GlaxoSmithKline application accepted by the FDA to expand use of Hycamtin® in combination with cisplatin for the treatment of advanced cervical cancer

New Indication Requested Based on Extended Survival in Advanced Cervical Cancer

Priority Review Granted

PHILADELPHIA, February 17, 2006 – GlaxoSmithKline (NYSE: GSK) today announced that the supplemental New Drug Application (sNDA) submitted to the U.S. Food and Drug Administration (FDA) on December 15, 2005 for Hycamtin® (topotecan HCl) for Injection, has been accepted. The FDA has also agreed to a Priority review. The sNDA seeks marketing approval for the new use of Hycamtin in combination with cisplatin, for the treatment of Stage IVB recurrent or persistent carcinoma of the cervix not amenable to curative treatment with surgery and/or radiation therapy. The application is based on results from a randomized, multicenter Phase III trial, designed and conducted by the Gynecologic Oncology Group (GOG). Hycamtin is currently indicated for the treatment of metastatic carcinoma of the ovary after failure of initial or subsequent chemotherapy, and for the treatment of small cell lung carcinoma sensitive disease after failure of first-line therapy.
Cervical cancer is the third most common gynecological cancer among American women, with close to 12,000 new cases diagnosed annually.1 “Prognosis is positive if the disease is discovered early; however, expectations drop dramatically for those patients with advanced stage disease,” explains Kevin Lokay, Vice President of Oncology and Acute Care at GSK. “We are committed to improving the options available for these patients, and we see our collaboration with the GOG, in submitting their pivotal trial results, as very important to our commitment and achieving that goal.”
The trial demonstrated a survival advantage with the use of Hycamtin in combination with cisplatin compared to cisplatin alone. The trial enrolled women with measurable, histologically-proven stage IVB recurrent or persistent carcinoma of the cervix, who had recovered from the effects of prior surgery, radiation or chemoradiation. Patients were originally randomized into three arms: single-agent cisplatin (50 mg/m2 q 3 weeks), cisplatin plus Hycamtin (Hycamtin 0.75 mg/m2 d1-3 plus cisplatin 50 mg/m2 d1 q 3 weeks), or MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin q 4 weeks). However, the MVAC arm was closed after 64 patients were enrolled, due to excessive toxicity.
Harry J. Long III, M.D., Professor of Oncology at Mayo Clinic College of Medicine in Rochester, Minn. and colleagues2 reported the results from 146 patients who received cisplatin alone and 147 who received the combination of cisplatin plus Hycamtin. The study showed a statistically significant improvement in median overall survival of 6.5 and 9.4 months, respectively (P = 0.017), median progression-free survival of 4.6 and 2.9 months (P = 0.014). There was also an increased overall response rate (13 percent for cisplatin alone and 27 percent for cisplatin plus Hycamtin, (P = 0.004). “The successful results observed in this trial, especially the extension of patient survival, marks progress in our efforts to extend the lives of women with advanced cancer of the cervix,” said Long. The Hycamtin-containing treatment arm in the Long study was developed based on a GSK funded, investigator initiated, Phase II trial of the combination pioneered by Dr. James Fiorica.
Major toxicities (Grade 3 and 4) were more frequent in the combination arm than in the single-agent arm and included neutropenia (70.0 percent vs. 1.4 percent), thrombocytopenia (31.3 percent vs. 3.4 percent), febrile neutropenia/infection (17.7 percent vs. 7.5 percent), respectively. The most common non-hematologic toxicities reported were nausea, emesis, pain and metabolic toxicities.
About Hycamtin
Hycamtin® (topotecan HCl for Injection) is currently marketed in the United States by GlaxoSmithKline. It belongs to a class of drugs known as the topoisomerase I (topo-I) inhibitors. Topo-I is a naturally produced protein essential for cell division in both normal and cancer cells. Interaction between topo-I and Hycamtin results in permanent damage to the cell’s genetic material and the death of dividing cancer cells. Hycamtin is indicated for the treatment of small cell lung cancer sensitive disease after failure of first-line chemotherapy and for the treatment of metastatic carcinoma of the ovary after failure of initial or subsequent chemotherapy. For more information and full prescribing information, visit www.hycamtin.com.
Important Safety Information
Hycamtin (topotecan HCl for Injection) can suppress the body’s ability to produce disease fighting white blood cells, a condition known as neutropenia. In addition, the amount of clotting cells can decrease (thrombocytopenia). Generally, Hycamtin has a mild to moderate non-hematologic toxicity profile. Side effects include nausea, vomiting, diarrhea and hair loss (alopecia).
About GlaxoSmithKline
GlaxoSmithKline – 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. For company information, visit www.gsk.com.

References
1. http://www.information-on-cervical-cancer.com/.
2. Long HJ. Randomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: A Gynecologic Oncology Group Study. J Clin Oncol. 2005;23:4626-4633.

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