Doxil and docetaxel combination treatment delays disease progression in metastatic breast cancer

Results from a Phase 3 study show that patients with metastatic breast cancer who were treated previously with an anthracycline in the adjuvant setting experienced a significant improvement in time to disease progression (TTP) and overall response rates after receiving a combination of Doxil (doxorubicin HCl liposome injection) and docetaxel as compared to docetaxel alone.

Results from this randomized, parallel-group, open-label, multi-center study were presented today at the 31st Annual San Antonio Breast Cancer Symposium (SABCS). The study included only patients previously treated with anthracyclines who had a disease-free interval of at least one year.

The study found that patients treated with the Doxil and docetaxel combination had a 35% risk reduction for developing disease progression compared with docetaxel alone (hazard ratio = 0.65; 95% confidence interval [0.55, 0.77]; p=0.000001). There is an almost three-month improvement in median TTP for patients treated with the combination compared with docetaxel monotherapy (9.8 versus 7.0 months, respectively).

The safety profile was consistent with known toxicities of the two agents. Additionally, the incidence of symptomatic cardiac events was 5% in the combination group versus 4% in the monotherapy group (>/= Grade 2 cardiac adverse events). Symptomatic congestive heart failure was reported in 1% of subjects in both groups. Arrhythmia was reported in 4% of the combination group and 3% of the monotherapy group. Protocol-defined LVEF decreases occurred in 5% of subjects in both groups.

"Anthracyclines are active drugs for metastatic breast cancer, but concerns about cardiac toxicity have prevented oncologists from using them in those who received anthracyclines as part of their adjuvant therapy," said Dr. Joseph Sparano, Director of the Breast Evaluation Center at the Montefiore-Einstein Cancer Center and Professor of Medicine & Women's Health at the Albert Einstein College of Medicine in New York, and lead investigator on the study. "The study suggests that the combination of DOXIL and docetaxel may be an effective treatment for patients with metastatic breast cancer who have relapsed after prior adjuvant anthracycline therapy."

The study enrolled 751 women in 19 countries. Patients were randomly assigned to one of two treatment arms: Doxil 30 mg/m2 followed by docetaxel 60 mg/m2 on the first day of every 21-day cycle; or docetaxel 75 mg/m2 on the first day of every 21-day cycle. Treatment continued until an unacceptable treatment-related toxicity or disease progression occurred.

The primary endpoint of the study was time to progression, as determined by independent reviewers blinded to study treatment. Secondary endpoints included response rate, overall survival and safety.

Response rates (the percentage of patients whose cancer shrinks after treatment) in patients treated with the DOXIL and docetaxel combination were significantly higher than those treated with docetaxel monotherapy (35% versus 26% respectively; p= 0.0085). Overall survival data were not yet mature; a final protocol-specified survival analysis is planned after the occurrence of 485 events.

The most common adverse reactions (e.g., those occurring in at least 20% of the patients) for the Doxil and docetaxel combination compared to the monotherapy group, respectively, were:

• Hematological toxicities and infections, including:
• Neutropenia - 66% (Grade 3/4 57%) versus 65% (Grade 3/4 59%), with febrile neutropenia reported in 7% versus 6% of patients
• Anemia - 20% (Grade 3/4 2%) versus 17% (Grade 3/4 1%)
• Infection - 30% (Grade 3/4 5%) versus 25% (Grade 3/4 2%)
• Hand-foot syndrome: 61% (Grade 3/4 24%) versus 1% (Grade 3/4 0%)
• Stomatitis: 52% (Grade 3/4 11%) versus 14% (Grade 3/4 1%)
• Alopecia: 48% versus 45%
• Asthenia: 29% (Grade 3/4 4%) versus 20% (Grade 3/4 3%)
• Nausea: 28% (Grade 3/4 1%) versus 22% (Grade 3/4 <1%)
• Fatigue: 20% (Grade 3/4 3%) versus 15% (Grade 3/4 2%)      

The study was sponsored by Ortho Biotech Oncology Research & Development (ORD), a unit of Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

About Doxil

Doxil is indicated for the treatment of patients with ovarian cancer whose disease has progressed or recurred after prior platinum based therapy. DOXIL in combination with Velcade (bortezomib) is indicated for the treatment of patients with multiple myeloma who have not previously received Velcade and have received at least one prior therapy. Doxil is also indicated for the treatment of AIDS-related Kaposi's sarcoma in patients after failure of prior systemic chemotherapy or intolerance to such therapy.

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