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Avastin plus PC: A significant advance in first-line non-squamous NSCLC treatment

Efficacy overview

In a pivotal Phase III trial in the first-line treatment of metastatic non-squamous NSCLC (ECOG Study E4599), Avastin plus PC demonstrated important first-line clinical benefits over PC alone, including a significant increase in overall survival (OS).1,2

In Study E4599, Avastin plus PC demonstrated clinically meaningful 1- and 2-year survival rates in first-line metastatic non-squamous NSCLC (51% and 23%, respectively, vs 44% and 15% with PC alone)2

Avastin plus PC significantly increased median OS by 19% (12.3 vs 10.3 months with PC alone) in Study E45991

Median overall survival in Avastin E4599 study on non-small cell lung cancer (NSCLC) efficacy: 12.3 vs 10.3 months (HR=0.80,* P=0.013)

  • ECOG=Eastern Cooperative Oncology Group.
  • HR=hazard ratio; CI=confidence interval.

The significant survival benefit of Avastin plus PC in non-squamous NSCLC was achieved with Avastin given until disease progression. Per the pivotal trial protocol, patients in the investigational arm received Avastin 15 mg/kg solution for intravenous (IV) infusion every 3 weeks (q3w) plus chemotherapy for up to 6 cycles, after which patients continued to receive Avastin 15 mg/kg IV q3w alone until disease progression or unacceptable toxicity. Chemotherapy dose modifications or delays did not impact the administration of Avastin therapy.1,3

  • Avastin plus PC demonstrated a median progression-free survival of 6.2 months (vs 4.5 months with PC alone, HR=0.66 [95% CI, 0.57–0.77], P<0.001) in Study E4599, based on investigator assessment (not independently verified)1,2
  • Avastin plus PC had a response rate of 35% vs 15% with PC alone (P<0.001), based on investigator assessment (not independently verified)2
  • In the absence of disease progression, 60% of patients receiving Avastin + PC in Study E4599 completed 6 cycles of therapy (vs. 44% in the PC alone arm), thereby making those patients eligible to continue Avastin alone until disease progression or unacceptable toxicity3

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

Important safety information—Study E4599

  • Grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a ≥2% higher incidence in Avastin-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thrombus/embolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%)
Indication

Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.

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 NSCLC, grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a ≥2% higher incidence in Avastin-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thrombus/embolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%)

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

Next: Overall Survival

References:
  1. Avastin Prescribing Information. Genentech, Inc. September 2011.
  2. Sandler A, Gray R, Perry MC, et al. N Engl J Med. 2006;355:2542-2550.
  3. Data on file. Genentech, Inc.