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Avastin
Clinical Trial Results
Results From the Pivotal Phase III Trials
Safety Profile
Dosing and Administration
Reimbursement Support and Customer Service
Summary

Avastin

arrow up What is Avastin?

Avastin is a therapeutic advance in the combination treatment of metastatic colorectal cancer (MCRC). It is the only biologic agent, in combination with IV 5-FU-containing chemotherapy, clinically proven to extend survival in first- or second-line 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

arrow up What is Avastin indicated for?

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

Avastin, in combination with carboplatin and paclitaxel, is indicated for first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic non-squamous, non-small cell lung cancer.1

arrow up What therapies contain IV 5-FU?

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

arrow up What is Avastin contraindicated for?

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

Clinical Trial Results

arrow up 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:

  • 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 every 2 weeks plus IFL (Arm 2), or Avastin 5 mg/kg every 2 weeks 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 rigorous Phase III trial was overall survival1,9

  • IV 5-FU/LV: A combined analysis (N=490) of 3 randomized clinical trials, which included patients from studies 0780, 2192, and 2107, examined the addition of Avastin to IV 5-FU/LV chemotherapy in previously untreated patients with MCRC. These 3 studies were combined into a single analysis evaluating the efficacy of Avastin plus IV 5-FU/LV vs a "combined control" of either IFL or IV 5-FU/LV alone10

  • 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 every 2 weeks plus FOLFOX4 (Arm 2), or Avastin 10 mg/kg every 2 weeks alone (Arm 3). The primary endpoint was overall survival. Patients were previously treated with irinotecan and 5-FU for initial therapy for metastatic disease or as adjuvant therapy1

Per MCRC trial protocols, Avastin administration was continued until disease progression and was not modified due to chemotherapy-related toxicity or stopped when tumor response or disease stabilization was achieved.9,11,12

arrow up What were the clinical trial results with Avastin?

In both first- and second-line MCRC, Avastin-based therapy has consistently demonstrated superior survival results over chemotherapy alone.

  • Avastin plus IFL (Study 2107) resulted in a 4.7-month (30%) increase in median overall survival vs IFL alone 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 weeks1,9

  • Avastin plus IV 5-FU/LV (combined analysis) resulted in a 3.3-month (23%) increase in median overall survival vs a "combined control" of IV 5-FU/LV or IFL alone in previously untreated patients10

  • Avastin plus FOLFOX4 (Study E3200) resulted in a 2.2-month (20%) increase in median overall survival vs FOLFOX4 alone. This is the first treatment to extend median overall survival beyond 1 year in a Phase III trial for second-line MCRC1

Significant survival benefit across MCRC treatment lines and regimens1,9,10

Avastin Efficacy - Results from randomized clinical trials

  • *Difference statistically significant.
  • †Phase III trial evaluating placebo plus IFL (Arm 1) and Avastin 5 mg/kg q2w plus IFL (Arm 2).
  • ‡Combined analysis of 3 randomized, controlled trials comparing Avastin 5 mg/kg q2w plus IV 5-FU/LV vs a “combined control” of IV 5-FU/LV or IFL alone.
  • §Phase III trial of patients previously treated with irinotecan and 5-FU evaluating FOLFOX4 (Arm 1) and Avastin 10 mg/kg q2w plus FOLFOX4 (Arm 2).

Results From the Pivotal Phase III Trials

arrow up What was the effect of Avastin-based therapy on other efficacy endpoints?

Avastin-based therapy resulted in significant increases in progression-free survival and overall response rate in the pivotal Phase III trials.

Progression-free survival and response rates in studies 2107 and E32001,9,11

  • ǁDifference statistically significant.
  • ¶In Study 2107, 143 patients in the placebo plus IFL group and 180 patients in the Avastin plus IFL group responded to treatment.11

    Tumor response was determined based on RECIST criteria. Partial response was defined as ≥30% decrease in the sum of the longest diameter of all target lesions; complete response was defined as the disappearance of all target lesions; measurements confirmed after 4 weeks.13

arrow up What patient subgroups were analyzed in clinical trials?

