FDA Approves Abraxane for Metastatic Breast Cancer

ROCKVILLE, Maryland—Abraxane (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 drugs—one that exploits the gp60 receptor-mediated pathway to achieve high intracellular tumor concentrations of the active drug (see also page 14).

"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 breast cancer.

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 paclitaxel formulations.

Safety Data

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