FAQ

Avastin

• What is Avastin?
• What is the Avastin indication in MCRC?
• What therapies contain IV 5-FU?
• What is Avastin contraindicated for?

Clinical Trial Results

• How was Avastin studied in MCRC?
• What were the clinical trial results with Avastin?
• What was the effect of Avastin plus IV 5-FU–based therapy on other efficacy endpoints?
• What patient subgroups were analyzed in clinical trials?

Safety Profile

• What is the safety profile of Avastin?
• What are the most serious adverse events associated with Avastin?
• What are additional serious adverse events?
• What are the most common adverse events associated with Avastin?
• What should I know about hypertension?
• What should I know about proteinuria and nephrotic syndrome?
• What should I know about arterial thromboembolic events (ATEs)?
• What should I know about gastrointestinal (GI) perforation?
• What should I know about surgery and wound healing complications?
• What should I know about hemorrhage?
• What should I know about ovarian failure/fertility?
• What monitoring and laboratory tests are necessary?

Dosing and Administration

• How should Avastin be dosed and administered?
• How should Avastin vials be stored?
• How long should Avastin be continued?
• What are the dose modification recommendations for Avastin?

Reimbursement Support and Customer Service

• What reimbursement support services are available for Avastin?
• Where can I find additional information about Avastin?

Summary

• Avastin plus IV 5-FU–based chemotherapy: Significant survival benefits vs IV 5-FU–based chemotherapy alone in both first- and second-line MCRC

Avastin

What is Avastin?

Avastin is a therapeutic advance in the combination treatment of MCRC. Avastin is a recombinant humanized monoclonal antibody to vascular endothelial growth factor (VEGF), a protein that has been identified as one of the most potent and predominant mediators of tumor angiogenesis.^1,2

What is the Avastin indication in MCRC?

Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy.¹

What therapies contain IV 5-FU?

Therapies that contain IV 5-FU include IFL, FOLFIRI, FOLFOX, and 5-FU/LV chemotherapy regimens.

What is Avastin contraindicated for?

There are no known contraindications to the use of Avastin.¹

Clinical Trial Results

How was Avastin studied in MCRC?

The clinical benefits of Avastin have been evaluated across several randomized clinical trials and in combination with multiple IV 5-FU–containing regimens, including:

• First line in combination with IFL: 923 patients with previously untreated MCRC were evaluated in Study 2107 (a Phase III trial). Patients in the study received placebo plus IFL (Arm 1), Avastin 5 mg/kg IV every 2 weeks (q2w) plus IFL (Arm 2), or Avastin 5 mg/kg IV q2w plus IV 5-FU/LV (Arm 3). As prespecified, Arm 3 was discontinued when the relative safety of Avastin plus IFL was established in an interim analysis. The primary endpoint in this Phase III trial was OS^1-3

• Second line in combination with FOLFOX4: 829 patients with previously treated MCRC were evaluated in Study E3200 (a Phase III trial). Patients in the study received FOLFOX4 (Arm 1), Avastin 10 mg/kg IV q2w plus FOLFOX4 (Arm 2), or Avastin 10 mg/kg IV q2w alone (Arm 3). The primary endpoint was OS. Patients were previously treated with irinotecan and 5-FU for initial therapy for metastatic disease or as adjuvant therapy^1,4

Per MCRC trial protocols, Avastin administration was continued until disease progression or unacceptable toxicity.^1,2,5

What were the clinical trial results with Avastin?

In pivotal studies in both first- and second-line MCRC, Avastin plus IV 5-FU–based therapy has consistently demonstrated superior survival results over IV 5-FU–based chemotherapy alone.

• In first-line Study 2107, Avastin plus IFL resulted in a 4.7-month (30%) increase in median OS vs placebo plus IFL in previously untreated patients. The survival benefit associated with Avastin was observed early in treatment and persisted throughout the course of the trial. Median duration of Avastin therapy was 40.4 weeks^1,2

• In second-line Study E3200, Avastin plus FOLFOX4 resulted in a 2.2-month (20%) increase in median OS vs FOLFOX4 alone. This is the first treatment to extend median OS beyond 1 year in a Phase III trial for second-line MCRC^1,4

Raising the survival standard, as observed in pivotal Phase III trials^1,2,4

• *Difference statistically significant. HRs for survival: Study 2107, HR=0.66 (95% CI, 0.54–0.81); Study E3200, HR=0.75 (95% CI, 0.63–0.89).

