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Avastin Approved as First-Line Rx of Nonsquamous NSCLC

Avastin Approved as First-Line Rx of Nonsquamous NSCLC

ROCKVILLE, Maryland--Avastin
(bevacizumab, Genentech) has gained
Food and Drug Administration (FDA)
approval in combination with carboplatin
and paclitaxel for the first-line treatment
of unresectable, locally advanced, recurrent,
or metastatic non-squamous-cell,
non-small-cell lung cancer (NSCLC),
which accounts for about three-quarters
of newly diagnosed cases in the United
States. The agency acted after reviewing
findings from a pivotal phase III study
that found the Avastin/chemotherapy
combination increased overall survival by
25%, compared with the two chemotherapeutic
agents alone.

"Bevacizumab, in combination with
chemotherapy, is the first therapy in 10
years to improve on standard first-line
treatment for advanced lung cancer, and
the first FDA-approved therapy ever to
extend survival for these patients beyond
one year in a large, randomized clinical
trial," said Alan Sandler, MD, director
of Medical Thoracic Oncology at Vanderbilt-
Ingram Cancer Center. "With this
survival benefit, bevacizumab represents
an important therapy for many advanced
lung cancer patients fighting this difficult
disease."

Dr. Sandler served as the lead investigator
for the phase III trial, designated
E4599, which was led by the Eastern Cooperative
Oncology Group (ECOG).

Avastin is an antiangiogenic, recombinant,
humanized monoclonal IgG1 antibody
that inhibits the biologic activity
of human vascular endothelial growth
factor. As a result, tumors apparently cannot
acquire the new blood vessels required
for them to grow. FDA initially
approved Avastin in combination with
intravenous fluorouracil (5-FU) in February
2004 for the first-line treatment of
metastatic colorectal cancer. In June of
this year, the drug received approval in
combination with 5-FU as a second-line
treatment in the same disease.

Pivotal Study
Genentech supported its pivotal
study--E4599, a randomized, activecontrolled,
open-label, multicenter
trial--with data from a smaller randomized,
dose-ranging, active-controlled phase II study. E4599 researchers enrolled
878 patients without prior chemotherapy
and randomized them 1:1 to
receive six 21-day cycles of paclitaxel 200
mg/m2 and carboplatin to AUC 6 (PC)
on day 1 or PC plus 15 mg/kg of Avastin
on day 1. When patients in the Avastintreated
arm completed or discontinued
chemotherapy, they continued to receive
Avastin alone until disease progression
or unacceptable toxicity. Duration of survival
served as the primary outcome.

Median overall survival was a statistically
significant 12.3 months in the
Avastin plus PC arm vs 10.3 months in
the PC-alone group (HR 0.80, P = .013).
One-year survival was 51% in the
Avastin-treated patients vs 44% in the
PC-alone arm. Investigators reported
that the Avastin-treated patients had
longer progression-free survival, compared
with PC alone, but their assessments
were not independently verified. Exploratory analyses of subgroups found
Avastin had less overall survival impact
in women, patients age 65 and older,
and in those with 5% or greater weight
loss at accrual.

The most common side effects associated
with Avastin included weakness,
abdominal pain, headache, diarrhea, and
vomiting. The grade 3 to 5 adverse events
observed in E4599 were neutropenia,
fatigue, hypertension, infection, and
hemorrhage. Clinical experience with
Avastin has revealed two different hemorrhage
patterns. One is minor, most
commonly NCI-CTC grade 1 epistaxis.
The second causes serious, sometimes fatal
bleeding.

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