Efficacy in CRC

Significant survival benefits seen in first-line MCRC with Avastin plus
IV 5-FU–containing regimens

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 IV every 2 weeks (q2w) (Arm 2), or IV 5-FU/LV plus Avastin 5 mg/kg IV 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 21071-3

Avastin based therapy - Overall survival in Study 2107

  • *Median OS: 20.3 vs 15.6 months
    (HR=0.66, P<0.001).1,2

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.1-3

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

Early separation of the PFS curves in Study 2107 reflects the significant reduction in the risk of disease progression with Avastin plus IFL. In pivotal first-line Study 2107, nearly 90% of patients who remained progression free at 1 year were still receiving Avastin.2,3 Compared with IFL alone, Avastin plus IFL also resulted in a significant increase in overall response rate (45% vs 35%, P<0.01).1,2

Progression-free survival† in Study 21071,2

Avastin based therapy - Progression-free survival in Study 2107

  • †Median PFS: 10.6 vs 6.2 months
    (HR=0.54, P<0.001).1,2

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.4
  • §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

 

 

Indication

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.

Boxed WARNINGS and Additional Important Safety Information

  • Gastrointestinal (GI) perforation: The incidences of GI perforation, some fatal, in Avastin-treated patients range from 0.3% to 2.4%. Discontinue Avastin in patients with 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. Do not initiate Avastin for at least 28 days after surgery or until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound dehiscence requiring medical intervention

  • Hemorrhage: Severe or fatal hemorrhage, including hemoptysis, GI bleeding, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6%. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood). Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)

  • Additional serious adverse events for which the incidence was increased in the Avastin-treated arm vs control included non-GI fistula formation, arterial thromboembolic events, hypertension, reversible posterior leukoencephalopathy syndrome, proteinuria including nephrotic syndrome, and infusion reactions

  • 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, and exfoliative dermatitis

  • 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

  • The most common grade 3–5 (nonhematologic) 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

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

References
  1. Avastin Prescribing Information. Genentech, Inc. November 2008.
  2. Hurwitz H, Fehrenbacher L, Novotny W, et al. N Engl J Med. 2004;350:2335-2342.
  3. Data on file. Genentech, Inc.
  4. Therasse P, Arbuck SG, Eisenhauer EA, et al. J Natl Cancer Inst. 2000;92:205-216.