Efficacy in CRC

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

Avastin in combination with IFL

Study 2107

The pivotal trial of Avastin in first-line MCRC was Study 2107. In this randomized, controlled Phase III trial (N=923), patients were randomized to receive IFL plus placebo (Arm 1), IFL plus Avastin 5 mg/kg q2w (Arm 2), or IV 5-FU/LV plus Avastin 5 mg/kg q2w (Arm 3). The primary endpoint in Study 2107 was overall survival; secondary efficacy endpoints—overall response rate, progression-free survival, and response duration—were also assessed.1,2 In situations where early discontinuation of chemotherapy was required due to increased toxicity, Avastin could be continued until disease progression per study protocol.2

Phase III study design1,2

Avastin based therapy - Phase III Study design

Arm 3 was initiated so that an analysis could be completed in the event that safety issues required discontinuation of Arm 2. As prespecified, enrollment in this treatment arm was discontinued when the relative safety of Avastin plus IFL was established in an interim analysis.1,2

Significant increase in overall survival

In Study 2107, Avastin plus IFL achieved its primary endpoint by demonstrating a statistically significant 30% increase in median overall survival vs IFL alone (20.3 vs 15.6 months, HR=0.66, P<0.001). The 4.7-month increase in survival attributable to Avastin plus IFL is larger than that observed in any Phase III MCRC trial to date. This survival benefit was achieved with Avastin given until disease progression, per study protocol. The median duration of therapy in the treatment group was 40.4 weeks.1,2

Overall survival in Study 21071,2,5

Avastin based therapy - Overall survival in Study 2107

The hazard ratio of death of 0.66 in this trial with Avastin plus IFL corresponds to a 34% reduction in the risk of death vs IFL alone. Moreover, the survival benefit of Avastin plus IFL was observed early in treatment and was durable. At 2 years, nearly half of patients in the Avastin plus IFL arm (45%) remained alive.1,2,5

Significant increases in other efficacy endpoints

In addition to the significant increase in overall survival, Avastin plus IFL also demonstrated significant benefits in secondary trial endpoints. Compared with IFL alone, Avastin plus IFL resulted in a 4.4-month (71%) increase in median progression-free survival (10.6 vs 6.2 months, P<0.001).1,2

Progression-free survival in Study 21071,2

Avastin based therapy - Progression-free survival in Study 2107

Avastin plus IFL also resulted in significant increases in tumor response. Overall response rate was 45% with Avastin plus IFL vs 35% with IFL alone (P<0.01), while duration of response increased by 46% in the Avastin arm (10.4 vs 7.1 months).1,2

Tumor response in Study 21071,2

Avastin based therapy - Tumor response in Study 2107

  • *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
  • †Difference statistically significant.
Important safety information-Study 2107

The most common grade 3–4 events in Study 2107, which occurred at a higher incidence (≥2%) in the Avastin plus IFL vs IFL groups, were asthenia, abdominal pain, pain, hypertension, deep vein thrombosis, intra-abdominal thrombosis, syncope, diarrhea, constipation, leukopenia, and neutropenia.

Next: Survival Benefit Across All Patient Subgroups

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. Hurwitz H, Fehrenbacher L, Novotny W, et al. N Engl J Med. 2004;350:2335-2342.
  1. Data on file. Genentech, Inc.
  1. Therasse P, Arbuck SG, Eisenhauer EA, et al. J Natl Cancer Inst. 2000;92:205-216.