Results from second phase II trial suggest synergistic effects of navelbine in combination with herceptin for Her2 positive metastatic breast cancer

December 12, 2001

Multi-center phase II study reports similar activity as seen in earlier single institution trial

SAN ANTONIO, TEXAS, December 13, 2001 - Researchers investigating the combination of Navelbine® (vinorelbine tartrate) Injection, a first-line chemotherapy treatment for advanced non-small cell lung cancer, and the monoclonal antibody therapy Herceptin® (trastuzumab), reported an overall response rate of 78 percent in women with HER2 positive metastatic breast cancer, in presenting results of a Phase II study at the 24th Annual San Antonio Breast Cancer Symposium. Navelbine is not indicated for use in women with metastatic breast cancer. "The response rate from our multicenter study and a previously reported response rate of 75 percent from an earlier single-site trial are both very encouraging," said Mohammed Jahanzeb, M.D., research director of the Boca Raton Comprehensive Cancer Center and professor of biomedical research at Florida Atlantic University, in reference to a single-center investigation at the Dana-Farber Cancer Institute in Boston.1 The Phase II clinical trial investigated the safety and efficacy of Herceptin and Navelbine as first-line therapy, in metastatic breast cancer, for women with tumors that overexpress HER2 protein, a growth-promoting chemical that has been closely linked to a poor prognosis in breast cancer. Nearly a quarter of women with breast cancer have tumors that over-express HER2. The acquired gene aberration that produces HER2 is associated with more rapid cancer progression and shortened survival.

Forty patients were enrolled in the trial. Weekly intravenous doses of Herceptin and Navelbine were administered over four-week cycles. Thirty-seven patients were evaluated for a response after receiving at least two cycles. A total of four complete responses and 25 partial responses were observed for an overall response rate of 78 percent. Progression of disease occurred in four patients and four remained stable.

Tolerability with Combination After a cumulative total of 313 cycles, significant toxicity, consisting of a grade 4 reduction in infection-fighting white blood cells (neutropenia), was observed in 30% of patients, in 14% of cycles. Grade 3 neutropenia occurred in 50% of patients, in 20% of cycles. One patient was hospitalized with neutropenic fever. Furthermore, there was no severe (grade 3-4) nausea, vomiting, heart disturbance or hair loss reported in the study. Grade 3-4 non-hematologic toxicity consisted of grade 3 fatigue in one patient, grade 4 fatigue in one patient, and grade 3 neurotoxicity in one patient. The addition of Navelbine did not appear to change the side effect profile of Herceptin which also has been shown to be well tolerated. "We didn't want to increase side effects in our efforts to potentially increase efficacy, so in selecting an agent to use in combination with Herceptin, which is well tolerated, we chose to study Navelbine," said Dr. Jahanzeb.

These results appear to support previous findings of a single-center investigation at the Dana-Farber Cancer Institute in Boston.1 In that study, investigators observed responses in 30 of 40 patients administered concurrent weekly doses of Navelbine and Herceptin, for an overall response rate of 75 percent. Grade 3 or 4 neutropenia was observed in 43 percent of patients. Neutropenia was the only reported grade 4 toxicity associated with the treatment. No patients had symptomatic heart failure. Navelbine has also been studied as a single agent in both first-line and second-line chemotherapy for advanced breast cancer. 2,3,4 Dr. Jahanzeb reported that the present multicenter trial suggests a possible synergistic effect between Navelbine and Herceptin, in which these two drugs together may produce a greater effect than either one taken alone, for the treatment of metastatic breast cancer. Additional Phase III trials are warranted.

Metastatic Breast Cancer

According to the American Cancer Society, an estimated 192,200 cases of invasive breast cancer are expected to occur among women in the United States in 2001, and an estimated 40,200 are expected to die from the disease. Breast cancer is said to have metastasized when it spreads from the breast to other organs in the body. Metastatic breast cancer is difficult to treat, particularly because it can develop in women who have failed or relapsed following previous treatments, and is usually associated with a poor prognosis.
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About Navelbine

Navelbine® (vinorelbine tartrate) Injection, which is available in the United States from GlaxoSmithKline, is not indicated for the treatment of advanced breast cancer, either as a single agent or in combination with Herceptin. Navelbine Injection is indicated as a single agent or in combination with cisplatin for the first-line treatment of ambulatory patients with inoperable, advanced non-small cell lung cancer (NSCLC). In clinical trials to date, granulocytopenia is the major dose-limiting toxicity with Navelbine, although it has been generally reversible and not cumulative over time. Administration of Navelbine is contraindicated in patients with pretreatment granulocyte counts of < 1000 cells/mm3. Patients treated with Navelbine should be frequently monitored for myelosuppression during and after therapy. In North American clinical trials with single-agent Navelbine, nonhematologic toxicities were usually mild or moderate and included injection-site reactions (38%), nausea (34%), vomiting (15%), constipation (29%), fatigue (27%), peripheral neuropathy (20%), diarrhea (13%), and alopecia (12%).

About GlaxoSmithKline

GlaxoSmithKline (NYSE:GSK) - one of the world's leading research-based pharmaceutical and healthcare companies - is committed to improving the quality of human life by enabling people to do more, feel better and live longer.

GlaxoSmithKline is committed to the research, development, manufacturing and marketing of therapeutic and supportive care products for hematology and oncology patients. Currently, GlaxoSmithKline Oncology markets Zofran® (ondansetron HCl), Hycamtin® (topotecan hydrochloride) for Injection, Navelbine® (vinorelbine tartrate) Injection, Argatroban Injection, Alkeran® (melphalan), Leukeran® (chlorambucil), Compazine® (prochlorperazine), Purinethol® (mercaptopurine), Myleran® (busulfan), and Thioguanine. GlaxoSmithKline Oncology has novel agents in late-stage development, including a radioimmunotherapy Bexxar® (tositumomab and iodine I 131 tositumomab). For company information, visit GlaxoSmithKline on the World Wide Web at www.gsk.com. Full prescribing information for all GlaxoSmithKline products is available upon request or on the company web site.

*Herceptin is a registered trademark of Genentech.

1. Burstein HJ, Kuter I, Campos SM, et al. Clinical activity of trastuzumab and vinorelbine in women with HER2-overexpressing metastatic breast cancer. J Clin Oncol. 19:2722-2730, 2001.

2. Fumoleau P, Delgado FM, Delozier T, et al. Phase II trial of weekly intravenous vinorelbine in First-line advanced breast cancer chemotherapy. J Clin Oncol 1993;11(7):1245-1252.

3. Weber B, Vogel C, Jones S, et al. Intravenous vinorelbine as first-line and second-line therapy in advanced breast cancer. J Clin Oncol 1995;13(11):2722-2730.

4. Vogel C, O'Rourke M, Winer E, et al. Vinorelbine as first-line chemotherapy for advanced breast cancer in women 60 years of age or older. Ann Oncol 1999;10:397-402.

For more information:
Julie McQuain 212-477-0472
Media Contact: Sam Brown Inc.
Holly Russell 919-483-839
GlaxoSmithKline

JMPR Associates, Inc.

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