Efficacy in MCRC

Avastin plus FOLFOX4 results in significant clinical benefits in second-line 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 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 for initial therapy for metastatic disease or as adjuvant therapy.1

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%)
Avastin plus FOLFOX4 results in significant clinical benefits in second-line MCRC

Avastin plus FOLFOX4 increased OS by 2.2 months (20%) over FOLFOX4 alone (13.0 vs 10.8 months, P=0.001). The 13-month median OS 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 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, 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-treated group, median PFS was increased by 67% (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 FOLFOX.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 and additional important safety information

  • 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 dehiscence 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 and sometimes fatal adverse events for which the incidence was increased in the Avastin-treated arm vs control included non-GI fistula formation (≤0.3%), arterial thromboembolic events (grade ≥3, 2.4%), and proteinuria including nephrotic syndrome (<1%). Additional serious adverse events for which the incidence was increased in the Avastin-treated arm vs control included hypertension (grade 3–4, 5%–18%) and 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

  • 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, back pain, and exfoliative dermatitis. Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions

  • 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 safety information.

Next: Dose and Duration in MCRC

References
  1. Avastin Prescribing Information, Genentech, Inc. July 2009.
  2. Giantonio BJ, Catalano PJ, Meropol NJ, et al. J Clin Oncol. 2007;25:1539-1544.
  3. Data on file. Genentech, Inc.