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When combined with FOLFOX4, Avastin is the only FDA-approved biologic with an OS benefit in second-line MCRC1

Avastin in combination with FOLFOX4

Study E3200

The clinical benefits of Avastin plus IV 5-FU–based chemotherapy in second-line MCRC were demonstrated in Study E3200, a large trial conducted by ECOG. This was the first randomized Phase III trial of Avastin in combination with FOLFOX4. The primary endpoint was OS.1,2

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.1,2 However, per the study protocol, patients in the Avastin plus FOLFOX4 arm could continue to receive Avastin until disease progression or unacceptable toxicity. If IV 5-FU–containing chemotherapy was modified, treatment with Avastin could be continued until disease progression or unacceptable toxicity.3 Patients in this trial had previously been treated with irinotecan and 5-FU as initial therapy for metastatic disease or as adjuvant therapy.2

Phase III Study E3200 study design1,2

Phase III Study E3200 study design

Important safety information—Study E3200

  • 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 (18% vs 13%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), ileus (4% vs 1%), neuropathy–sensory (17% vs 9%), neurologic–other (5% vs 3%), fatigue (19% vs 13%), abdominal pain (8% vs 5%), headache (3% vs 0%), hypertension (9% vs 2%), and hemorrhage (5% vs 1%)
When combined with FOLFOX4, Avastin is the only FDA-approved biologic with an OS benefit in second-line MCRC1

Avastin plus FOLFOX4 increased OS by 2.2 months (20%) over FOLFOX4 alone (13.0 vs 10.8 months [HR=0.75 (95% CI, 0.63–0.89)], P=0.001). With these results, Avastin (in combination with IV 5-FU–based chemotherapy) is the first biologic therapy proven to extend median OS beyond 1 year in second-line MCRC.1,2

20% increase in median OS* with Avastin plus FOLFOX4 in second-line MCRC1-3

20% increase in median OS with Avastin plus FOLFOX4 in second-line MCRC

  • *Median OS: 13.0 vs 10.8 months (HR=0.75 [95% CI, 0.63–0.89], P=0.001).1,2
Significant increases in secondary study endpoints

In addition to the survival benefit demonstrated in Study E3200, Avastin plus FOLFOX4 also resulted in significant increases in secondary study endpoints. In the Avastin plus FOLFOX4–treated group, median PFS was increased by 55% (HR=0.61; 7.3 vs 4.7 months, P<0.0001) and ORR more than doubled (23% vs 9%, P<0.0001). Early separation of the PFS curves in Study E3200 reflects the significant reduction in the risk of disease progression with Avastin plus FOLFOX4.2

55% increase in median PFS† in second-line MCRC2

Progression-free survival and tumor response in Study E3200

  • †Median PFS: 7.3 vs 4.7 months (HR=0.61, P<0.0001).
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
  • Gastrointestinal (GI) perforation
    • Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls
    • The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies
    • 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 and 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 healing complications requiring medical intervention
  • Hemorrhage
    • Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, 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
  • Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs control included
    • Non-GI fistula formation (≤0.3%)
    • Arterial thromboembolic events (grade ≥3, 2.4%)
    • Proteinuria including nephrotic syndrome (<1%)
  • Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included
    • Hypertension (grade 3–4, 5%–18%)
    • Reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%)
  • Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients
  • Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin
Most common adverse events
  • 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
    – Back pain
    – Exfoliative dermatitis
  • Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions
Pregnancy warning
  • Avastin may impair fertility
  • Based on animal data, Avastin may cause fetal harm
  • Advise patients of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following the last dose of Avastin
  • For nursing mothers, discontinue nursing or Avastin, taking into account the importance of Avastin to the mother
  • In first-line MCRC, the most common grade 3–4 events in Study 2107, which occurred at a ≥2% higher incidence in the Avastin plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%)
  • In second-line MCRC, 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 (18% vs 13%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), ileus (4% vs 1%), neuropathy–sensory (17% vs 9%), neurologic–other (5% vs 3%), fatigue (19% vs 13%), abdominal pain (8% vs 5%), headache (3% vs 0%), hypertension (9% vs 2%), and hemorrhage (5% vs 1%)

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

Next: Dose and Duration in MCRC

References:
  1. Giantonio BJ, Catalano PJ, Meropol NJ, et al. J Clin Oncol. 2007;25:1539-1544.
  2. Avastin Prescribing Information. Genentech, Inc. September 2011.
  3. Data on file. Genentech, Inc.