ROCKVILLE, MarylandAbraxane (paclitaxel
protein-bound particles for injectable suspension, American Bioscience) has
received Food and Drug Administration approval for the treatment of breast
cancer after failure of combination chemotherapy for metastatic disease or
relapse within 6 months of adjuvant chemotherapy. Previous therapy should
include an anthracycline unless clinically contraindicated.
The FDA approved the drug on the basis of a randomized,
comparative study with standard paclitaxel (Taxol) that enrolled 460 women
with metastatic breast cancer, and two single-arm, open-label studies with a
total of 106 participants. The agency based its safety evaluation on findings
from the pivotal study.
"Abraxane provides a much-needed new treatment option for
women with metastatic breast cancer," said William J. Gradishar, MD,
co-director of the Lynn Sage Breast Cancer Program, Northwestern Memorial
Hospital, the principal clinical trial investigator for the 460-patient
pivotal study. "The pivotal clinical trial results demonstrated that Abraxane
had superior response rate when compared to Taxol in patients with metastatic
breast cancer. For the first time, we are able to offer patients the full
therapeutic benefits of paclitaxel. This makes Abraxane a significant advance
in the way we treat breast cancer."
The newly approved drug consists of albumin-bound
paclitaxel nanoparticles with a mean particle size of approximately 130
nanometers. The drug contains no toxic solvents, which enables the
administration of 50% more chemotherapy, requires no premedication to prevent
hypersensitivity reactions, and can be given over 30 minutes using standard IV
tubing, according to the company. It represents a new class of biologically
interactive drugsone that exploits the gp60 receptor-mediated pathway to
achieve high intracellular tumor concentrations of the active drug (see also
"Abraxane has an improved therapeutic index, compared to
Taxol, in the treatment of metastatic breast cancer based on its superior
response rate and well- tolerated safety profile," said Joyce A.
O’Shaughnessy, MD, director of Breast Cancer Prevention at Baylor-Charles A.
Sammons Cancer Center, Dallas. "Patients receiving Cremophor-based tax-anes
unfortunately are exposed to toxicities caused by the solvent rather than the
active chemotherapy drug. The patients with metastatic breast cancer who were
treated with Abraxane not only achieved the superior response rate, but they
also benefited from the fact that Abraxane does not use toxic solvents to
deliver the active drug."
American Bioscience plans to study the drug in combination
with other chemotherapeutic agents in the treatment of front-line metastatic
In the pivotal study, 233 patients were randomized to
receive Abraxane 260 mg/m2 given as a 30-minute infusion, and 227
to receive Taxol at 175 mg/m2 as a 3-hour infusion. At study entry,
64% of the women had impaired performance status (ECOG 1 or 2), 79% had
visceral metastases, and 76% had more than three sites of metastases; 77% had
previously received anthracycline-based therapy. The primary endpoint was the
reconciled target lesion response rate (RR), which was based on independent
radiologic assessments of tumor responses reconciled with
investigator-reported responses for the first six therapy cycles.
Higher Response Rate
Reconciled RR was significantly higher among the Abraxane-treated
women (21.5%)almost double the 11.1% rate of the Taxol patients (P =
.003). Investigator-reported RRs for Abraxane and Taxol were 33% and 19%,
respectively. Among those who had failed combination chemotherapy or relapsed
within 6 months of adjuvant chemotherapy, the RR was 15.5% for the Abraxane
group and 8.4% for the Taxol arm.
Objective responses were also observed in the two
single-arm, open-label studies. In one, 43 metastatic breast cancer patients
received Abraxane 175 mg/m2 over 30 minutes. In the second trial,
63 patients received 30-minute infusions of 300 mg/m2. The
recommended regimen for Abraxane calls for its intravenous infusion every 3
weeks at 260 mg/m2.
Bone marrow suppression, primarily neutropenia, is a
dose-dependent and dose-limiting adverse event associated with Abraxane. In a
black-box warning, the drug’s labeling advises against administering it to
patients "who have baseline neutrophil counts of less than 1,500 cells/µL."
The warning also advises that Abraxane should be administered under the
supervision of a physician experienced in the use of cancer chemotherapeutics,
and states that Abraxane should not be substituted for or used with other
Safety data was obtained from 229 Abraxane and 225 Taxol
patients participating in the pivotal study. Neutropenia was the most
important and most common hematologic adverse event, occurring in 80% of
Abraxane and 82% of Taxol patients; it was reversible. Grade 4 neutropenia
occurred in 9% and 22% of patients, respectively. Symptoms of sensory
neuropathy were reported by 71% of Abraxane and 56% of Taxol patients;
neuropathy was severe (grade 3) in 10% and 2%, respectively. There were no
episodes of grade 4 neuropathy.
"Grade 4 neutropenia occurred in less than 10% of the
Abraxane patients," said Edith Perez, MD, professor of medicine, Mayo Clinic
College of Medicine. "In the patients who developed grade 3 peripheral
neuropathy, rapid improvement occurred after a median of only 22 days."
Hypersensitivity reactions occurred in 4% and 12% of the Abraxane and Taxol
patients; it was severe in 2% of Taxol patients and 0% of Abraxane patients.I