Efficacy in CRC

Avastin-based therapy in first-line MCRC: Superior survival results over chemotherapy alone

Avastin in combination with IV 5-FU/LV

Multiple randomized, controlled trials

Avastin has been evaluated in combination with IV 5-FU/LV in 3 randomized, controlled studies in the first-line treatment of MCRC. In each of these trials, the clinical benefits of Avastin plus IV 5-FU/LV were achieved when Avastin was used until disease progression, per study protocols.6,7,9

Results from 3 randomized trials1,6,7,9

Results from 3 randomized trials

  • *Difference statistically significant.
Study designs

  • Study 0780: Randomized, controlled Phase II study of IV 5-FU/LV ± Avastin6

  • Study 2192: Randomized, controlled Phase II study of IV 5-FU/LV ± Avastin in patients deemed not suitable for first-line irinotecan (age ≥65 years, ECOG† 1 or 2, albumin ≤3.5 g/dL, or prior radiotherapy to abdomen or pelvis)7

  • Study 2107: Pivotal Phase III study included a group receiving Avastin plus IV 5-FU/LV (Arm 3); enrollment in this group was discontinued when the relative safety of Avastin plus IFL was established9

    • For this comparison, the control group was Arm 1(IFL)

  • †Eastern Cooperative Oncology Group
Combined analysis of Avastin plus IV 5-FU/LV studies

The 3 randomized, controlled trials that evaluated Avastin plus IV 5-FU/LV were subsequently combined into a single analysis, which allowed investigators to increase the sample size to better detect differences in overall and progression-free survival. This combined analysis (N=490) compared Avastin plus IV 5-FU/LV vs a “combined control” of either IV 5-FU/LV (n=141) or IFL (n=100) alone.3

Significant increases in overall and progression-free survival3‡

Significant increases in overall and progression-free survival

  • ‡Analysis includes patients from Study 0780 (Phase II trial), Study 2192 (Phase II trial of patients deemed not suitable for first-line irinotecan), and Study 2107 (pivotal first-line MCRC trial). In Study 2107, enrollment in the Avastin plus IV 5-FU/LV arm was discontinued when the relative safety of Avastin plus IFL was established. This analysis includes only patients who had enrolled in the study before this arm was discontinued.
  • §Difference statistically significant.
Clinical utility of Avastin plus IV 5-FU/LV

For patients who cannot tolerate intensive chemotherapy: With significant first-line clinical benefits, Avastin plus IV 5-FU/LV is recommended by NCCN guidelines as first-line treatment for patients who cannot tolerate intensive chemotherapy10—challenging patient types such as elderly or poor performance status patients.

The benefits of Avastin plus IV 5-FU/LV in this population were evaluated in Study 2192, which specifically included patients deemed not suitable for first-line irinotecan. The mean age in this study was 71 years (in the Avastin plus IV 5-FU/LV arm, 85% were >65 years). Approximately 75% of patients had an ECOG performance score of 1 or poorer (in the Avastin plus IV 5-FU/LV arm, 64% were ECOG 1 and 8% were ECOG 2). In this study, Avastin plus IV 5-FU/LV resulted in a 67% increase in progression-free survival over IV 5-FU/LV alone (9.2 vs 5.5 months, HR=0.50, P=0.0002).7

67% increase in PFS in patients not suitable for first-line combination chemotherapy7

67% increase in PFS

When chemotherapy-related toxicity requires treatment change: Per MCRC study protocols, Avastin administration was continued until disease progression and was not modified due to chemotherapy-related toxicity. In the pivotal trials for first-line MCRC (Study 2107) and second-line MCRC (Study E3200), the treatment strategy involved maintaining Avastin plus IV 5-FU/LV following titration or discontinuation of oxaliplatin or irinotecan, agents which are often associated with treatment-limiting toxicity.2,4,5 In particular, in clinical trials with oxaliplatin, cumulative neuropathy typically became intolerable after approximately 4 to 6 months, while gastrointestinal toxicity associated with irinotecan commonly required 1 or more dose reductions.11-14

A potential treatment strategy: Avastin plus IV 5-FU/LV after discontinuation of oxaliplatin or irinotecan, per study protocols5

Avastin plus IV 5-FU/LV

Next: In Combination with FOLFOX4

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. Genetech, Inc. March 2008.
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  1. Data on file. Genentech, Inc.
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  1. The Colon Cancer Clinical Practice Guidelines in Oncology (version 2.2007). ©2007 National Comprehensive Cancer Network, Inc. http://www.nccn.org. Accessed May 9, 2007. To view the most recent and complete version of the guidelines, go online to www.nccn.org.
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  1. Goldberg RM, Sargent DJ, Morton RF, et al. J Clin Oncol. 2004;22:23-30.
  1. Saltz LB, Cox JV,Blanke C, et al. N Engl J Med. 2000;343:905-914.
  1. Tournigand C, André T, Achille E, et al. J Clin Oncol. 2004;22:229-237.