In the pivotal Phase III trials, a number of subgroups were analyzed based on patient- and disease-related parameters, including age, sex, race, ECOG performance status, location of primary tumor, prior adjuvant therapy, number of metastatic sites, tumor burden, and prior radiotherapy.1,9,11

The clinical benefit of Avastin, as measured by overall survival, was observed across all patient subgroups analyzed.1,9,11

Safety Profile

arrow up What is the safety profile of Avastin?

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

Avastin plus IFL (first-line MCRC)1
Selected grade 3–4 adverse events

  • †Difference statistically significant (P<0.01).
  • ‡Central laboratories were collected on days 1 and 21 of each cycle. Neutrophil counts are available in 303 patients receiving placebo plus IFL and 276 patients receiving Avastin plus IFL.
Avastin plus FOLFOX4 (second-line MCRC)1
Selected grade 3–5 adverse events

  • In second-line MCRC, Avastin 10 mg/kg q2w plus FOLFOX4 maintained a safety profile consistent with Avastin 5 mg/kg q2w plus IFL in first-line treatment, while significantly extending overall survival1,9

arrow up What are the most serious adverse events associated with Avastin?

The most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events that may have occurred in Avastin indications (first-line NSCLC, first- and second-line MCRC) included neutropenia, fatigue, hypertension, infection, hemorrhage, asthenia, abdominal pain, pain, deep vein thrombosis, intra-abdominal thrombosis, syncope, diarrhea, constipation, leukopenia, nausea, vomiting, dehydration, ileus, neuropathy–sensory, neurologic-other, and headache.

arrow up What are the most common adverse events associated with Avastin?

The most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events that may have occurred in Avastin indications (first-line NSCLC, first- and second-line MCRC) included neutropenia, fatigue, hypertension, infection, hemorrhage, asthenia, abdominal pain, pain, deep vein thrombosis, intra-abdominal thrombosis, syncope, diarrhea, constipation, leukopenia, nausea, vomiting, dehydration, ileus, neuropathy–sensory, neurologic-other, and headache.

arrow up What should I know about hypertension?

Incidence: In the pivotal Phase III trials, the incidence of severe hypertension was increased in patients receiving Avastin. Across clinical studies, the incidence of grade 3 or 4 hypertension ranged from 8% to 18%. Up to 1.7% of patients developed severe hypertension resulting in hospitalization or discontinuation of therapy.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: Standard oral antihypertensives (including angiotensin-converting enzyme inhibitors, beta blockers, calcium channel blockers, and diuretics) were used in the management of grade 3 hypertension. Avastin should be temporarily suspended in patients with severe hypertension not controlled with medical management and permanently discontinued in patients with hypertensive crisis.1

arrow up What should I know about proteinuria and nephrotic syndrome?

Incidence: In the pivotal Phase III trials, both the incidence and severity of proteinuria were increased in patients receiving Avastin. In pivotal MCRC trials, the incidence of grade 3–4 proteinuria (characterized as >3.5 g/24 hours) ranged up to 1.8% in Avastin-treated patients. Nephrotic syndrome was uncommon in clinical trials, occurring in 5 of 1032 (<0.5%) patients.1

Monitoring: Patients should also be monitored for the development or worsening of proteinuria with serial urinalysis. Patients with 2+ or greater urine dipstick reading should undergo further assessment (eg, 24-hour urine collection).1

Management: In most clinical studies, Avastin was interrupted for ≥2 g of proteinuria/24 hours and resumed when proteinuria was <2 g/24 hours. Avastin should be discontinued in patients with nephrotic syndrome. 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

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

Arterial thromboembolic events occurred at a higher incidence in patients receiving Avastin with chemotherapy (4.4%) vs chemotherapy alone (1.9%); less than 1% of events were fatal. There was a correlation between age (65 years and older) and increased risk. Avastin should be permanently discontinued in patients who experience a severe AT event while on treatment. The safety of resuming Avastin therapy after resolution of an AT event has not been studied.1

arrow up What should I know about gastrointestinal (GI) perforation?

