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Combination of TYKERB(R) (lapatinib) Plus Letrozole Demonstrated Significant Improvement in Delaying Disease Progression for HER2+/ErbB2+ Post-Menopausal Metastatic Breast Cancer

Friday, December 12, 2008 General News J E 4
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Findings from one of the largest studies in hormone receptor positive women with first-line oral treatment regimen



PHILADELPHIA, Dec. 11 /PRNewswire-USNewswire/ -- New results from a study evaluated the combination of TYKERB(R) (lapatinib) plus Femara(R) (letrozole) versus letrozole alone as a first-line treatment regimen in hormone receptor positive (HR+) metastatic breast cancer. In the study, women diagnosed with post-menopausal, hormone receptor positive (HR+) and HER2+/ErbB2+ metastatic breast cancer experienced a 5.2 month increase in median progression-free survival (PFS) compared to women treated with letrozole alone. Results from the intent-to-treat group (ITT; all patients, irrespective of HER2/ErbB2 status) showed that lapatinib plus letrozole provided an additional 1.1 month before disease progression compared to letrozole treatment alone. These data were unveiled at the 31st Annual CTRC-AACR San Antonio Breast Cancer Symposium, December 10th-14th, 2008.



This double-blind, placebo-controlled study (EGF30008) included 1,286 post-menopausal women with HR+ breast cancer who were randomized to treatment with lapatinib plus letrozole or to letrozole alone. Letrozole, an aromatase inhibitor (AI), is a recognized therapy in the treatment of HR+ breast cancer. The HER2/ErbB2 status of patients was not required for randomization into the study, however, PFS was the primary endpoint in the HR+ and HER2+/ErbB2+ patient post study analysis.



Independent central testing revealed that 219 patients were HER2+/ErbB2+. In women who were HR+ and HER2+/ErbB2+, combination therapy with lapatinib and letrozole significantly increased median PFS, compared to treatment with letrozole alone (8.2 months versus 3.0 months respectively, HR=0.71, p=0.019).



"The encouraging positive results seen in women who are HR positive and ErbB2 positive shows that the lapatinib and letrozole combination has the potential to become a first-line, oral treatment option for clinicians and patients in this setting in the future," says Paolo Paoletti, SVP Oncology R&D, GSK. "We plan to discuss these data with regulators in the near future."



Results from the ITT group (all patients, irrespective of HER2/ErbB2 status) showed that lapatinib plus letrozole provided, on average, an additional month before disease progression compared to letrozole treatment alone (11.9 months versus 10.8 months, HR=0.86, p=0.026).



The most common adverse events were diarrhea, rash, nausea, arthralgia and fatigue. Grade 3/4 adverse events that occurred in more than two percent of patients in either the combination arm or monotherapy arm included diarrhea (9 percent vs. <1 percent, respectively); fatigue (2 percent vs. <1 percent, respectively); increased ALT (2 percent vs. <1 percent, respectively) and increased AST (2 percent vs. <1 percent, respectively). Two percent of patients experienced a related serious adverse event of a decreased ejection fraction in the lapatinib plus letrozole group compared with 1% in the letrozole alone group.



Growth factor receptors such as those in the HER2/ErbB family play a key role in cell growth and survival.(1) Targeting these protein receptors is a way in which cancer cells can be killed and tumor growth curtailed. Approximately 70 percent of all breast cancer cases are HR+.(2) Furthermore, tumors that initially respond to AIs can become resistant, leading to disease progression and ultimately, patient death.(3) Recent studies have revealed interactions between HR and HER2/ErbB receptors as a primary contributor to the development of resistance, and served as the hypothesis basis for this study.(4)



About EGF30008

EGF30008 is a Phase III, randomized, double-blind, placebo-controlled trial in 1,286 post-menopausal women with HR+ metastatic breast cancer. Women in the study were randomized to compare the efficacy of first-line therapy with lapatinib, a small-molecule tyrosine kinase inhibitor, and the aromatase inhibitor letrozole versus letrozole monotherapy. At randomization patients received either letrozole 2.5 mg once daily (QD) plus lapatinib 1500 mg QD, or letrozole 2.5 mg QD plus placebo. The primary endpoint of EGF30008 was PFS in the HR+/HER2+/ErbB2+ population, and secondarily in the overall ITT population. Secondary endpoints included overall response rate (ORR), clinical benefit rate (CBR), time to response, duration of response, overall survival, safety assessments and quality of life. Hormonal therapy was allowed in the adjuvant setting only (1 year prior to study entry) and crossover was not permitted.



About TYKERB(R) (lapatinib)

Lapatinib is an oral small-molecule inhibitor of the HER2/ErbB2 tyrosine kinase receptor. Stimulation of HER2/ErbB2 is associated with cell proliferation and with multiple processes involved in tumor progression and metastases. Overexpression of these receptors has been reported in a variety of human tumors and is associated with poor prognosis and reduced overall survival.



Lapatinib is approved in 63 countries. On March 13, 2007, the United States Food and Drug Administration (FDA) approved lapatinib in combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2/ErbB2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab. On June 10, 2008, the European Commission adopted a decision to grant a conditional marketing authorization for lapatinib in all 27 European Union (EU) member states. Other countries include Australia, India, Brazil, Russia, Turkey, South Korea, Taiwan and others around the world. Registration dossiers for lapatinib have been filed in Canada, China, Japan, Mexico and a number of countries in Latin America, Middle East, Africa and Asia Pacific.