Avastin plus IV 5-FU–based therapy offers broad and consistent clinical benefits

What was the effect of Avastin plus IV 5-FU–based therapy on other efficacy endpoints?

Avastin plus IV 5-FU–based therapy resulted in significant increases in PFS and ORR in the pivotal Phase III trials.

Increases in median PFS in first- and second-line MCRC^1,2,4

• ^†HR=0.54 (95% CI, 0.45–0.66), P<0.001.
• ^‡HR=0.61, P<0.0001.
• ^§Chemotherapy regimens with Avastin plus IV 5-FU–based therapy: Study 2107, IFL; Study E3200, FOLFOX4.

Increases in ORR in first- and second-line MCRC^1,2,4

• ^||P<0.01.
• ^¶P<0.0001.
• ^#Chemotherapy regimens with Avastin plus IV 5-FU–based therapy: Study 2107, IFL; Study E3200, FOLFOX4.

What patient subgroups were analyzed in clinical trials?

In pivotal Phase III Study 2107, a number of subgroups were analyzed based on patient- and disease-related parameters, including age, sex, race, ECOG PS, location of primary tumor, prior adjuvant therapy, number of metastatic sites, tumor burden, and prior radiotherapy.^1,2,5

Safety Profile

What is the safety profile of Avastin?

The positive benefit-risk ratio of Avastin has been observed in both first- and second-line MCRC.¹

Avastin plus IFL (first-line MCRC)
Selected grade 3–4 adverse events (≥2 higher incidence in the Avastin arm)¹

• **Central laboratories were collected on days 1 and 21 of each cycle. Neutrophil counts were available in 303 patients receiving placebo plus IFL and 276 patients
    receiving Avastin plus IFL.

Avastin plus FOLFOX4 (second-line MCRC)
Selected grade 3–5 adverse events (≥2% higher incidence in the Avastin arm)

• In second-line MCRC, Avastin 10 mg/kg IV q2w plus FOLFOX4 maintained a safety profile consistent with Avastin 5 mg/kg IV q2w plus IFL in first-line treatment, while significantly extending OS^1,2,4

What are the most serious adverse events associated with Avastin?

• Gastrointestinal (GI) perforation: Serious and sometimes fatal GI perforation occurs at a higher incidence (up to 2.4%) in Avastin-treated patients compared to controls. Discontinue Avastin for 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. Discontinue in patients with wound dehiscence. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed
• Hemorrhage: Severe or fatal hemorrhage, hemoptysis, GI bleeding, CNS hemorrhage, and vaginal bleeding are increased in Avastin-treated patients. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis

What are additional serious adverse events?

• Additional serious and sometimes fatal adverse events for which the incidence was increased in the Avastin-treated arm vs control included non-GI fistula formation (≤0.3%), arterial thromboembolic events (grade ≥3, 2.4%), and proteinuria including nephrotic syndrome (<1%). Additional serious adverse events for which the incidence was increased in the Avastin-treated arm vs control included hypertension (grade 3–4, 5%–18%) and 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

What are the most common adverse events associated with Avastin?

• 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, and exfoliative dermatitis. Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions

What should I know about hypertension?

Incidence: The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies, the incidence of grade 3 or 4 hypertension ranged from 5% to 18%.¹

Monitoring: Blood pressure (BP) monitoring should be conducted every 2 to 3 weeks during treatment with Avastin. Patients who develop hypertension may require BP monitoring at more frequent intervals (even if they have discontinued therapy).¹

Management: Hypertension should be treated with appropriate antihypertensive therapy and BP should be monitored regularly. Avastin should be temporarily suspended in patients with severe hypertension not controlled with medical management and discontinued in patients with hypertensive crisis or hypertensive encephalopathy.¹

What should I know about proteinuria and nephrotic syndrome?

