative Oncology Group performance status.

Bevacizumab has an NCCN category 1 recommendation for continuation maintenance^† (based on high-level evidence and uniform consensus)^[9]

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.

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.

Treatment algorithm

Use of bevacizumab (Avastin) in the first line increases availability of second-line therapeutic options in the treatment of nsNSCLC^[9]

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

1L metastatic non-squamous NSCLC Treatment Algorithm

Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.5.2019. © 2019 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.^[9]
^‡Chemotherapy given for up to 6 cycles.^[1,8]
^§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.^[9]

View Avastin dosing across all approved cancer types

Indication

First-line non-squamous non-small cell lung cancer (NSCLC)

Avastin, in combination with carboplatin and paclitaxel, is indicated for the first‑line treatment of patients with unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer.

Serious adverse reactions (Warnings and Precautions)

Serious and sometimes fatal adverse reactions with increased incidence in the Avastin-treated arm vs chemotherapy arm included:
- Gastrointestinal (GI) perforation ranged from 0.3% to 3% of patients across clinical studies
- Non-GI fistulae (<1% to 1.8%, highest in patients with cervical cancer)
- Arterial thromboembolic events (Grade ≥3, 5%, highest in patients with GBM)
- The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients
- Hemorrhage (Grade 3–5) ranged from 0.4% to 7% of patients across clinical studies
- Renal injury and proteinuria
  - Grade 3–4 proteinuria ranged from 0.7% to 7% in clinical studies
  - Nephrotic syndrome (<1%)
Additional serious adverse reactions 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): Grade ≥3 left ventricular dysfunction (1%)
Infusion-related reactions with the first dose of Avastin occurred in <3% of patients, and severe reactions occurred in 0.4% of patients
Avoid use in patients with ovarian cancer who have evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction
Inform females of reproductive potential of the risk of ovarian failure prior to initiating treatment with Avastin
An evaluation for the presence of varices is recommended within 6 months of initiation of Avastin in patients with HCC

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 not to breastfeed during treatment with Avastin and for 6 months following their last dose of treatment
Avastin may impair fertility

Most common adverse reactions

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
- 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 reactions

In NSCLC, Grade 3–5 (nonhematologic) and Grade 4–5 (hematologic) adverse reactions 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 thromboembolism (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 for additional important safety information.

- Avastin Prescribing Information. Genentech, Inc. 2022.
  
  Avastin Prescribing Information. Genentech, Inc. 2022.
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