GSK in Oncology

GSK Oncology is dedicated to producing innovations in cancer that will make profound differences in the lives of patients. Through GSK's revolutionary 'bench to bedside' approach, we are transforming the way treatments are discovered and developed, resulting in one of the most robust pipelines in the oncology sector. Our worldwide research in oncology includes collaborations with more than 160 cancer centers. GSK is closing in on cancer from all sides with a new generation of patient-focused cancer treatments in prevention, supportive care, chemotherapy and targeted therapies.



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.



BOXED WARNING and Additional Important Safety Information



Hepatotoxicity - TYKERB has been associated with hepatotoxicity. Hepatotoxicity (ALT or AST >3 times the upper limit of normal and total bilirubin >1.5 times the upper limit of normal) has been observed in clinical trials (<1% of patients) and postmarketing experience. The hepatotoxicity may be severe and deaths have been reported. Causality of the deaths is uncertain. The hepatotoxicity may occur days to several months after initiation of treatment. Liver function tests should be monitored before initiation of treatment, every 4 to 6 weeks during treatment, and as clinically indicated. If changes in liver function are severe, therapy with TYKERB should be discontinued and patients should not be re-treated with TYKERB.



Decreased Left Ventricular Ejection Fraction - TYKERB has been reported to decrease LVEF. Caution should be taken if TYKERB is to be administered to patients with preexisting cardiac conditions, including uncontrolled or symptomatic angina, arrhythmias, or congestive heart failure. Confirm normal LVEF before starting TYKERB, and continue evaluations during treatment.



Patients with Severe Hepatic Impairment - If TYKERB is to be administered to patients with severe hepatic impairment, dose reduction should be considered.



Diarrhea - Diarrhea, including severe diarrhea, has been reported during treatment with TYKERB and was the most common adverse reaction resulting in discontinuation of TYKERB therapy. Proactive management of diarrhea with anti-diarrheal agents is important, and severe cases of diarrhea may require administration of oral or intravenous electrolytes and fluids, and interruption or discontinuation of therapy with TYKERB.



Interstitial Lung Disease/Pneumonitis - TYKERB has been associated with interstitial lung disease and pneumonitis. Patients should be monitored for pulmonary symptoms indicative of interstitial lung disease or pneumonitis and if symptoms are = Grade 3 (NCI CTCAE), TYKERB should be discontinued.



QT Prolongation - TYKERB prolongs the QT interval in some patients. TYKERB should be administered with caution to patients who have or may develop prolongation of QTc. Hypokalemia or hypomagnesemia should be corrected prior to TYKERB administration. Baseline and on-treatment electrocardiograms with QT measurement should be considered.



Pregnancy: Pregnancy D - TYKERB can cause fetal harm when administered to a pregnant woman. Women should be advised not to become pregnant when taking TYKERB. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.



Adverse Reactions - The most common adverse reactions (>20%) during therapy with TYKERB plus capecitabine compared to capecitabine alone were diarrhea (65%, 40%), nausea (44%, 43%), vomiting (26%, 21%), palmar-plantar erythrodysesthesia (53%, 51%), rash (28%, 14%), and fatigue (46%, 47%).



The most common grade 3 and 4 adverse reaction (NCI CTC v3) with TYKERB plus capecitabine compared to capecitabine alone were diarrhea (14%, 10%) and palmar-plantar erythrodysesthesia (12%, 14%).



Please see full prescribing information, including BOXED WARNING.



Notes to Editors:



TYKERB(R) is a registered trademark of the GlaxoSmithKline group of companies in the United States and the countries outside of Europe.



FEMARA(R) is a registered trademark of Novartis in the United States and the European Union.



Cautionary statement regarding forward-looking statements

Under the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995, GSK cautions investors that any forward-looking statements or projections made by GSK, including those made in this announcement, are subject to risks and uncertainties that may cause actual results to differ materially from those projected. Factors that may affect GSK's operations are described under 'Risk Factors' in the 'Business Review' in the company's Annual Report on Form 20-F for 2007.



References

(1) Normanno N, Bianco C, De Luca A, Maiello MR, Salomon, DS. Target-based agents against ErbB receptors and their ligands: a novel approach to cancer treatment. Endocrine-Related Cancer 2003; 10;1-21

(2) Bedard PE, Freedman OC, Howell A et al. Overcoming endocrine resistance in breast cancer - are signal transduction inhibitors the answer. Breast Cancer Res Treat. 2008 108:307-317

(3) Prat, A and Baselga, J. The role of hormonal therapy in the management of hormonal-receptor-positive breast cancer with co-expression of HER2. Nature Clinical Practice Oncology. 2008;5:531-542

(4) Arpino G, Wiechmann L, Osborne CK, et al. Crosstalk between the Estrogen Receptor and the HER Tyrosine Kinase Receptor Family: Molecular Mechanism and Clinical Implications for Endocrine Therapy Resistance. Endocrine Reviews. 2008; 29(2): 217-233





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SOURCE GlaxoSmithKline
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