Incidence: The incidence and severity of proteinuria are increased in patients receiving Avastin as compared to controls. Across clinical studies, the incidence of grade 3 and 4 proteinuria (characterized as >3.5 g/24 hours) ranged from 0.7% to 7.4% in Avastin-treated patients. Nephrotic syndrome occurred in <1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome.¹

Monitoring: Patients should be monitored for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with 2+ or greater urine dipstick reading should undergo further assessment with a 24-hour urine collection.¹

Management: Suspend Avastin administration for ≥2 g of proteinuria/24 hours and resume when proteinuria is <2 g/24 hours. Avastin should be discontinued in patients with nephrotic syndrome. Data from a postmarketing safety study showed poor correlation between urine protein/creatinine ratio (UPCR) and 24-hour urine protein (Pearson Correlation 0.39 [95% CI, 0.17%–0.57%]). Patients with moderate to severe proteinuria based on 24-hour collections should be monitored regularly until improvement and/or resolution is observed. The safety of continued treatment in patients with moderate to severe proteinuria has not been evaluated.¹

What should I know about arterial thromboembolic events (ATEs)?

Serious, and sometimes fatal, ATEs, including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATEs, occurred at a higher incidence in patients receiving Avastin compared to the control arms. Across indications, the incidence of grade ≥3 ATEs in the Avastin-containing arms was 2.4% compared to 0.7% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing an ATE during therapy was increased in patients with a history of ATE or age greater than 65 years. Permanently discontinue Avastin in patients who experience a severe ATE. The safety of resumption of Avastin therapy after resolution of an ATE has not been studied.¹

What should I know about gastrointestinal (GI) perforation?

Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls. The incidence of GI perforation ranged from 0.3%–2.4% across clinical studies. The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra-abdominal abscess and fistula formation. The majority of cases occurred within the first 50 days of initiation of Avastin. Discontinue Avastin in patients with GI perforation.¹

What should I know about surgery and wound healing complications?

Avasin impairs wound healing in animal models. In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with MCRC who underwent surgery during the course of Avastin treatment was 15%, and in patients who did not receive Avastin, the incidence of wound healing complications was 4%.¹

Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention. The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half-life of Avastin is estimated to be 20 days (range 11–50 days). Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed.

What should I know about hemorrhage?

Avastin can result in 2 distinct patterns of bleeding: minor hemorrhage, most commonly grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system (CNS) hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6%.

Serious or fatal pulmonary hemorrhage occurred in 4 of 13 (31%) patients with squamous cell histology and 2 of 53 (4%) patients with non-squamous non-small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone.

In clinical studies in non-small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic grade 2 CNS hemorrhage was documented in 1 of 83 Avastin-treated patients (rate 1.2%, 95% CI 0.06%–5.93%).

Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; 2 patients had grade 3–4 hemorrhage.

Do not administer Avastin to patients with recent history of hemoptysis of ≥1/2 tsp of red blood. Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention).

What should I know about ovarian failure/fertility?

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. The incidence of ovarian failure was higher (34% vs 2%) in premenopausal women receiving Avastin in combination with mFOLFOX chemotherapy as compared to those receiving mFOLFOX chemotherapy alone as adjuvant treatment for colorectal cancer, a use for which Avastin is not approved.¹

What monitoring and laboratory tests are necessary?

BP monitoring should be conducted every 2 to 3 weeks during treatment. Patients who develop hypertension may require BP monitoring at more frequent intervals (even if they have discontinued therapy). Patients should also be monitored for the development or worsening of proteinuria with serial urinalyses. Patients with a 2+ or greater urine dipstick reading should undergo further assessment (24-hour urine collection) and should be monitored regularly until improvement and/or resolution is observed.¹

Dosing and Administration

How should Avastin be dosed and administered?

