Efficacy in NSCLC

Efficacy results from Study E4599

A significant survival benefit

With a median overall survival of 12.3 months, a significant increase over PC alone, Avastin plus PC is the first treatment regimen to demonstrate median overall survival (OS) >1 year in any Phase III metastatic non-small cell lung cancer (NSCLC) trial.1 As shown in the Kaplan-Meier graph below, patients receiving Avastin plus PC vs PC alone were 16% more likely to be alive at 1 year (51% vs 44%) and 53% more likely to be alive at 2 years (23% vs 15%).2

Avastin, in combination with PC, significantly increased OS in first-line non-squamous NSCLC

The statistically significant survival benefit of Avastin was observed as early as 6 months and was sustained through 2 years in Study E45991,2

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)

Longer progression-free survival based on investigator assessment

In addition to the significant survival benefit, Avastin plus PC also demonstrated a significant increase in progression-free survival (PFS). Compared with PC alone, Avastin plus PC increased PFS by 38% (6.2 vs 4.5 months; HR=0.66 [95% CI, 0.57 to 0.77], P<0.001), with more than half of Avastin-treated patients progression free at 6 months. This increase in PFS with Avastin plus PC was investigator-assessed and has not been independently verified.1,2

Based on investigator assessment (not independently verified), Avastin plus PC resulted in a 38% increase in median PFS vs PC alone1,2

Progression Free Survival

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%).

Phase II trial: Study AVF0757g

The design for the definitive Phase III trial (Study E4599) was based on the findings from an earlier randomized, controlled trial. Study AVF0757g was a Phase II trial (N=99) of Avastin plus PC vs PC alone that evaluated Avastin at doses of 15 mg/kg IV every 3 weeks (q3w). In this trial, no significant increase in time to progression was seen in the lower dose (7.5 mg/kg IV q3w) vs the control arm (4.3 vs 4.2 months). However, Avastin-based therapy at a dose of 15 mg/kg IV q3w resulted in a 76% increase in time to progression vs the control arm (7.4 vs 4.2 months; P=0.023).3 Based on these results, ECOG established 15 mg/kg IV q3w as the dose of Avastin in Study E4599.2

15 mg/kg IV q3w is the only dose of Avastin proven to increase OS in first-line advanced non-squamous NSCLC

15 mg/kg IV q3w was proven superior to 7.5 mg/kg IV q3w in a Phase II trial (Study AVF0757g)3
Efficacy results in E4599 study on Avastin and non-small cell lung cancer (NSCLC)
  • *Patients in the PC alone arm could cross over to an Avastin arm upon progression.
  • †P=0.023 vs control arm.
  • ‡P value was not significant vs control arm.

Patients in the PC arm were allowed to cross over to Avastin alone at disease progression, and 19 of the 32 patients in this group did so. Among these patients, the median duration of treatment was 12 weeks, and 5 patients received Avastin for more than 6 months. One year after crossover, 47.4% (9 of 19) of these patients were still alive.3

Important safety information—Study AVF0757g

The most common events of any severity (≥10% incidence) in the Avastin plus PC group in Study AVF0757g were nausea, leukopenia, neuropathy, peripheral neuritis, infection, paresthesia, vomiting, diarrhea, thrombocytopenia, and fever. In this trial, the incidence of serious or fatal pulmonary hemorrhage was 31% (4 of 13) in Avastin-treated patients with squamous cell histology and 4% (2 of 53) in Avastin-treated patients with histology other than squamous cell. As a result, patients with squamous cell histology were excluded from Study E4599.

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 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

  • 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 safety information.

Next: Benefit-risk Ratio

References
  1. Avastin Prescribing Information, Genentech, Inc. July 2009.
  2. Sandler A, Gray R, Perry MC, et al. N Engl J Med. 2006;355:2542-2550.
  3. Johnson DH, Fehrenbacher L, Novotny WF, et al. J Clin Oncol. 2004;22:2184-2191.