The incidence of GI perforation in patients receiving Avastin plus chemotherapy for MCRC was 2.4%. Events were sometimes associated with intra-abdominal abscess and were not correlated to duration of therapy. Patients who developed GI perforation typically reported symptoms including abdominal pain, constipation, and vomiting. GI perforation should be included in the differential diagnosis of patients presenting with abdominal pain on Avastin.1

arrow up What should I know about wound healing complications?

Avastin administration can result in the development of wound dehiscence, in some instances resulting in fatality. The appropriate interval between termination of Avastin and subsequent elective surgery required to avoid the risks of impaired wound healing/wound dehiscence has not been determined. Therapy should not be initiated for at least 28 days following surgery. The half-life of Avastin (~20 days; range 11–50 days) should be considered when determining this interval. The surgical incision should be completely healed before starting therapy with Avastin. Permanently discontinue Avastin in patients with wound dehiscence requiring medical intervention.1

arrow up What should I know about hemorrhage?

Two distinct patterns of bleeding have occurred in patients receiving Avastin. The first is minor hemorrhage, most commonly grade 1 epistaxis. The second is serious, and in some cases fatal, hemorrhagic events, which occurred primarily in patients with non-small cell lung cancer.1

Mild epistaxis (grade 1) occurred in 35% of colorectal cancer patients receiving Avastin plus IFL in Study 2107. Epistatic events (nosebleeds) were generally mild in severity and resolved without medical intervention. Grade 3–5 bleeding events occurred in 5% of patients receiving Avastin plus FOLFOX4 in Study E3200. Patients with recent hemoptysis (≥1/2 tsp of red blood) should not receive Avastin. Permanently discontinue Avastin in patients with serious bleeding.1

arrow up 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 (eg, 24-hour urine collection) and should be monitored regularly until improvement and/or resolution is observed.1

arrow up What are the dose modification recommendations for Avastin?

Permanently discontinue Avastin in patients with GI perforation (GI perforation, fistula formation in the GI tract, intra-abdominal abscess), wound dehiscence requiring medical intervention, serious bleeding, fistula formation involving an internal organ, severe ATE, nephrotic syndrome, hypertensive crisis, or hypertensive encephalopathy. In patients developing RPLS, discontinue Avastin and initiate treatment of hypertension if present. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. Temporary suspension is recommended in patients with evidence of moderate to severe proteinuria, in patients with severe hypertension that is not controlled with medical management, and for at least several weeks prior to elective surgery. Avastin should not be resumed until the surgical incision is fully healed. Patients who become pregnant while on Avastin therapy should be counseled regarding possible risk to the fetus and/or loss of pregnancy.

Dosing and Administration

arrow up 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) every 2 weeks until disease progression, per study protocols. The only Avastin dosages proven to provide a survival benefit are 5 mg/kg every 2 weeks with IFL (studied in first-line MCRC) and 10 mg/kg every 2 weeks with FOLFOX4 (studied in second-line MCRC).1

Avastin dosing in MCRC clinical trials1*

Avastin dosing in MCRC clinical trials

  • *Avastin is indicated for use with IV 5-FU–containing regimens.

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

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.1

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 reactions and appropriate medical therapy administered.1

arrow up How should Avastin vials be stored?

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

arrow up How long should Avastin be continued?

Per MCRC trial protocols, Avastin was continued until disease progression and was not modified due to chemotherapy-related toxicity or stopped when tumor response or stable disease was achieved. As demonstrated in Study 2107 and Study E3200, Avastin plus IV 5-FU/LV could be maintained following titration or discontinuation of combination chemotherapy due to increased toxicity.9,11,12

MCRC trial protocols1,9-12

Duration of Avastin therapy

Reimbursement Support and Customer Service

arrow up 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

arrow up 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 Medical Information/Communications at 1-800-821-8590 between 5 AM and 5 PM (PST). Medical Information Request Forms may also be submitted through the "contact us" section of Avastin.com.