Avastin, used in combination with IV 5-FU–based chemotherapy, is administered as an IV infusion (5 mg/kg or 10 mg/kg) q2w until disease progression or unacceptable toxicity, per study protocols. The only Avastin dosages proven to provide a survival benefit are 5 mg/kg IV q2w with IFL (per Study 2107) and 10 mg/kg IV q2w with FOLFOX4 (per Study E3200).¹

Established doses in pivotal Phase III MCRC trials¹

• ^††5 mg/kg IV q2w dose evaluated in first-line MCRC in combination with IFL.
• ^‡‡10 mg/kg IV q2w dose evaluated in second-line MCRC in combination with FOLFOX4.

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

The initial Avastin dose should be delivered over 90 minutes following chemotherapy. If tolerated, the second infusion may be given over 60 minutes. If the 60-minute infusion is tolerated, all subsequent infusions may be given over 30 minutes.¹

In preparation for the infusion, withdraw the necessary amount of Avastin to obtain the required dose and dilute in a total volume of 100 mL of 0.9% Sodium Chloride Injection, USP. Avastin infusions should not be administered or mixed with dextrose solutions. DO NOT ADMINISTER AS AN IV PUSH OR BOLUS. DO NOT INITIATE AVASTIN UNTIL AT LEAST 28 DAYS FOLLOWING SURGERY AND UNTIL THE SURGICAL WOUND IS FULLY HEALED.¹

Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients. Infusion reactions in clinical trials and in postmarketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, NCI-CTC grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. Stop infusion if a severe adverse reaction occurs and administer appropriate medical therapy.¹

How should Avastin vials be stored?

Avastin vials must be refrigerated at 2°C–8°C (36°F–46°F) and should be protected from light. Store in the original carton until time of use. DO NOT FREEZE. DO NOT SHAKE.¹

How long should Avastin be continued?

In MCRC trial protocols, Avastin was continued until disease progression or unacceptable toxicity.^2,5

Duration of treatment

MCRC^a

• ^aIn first- and second-line MCRC, Avastin is indicated in combination with IV 5-FU–containing chemotherapy.¹

 

What are the dose modification recommendations for Avastin?

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

Reimbursement Support and Customer Service

What reimbursement support services are available for Avastin?

Genentech provides patient reimbursement support services for Avastin through Avastin Access Solutions. Avastin Access Solutions^® is committed to providing your patients with timely and appropriate coverage information related to Avastin.

Avastin Access Solutions can assist by answering questions related to reimbursement, providing payer coverage information, investigating policy benefits, consulting on appeals, and providing patient assistance resources.

To contact Avastin Access Solutions, call toll-free 1-888-249-4918, Monday through Friday, 6 am to 5 pm (PST). Messages can be left 24 hours a day. Enrollments can be faxed to 1-888-249-4919. Avastin Access Solutions is also accessible 24 hours a day on the Web at www.AvastinAccessSolutions.com.

Where can I find additional information about Avastin?

Additional information about Avastin clinical data and resources can be found on Avastin.com. For medical inquires, please call Genentech Medical Communications at 1-800-821-8590, Monday through Friday, 5:30 am to 4 pm (PST).

Summary

Avastin plus IV 5-FU–based chemotherapy: Significant survival benefits vs IV 5-FU–based chemotherapy alone in both first- and second-line MCRC

First-line MCRC^1,2:

• Proven efficacy in combination with IFL vs placebo plus IFL (pivotal Phase III trial, N=813)

  • 4.7-month (30%) increase in median OS (20.3 vs 15.6 months, HR=0.66 [95% CI, 0.54–0.81], P<0.001)

  • 4.4-month (71%) increase in median PFS (10.6 vs 6.2 months, HR=0.54 [95% CI, 0.45–0.66], P<0.001)

  • Increases in response rate (45% vs 35%, P<0.01) and duration of response (10.4 vs 7.1 months)

Second-line MCRC^1,4:

• Proven efficacy in combination with FOLFOX4 vs FOLFOX4 alone (pivotal Phase III trial, N=577)

  • 2.2-month (20%) increase in median OS (13.0 vs 10.8 months, HR=0.75 [95% CI, 0.63–0.89], P=0.001)

  • 2.6-month (55%) increase in median PFS (7.3 vs 4.7 months, P<0.0001)

  • Significant increase in ORR (23% vs 9%, P<0.0001)