Lung Cancer: Avastin Efficacy Data


Avastin® (bevacizumab) is a biologic cancer treatment that, when used in combination with paclitaxel/carboplatin (PC) chemotherapy, continues to remain a standard of care in first-line metastatic non-squamous non-small cell lung cancer (NSCLC), based on statistically significant overall survival (OS) demonstrated in Study E4599 over PC alone. [1,6,37]

Avastin plus PC prolonged survival in first-line advanced nsNSCLC

In Study E4599, median OS with Avastin plus PC was 12.3 months vs 10.3 months with PC alone (HR=0.80 [95% CI, 0.68–0.94], P=0.013) [1,6]

Avastin Clinical Study E4599 Overall Survival Percentage Graph
  • Median PFS with Avastin plus PC was 6.2 months vs 4.5 months with PC alone (HR=0.66 [95% CI, 0.57-0.77), P<0.001), based on investigator assessment (not independently verified) [1,6]
  • Response rate with Avastin plus PC was 35% vs 15% with PC alone (P<0.001), based on investigator assessment (not independently verified) [6]

Study E4599: Efficacy data overview [1,3,6]

Endpoint

 

Avastin + PC

PC alone

HR (95% CI)

P value

 

Number of patients

434

444

 

 

Primary

OS (median)

12.3 months

10.3 months

0.80 (0.68–0.94)

0.013

 

1-year survival

51%

44%

 

 

 

2-year survival

23%

15%

 

 

Secondary

PFS* (median)

6.2 months

4.5 months

0.66 (0.57–0.77)

<0.001

Secondary

Objective response rate*

35%

15%

 

<0.001

*PFS and response rate were based on investigator assessment (not independently verified). [1]

PFS=progression-free survival. 

Boxed WARNINGS

  • Gastrointestinal (GI) perforation
    • Serious and sometimes fatal GI perforation occurs at a higher incidence (up to 3.2%) 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. 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
    • 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, epistaxis, and vaginal bleeding are increased in Avastin-treated patients. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis

Study E4599: OS in the intent-to-treat population [1,6]

Study E4599 is the first and only prospective Phase III randomized clinical trial of an FDA-approved biologic in first-line metastatic non-squamous NSCLC to demonstrate statistically significant improvement in OS (>12 months), its primary endpoint, in an intent-to-treat population. [1,6]

The intent-to-treat population included all patients randomized before start of treatment. The results of Study E4599 included both progressors and non-progressors. [6]

Eastern Cooperative Oncology Group Study E4599 included a broad range of patients [6,39,40]

Patient characteristics included [6,39,40]

  • First-line, locally advanced, metastatic or recurrent NSCLC
  • All predominantly non-squamous histologies
    • Adenocarcinoma
    • Large cell tumors
    • Bronchioloalveolar carcinoma (BAC)
    • Undifferentiated NSCLC, not otherwise specified (NOS)
  • Centrally located tumors
  • Eastern Cooperative Oncology Group performance status 0–1

Histologies in Study E4599

  • The intent-to-treat population included the full range of non-squamous NSCLC histologies [40]:
    • Adenocarcinoma: 69% (n=300)
    • Undifferentiated NSCLC, NOS: 18% (n=79)
    • Large cell undifferentiated: 4% (n=18)
    • BAC: 3% (n=12)
    • Squamous: 0.2% (n=1)
    • Other: 5% (n=23)

Prescribing Information language regarding patients with central nervous system (CNS) metastases (from WARNINGS AND PRECAUTIONS section) [1]

In clinical studies in NSCLC where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic grade 2 CNS hemorrhage was documented in 1 of 83 Avastin-treated patients (rate 1.2%, 95% confidence interval, 0.06%–5.93%). [1]

Indications

Non-squamous non-small cell lung cancer (NSCLC)
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 3.2% 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 0.4% to 6.9% 
    • 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
    • GI fistulae (up to 2% in metastatic colorectal cancer and ovarian cancer patients)
    • Non-GI fistulae (<1% in trials across various indications; 1.8% in a cervical cancer trial) 
    • Arterial thromboembolic events (grade ≥3, 2.6%)
    • Proteinuria (nephrotic syndrome, <1%)
  • Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included 
    • GI-vaginal fistulae occurred in 8.3% of patients in a cervical cancer trial
    • Hypertension (grade 3–4, 5%–18%)
    • Posterior reversible encephalopathy syndrome (PRES) (<0.5%)
  • 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

Pregnancy warning

  • Based on the mechanism of action and animal studies, Avastin may cause fetal harm
  • Advise female patients that Avastin may cause fetal harm, and to inform their healthcare provider of a known or suspected pregnancy 
  • Advise females of reproductive potential to use effective contraception during treatment with Avastin and for 6 months after the last dose of Avastin
  • Advise nursing women that breastfeeding is not recommended during treatment with Avastin
  • Avastin may impair fertility

Most common adverse events

  • Across indications, 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
— Exfoliative dermatitis

  • Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions

Indication-specific adverse events

  • 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%)

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch.
You may also report side effects to Genentech at (888) 835-2555.

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