Summary

arrow up Avastin plus IV 5-FU–containing chemotherapy: superior survival results over chemotherapy alone in both first- and second-line MCRC

First-line MCRC1,9:

  • Proven efficacy in combination with IFL vs IFL alone (pivotal Phase III trial, n=813)

    • 4.7-month (30%) increase in median overall survival (20.3 vs 15.6 months, P<0.001)

    • 4.4-month (71%) increase in median progression-free survival (10.6 vs 6.2 months, 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 MCRC1,11:

  • Proven efficacy in combination with FOLFOX4 vs FOLFOX4 alone (pivotal Phase III trial, n=585)

    • 2.2-month (20%) increase in median overall survival (13.0 vs 10.8 months, P=0.001)

    • 3-month (67%) increase in median progression-free survival (7.5 vs 4.5 months, P<0.001)

    • Significant increase in overall response rate (22% vs 9%, P<0.001)

Avastin is approved in combination with all regimens containing IV 5-FU, including 5-FU/LV, IFL, FOLFIRI, and FOLFOX.

Next: Proteinuria and Hypertension QH

Boxed WARNINGS and Additional Important Safety Information

Gastrointestinal (GI) perforation: Avastin administration can result in the development of GI perforation, in some cases resulting in fatality. GI perforation, sometimes associated with intra-abdominal abscess, occurred throughout treatment with Avastin. Permanently discontinue Avastin therapy in patients with GI perforation.

Wound healing complication: Avastin administration can result in the development of wound dehiscence, in some instances resulting in fatality. Permanently discontinue Avastin therapy in patients with wound dehiscence requiring medical intervention. The appropriate interval between termination of Avastin and subsequent elective surgery has not been determined.

Hemorrhage: Severe, and in some cases fatal, pulmonary hemorrhage can occur in patients with NSCLC treated with chemotherapy and Avastin. Do not administer Avastin to patients with recent hemoptysis (≥1/2 tsp of red blood). Permanently discontinue Avastin in patients with serious hemorrhage and initiate aggressive medical management.

Additional serious adverse events included non-GI fistula formation, arterial thromboembolic events, hypertensive crisis, reversible posterior leukoencephalopathy syndrome, neutropenia and infection, nephrotic syndrome, and congestive heart failure.

The most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events that may have occurred in Avastin indications (first-line NSCLC, first- and second-line MCRC) included neutropenia, fatigue, hypertension, infection, hemorrhage, asthenia, abdominal pain, pain, deep vein thrombosis, intra-abdominal thrombosis, syncope, diarrhea, constipation, leukopenia, nausea, vomiting, dehydration, ileus, neuropathy–sensory, neurologic–other, and headache.

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

References
  1. Avastin Prescribing Information. Genentech, Inc. March 2008.
  2. Kerbel R, Folkman J. Nat Rev Cancer. 2002; 2:727-739.
  3. Lee CG, Heijn M, di Tomaso E, et al. Cancer Res. 2000;60:5565-5570.
  4. Inai T, Mancuso M, Hashizume H, et al. Am J Pathol. 2004;165:35-52.
  5. Gerber HP, Ferrara N. Cancer Res. 2005;65:671-680.
  6. Jain RK. Science. 2005; 307:58-62.
  7. Tong RT, Boucher Y, Kozin SV, et al. Cancer Res. 2004;64:3731-3736.
  8. Hicklin DJ, Ellis LM. J Clin Oncol. 2005;23:1011-1027.
  9. Hurwitz H, Fehrenbacher L, Novotny W, et al. N Engl J Med. 2004;350:2335-2342.
  10. Kabbinavar FF, Hambleton J, Mass RD, et al. J Clin Oncol. 2005;23:3706-3712.
  11. Data on file. Genentech, Inc.
  12. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology-v.1.2008. Colon Cancer. Available at: http://www.nccn.org/professionals/physician_gls/PDF/colon.pdf. Accessed July 13, 2006.
  13. Therasse P, Arbuck SG, Eisenhauer EA, et al. J Natl Cancer Inst. 2000;92:205-216.