Receive additional information

Register Now

Unsubscribe

Manage Your Communications


 

Significant survival benefits observed in first-line MCRC with Avastin plus IV 5-FU–based 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 as a solution for IV infusion 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 OS; secondary efficacy endpoints—ORR, PFS, 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 or unacceptable toxicity per study protocol.2

Phase III Study 2107 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 OS

In Study 2107, Avastin plus IFL achieved its primary endpoint by demonstrating a statistically significant 4.7-month (30%) increase in median OS vs placebo plus IFL (20.3 vs 15.6 months, HR=0.66 [95% CI, 0.54–0.81], P<0.001). Avastin is the only FDA-approved biologic to demonstrate a significant first-line survival benefit in the overall population of a Phase III MCRC trial. This survival benefit was achieved with Avastin given until disease progression or unacceptable toxicity, per study protocol. The median duration of therapy in the Avastin plus IFL treatment group was 40.4 weeks.1,2

Boxed WARNINGS

  • Gastrointestinal (GI) perforation
    • Serious and sometimes fatal GI perforation occurs at a higher incidence (up to 2.4%) in Avastin-treated patients compared to controls. Discontinue Avastin for 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
    • Discontinue in patients with wound dehiscence. Discontinue at least 28 days prior to elective surgery
    • Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed
  • Hemorrhage
    • Severe or fatal hemorrhage, hemoptysis, GI bleeding, CNS hemorrhage, and vaginal bleeding are increased in Avastin-treated patients. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis

Click here for additional important safety information.

30% increase in median OS* with Avastin plus IFL in first-line MCRC1-3

30% increase in overall survival (OS) with Avastin plus IFL in first-line MCRC

  • *Median OS: 20.3 vs 15.6 months (HR=0.66 [95% CI, 0.54–0.81], P<0.001).1,2

Significant increases in other efficacy endpoints

In addition to the significant increase in OS, Avastin plus IFL also demonstrated significant survival benefits in secondary trial endpoints. Compared with placebo plus IFL, Avastin plus IFL resulted in a 4.4-month (71%) increase in median PFS (10.6 vs 6.2 months, HR=0.54 [95% CI, 0.45–0.66], 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

71% increase in median PFS† in first-line MCRC1,2

Avastin based therapy - Progression-free survival in Study 2107

  • †Median PFS: 10.6 vs 6.2 months (HR=0.54 [95% CI, 0.45–0.66], P<0.001).

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

ORR in Study 21071,2

Avastin based therapy - Tumor response in Study 2107

  • ‡P<0.01.

Important safety information—Study 2107

  • 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%)

Avastin plus IV 5-FU–based therapy: Consistent first-line OS benefits across multiple MCRC patient subgroups1-3

OS demonstrated across a broad range of prespecified subgroups1-3§

Increased survival demonstrated across subgroups in first-line MCRC

  • §All of the above were prespecified analyses, with the exception of the liver-only disease subgroup analysis. Additional prespecified subgroups with survival increases
      included age <40, ages 40–64, race, location of primary tumor, duration of metastatic disease, baseline albumin, baseline alkaline phosphatase, baseline lactate
      dehydrogenase, duration of disease, sum of the longest diameters of target lesions, and prior radiotherapy.3
  • ||Eligible patients had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1, with less than 1% (n=3) of the study population having an
      ECOG score of >1.
  • The organs with the most frequent occurrence of metastatic disease were liver (78%), lung (48%), and lymph nodes (25%).3
  • #Based on an exploratory analysis of prospectively collected data.

Investigators observed consistent trends for increased PFS and ORR in the Avastin plus IFL arm across predefined baseline characteristics.2

Phase II first-line Study 2192

  • Study 2192 was a randomized, controlled Phase II study that evaluated Avastin plus IV 5-FU/LV vs placebo plus IV 5-FU/LV in patients unsuitable for first-line irinotecan and who were of advanced age (≥65 years) and/or had a poor ECOG PS (≥1)4

Median OS in first-line Phase II Study 2192: 16.6 months for Avastin plus IV 5-FU/LV vs 12.9 months for placebo plus IV 5-FU/LV (HR=0.79, P=0.16)4

3.7-month increase in PFS** in patients not suitable for first-line irinotecan-based chemotherapy4

67% increase in PFS in patients not suitable for first-line combination chemotherapy

  • **Median PFS: 9.2 vs 5.5 months (HR=0.50 [95% CI, 0.34–0.73], P=0.0002).

Resection of metastases with bevacizumab-based therapy is included in the NCCN guidelines for colorectal cancer5

Resection of metastases with bevacizumab-based therapy is supported by the 2011 NCCN guidelines for colorectal cancer

  • Adapted from National Comprehensive Cancer Network (NCCN) Colon Cancer Clinical Practice Guidelines.
  • FOLFIRI=5-FU/LV/irinotecan.
  • ††Treatment given before surgery in order to reduce the size of the tumor.

Avastin treatment considerations for resectable first-line MCRC patients

FDA-approved Prescribing Information treatment timeline to address surgery and wound healing complications1

NCCN treatment timeline for resectable first-line MCRC patients

  • ‡‡Hold Avastin for 28 days or until incision is fully healed.

  • Avastin therapy should not be initiated for at least 28 days following major surgery. The surgical incision should be fully healed prior to initiation of Avastin
  • The appropriate interval between discontinuation of Avastin and subsequent elective surgery required to reduce the risk of impaired wound healing/wound dehiscence has not been determined. The calculated half-life of Avastin (~20 days; range 11–50 days) should be taken into consideration. Suspend Avastin for at least 28 days prior to elective surgery
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: Second-line MCRC

References:
  1. Avastin Prescribing Information. Genentech, Inc. September 2011.
  2. Hurwitz H, Fehrenbacher L, Novotny W, et al. N Engl J Med. 2004;350:2335-2342.
  3. Data on file. Genentech, Inc.
  4. Kabbinavar FF, Schulz J, McCleod M, et al. J Clin Oncol. 2005;23:3697-3705.
  5. The NCCN Colon Cancer Clinical Practice Guidelines in Oncology (Version 3.2011). ©2011 National Comprehensive Cancer Network, Inc. http://www.nccn.org. Accessed March 4, 2011. To view the most recent and complete version of the guidelines, go online to www.nccn.org.