Efficacy in CRC

Avastin-based therapy in second-line MCRC: Expanding the survival standard in MCRC

Avastin in combination with FOLFOX4

Study E3200

The clinical benefits of Avastin plus IV 5-FU–containing chemotherapy in second-line MCRC were demonstrated in Study E3200, a large cooperative group (ECOG) trial. This is the first randomized Phase III trial of Avastin in combination with FOLFOX4. The primary endpoint was overall survival.1,4

The primary comparisons for safety and efficacy were made between Avastin plus FOLFOX4 and FOLFOX4 alone. A third arm (Avastin alone) was also initiated, but closed early due to lower efficacy.1,4 However, per the study protocol, patients in the Avastin plus FOLFOX4 arm could continue to receive Avastin until disease progression in situations where early discontinuation of chemotherapy was required due to increased toxicity.4,5 Patients in this trial had previously been treated with irinotecan and 5-FU for initial therapy for metastatic disease or as adjuvant therapy.1

Phase III study design1,4

Phase III study design

Important safety information—Study E3200

The most common grade 3–5 (non hematologic) and 4–5 (hematologic) events in Study E3200, which occurred at a higher incidence (≥2%) in the Avastin plus FOLFOX4 vs FOLFOX4 groups, were diarrhea, nausea, vomiting, dehydration, ileus, neuropathy-sensory, neurologic-other, fatigue, abdominal pain, headache, hypertension, and hemorrhage.

Superior survival results over chemotherapy alone

Avastin plus FOLFOX4 increased overall survival by 2.2 months (20%) over FOLFOX4 alone (13.0 vs 10.8 months, P=0.001). The 13-month median overall survival with Avastin plus FOLFOX4 is the longest observed in a Phase III trial in second-line MCRC to date. Moreover, with these results, Avastin (in combination with chemotherapy) is the first and only biologic therapy proven to extend survival in second-line MCRC. In fact, more than half of Avastin-treated patients were alive at 1 year.1,4

Overall survival in Study E32004,5

Overall survival in Study E3200

Significant increases in secondary study endpoints

In addition to the significant survival benefit demonstrated in Study E3200, Avastin plus FOLFOX4 also resulted in significant increases in secondary study endpoints. In the Avastin-treated group, median progression-free survival was increased by 67% (7.3 vs 4.7 months, P<0.0001) and overall response rate more than doubled (23% vs 9%, P<0.0001).4

Progression-free survival and tumor response in Study E32004

Progression-free survival and tumor response in Study E3200

  • *Difference statistically significant.
  • †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.8

Next: Dosing and Administration

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.
  1. Giantonio BJ, Catalano PJ, Meropol NJ, et al. J Clin Oncol. 2007;25:1539-1544.
  1. Data on file. Genentech, Inc.
  1. Therasse P, Arbuck SG, Eisenhauer EA, et al. J Natl Cancer Inst. 2000;92:205-216.