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New Data Offers Insights Into the Potential Role for TYKERB(R) (Lapatinib) in Non-Cytotoxic Chemotherapy-Based Treatment Regimens

TYKERB Demonstrates Activity in Combination with Other Targeted Therapies

and as Monotherapy Across A Range of Breast Cancer Settings - First Phase II data investigating the dual inhibition of HER2 and VEGF pathways with two oral, small molecule tyrosine-kinase inhibitors (TYKERB and pazopanib) demonstrates activity in first-line HER2 (ErbB2) positive

breast cancer(1)

- Phase II results combining TYKERB and AVASTIN(R) (bevacizumab), a monoclonal antibody, shows activity in recurrent metastatic HER2-positive

breast cancer(2)

- Final results from the largest prospective trial evaluating TYKERB monotherapy as a treatment for relapsed inflammatory breast cancer (IBC) demonstrates activity in this highly aggressive and difficult to treat


LONDON, and PHILADELPHIA, June 1 /PRNewswire-FirstCall/ -- GlaxoSmithKline today announced the results of three studies evaluating TYKERB -- an oral, small molecule inhibitor of HER2 -- in various breast cancer settings, either in combination with other targeted therapies or as a monotherapy. Use of TYKERB in these settings is investigational. Results from these studies are being presented during the annual American Society of Clinical Oncology (ASCO) meeting in Chicago, May 30 - June 3, 2008.

Multiple cellular pathways influence the growth and metastatic potential of tumors, which is thought to be related to the ability of cancer cells to develop primary or acquired resistance.(4) It is believed that targeted inhibition of several tumor cell signaling pathways may be more effective than inhibition of a single pathway alone.(4)

"Targeted therapies, either used in combination or as a single agent, are the future of cancer treatment and may have the potential to treat patients more effectively," said Dr. Paolo Paoletti, Senior Vice President of the Oncology Medicine Developmn 2008.

(9) Gonzalez-Angulo A, et al. Trends for Inflammatory Breast Cancer: Is Survival Improving? The Oncologist. 2007;12:904-912

ent Center at GSK. "GSK Oncology is committed to numerous trials across a wide range of settings that not only reflect clinical practice today but also the possible treatment practices of the future. The more we know about how and when to combine targeted therapies the closer we are to the ultimate goal -- personalized treatment regimens that better fit the individual needs of patients."

Two key drivers of the growth and spread of tumors are the HER family of tyrosine kinase receptors and vascular endothelial growth factors (VEGF).(4) HER2 overexpression is associated with poor prognosis(5) and reduced overall survival,(6) while VEGF is linked to formation of new blood vessels (angiogenesis).(7)

Lapatinib and pazopanib in HER2-positive advanced or metastatic breast cancer: abstract 1016(1)


TYKERB and pazopanib separately target the HER2 and VEGF pathways. This is the first Phase II trial to evaluate the combination of two oral, small molecule, targeted agents in first-line HER2-positive metastatic breast cancer. The primary endpoint was progressive disease rate (PDR) at week 12 as assessed by an independent review panel.(1) Progressive disease rate was defined as the percent of patients who had progressive disease by week 12 or had missing evaluations at week 12. In the study of 141 patients, 36.2 percent of patients treated with TYKERB plus pazopanib experienced disease progression versus 38.9 percent of patients who received TYKERB alone (p=0.37).

Additionally, response rate, a clinical term that is calculated by complete and partial disappearance of the tumor, was evaluated:

-- By investigator assessment, patients receiving the combination had a

44.9 percent response rate (90 percent CI 35.1-54.8) vs. a 27.8 percent

response rate (90 percent CI 19.1-36.5) for those in the monotherapy


-- By independent assessment patients receiving the combination had a 36.2

percent response rate (90 percent CI 26.7-45.8) at 12 weeks vs. a 22.2

percent response rate (90 percent CI 14.2-30.3) for those in the

monotherapy arm.

A retrospective analysis of response rate at any time up to 12 weeks was also performed:

-- By investigator assessment, patients receiving the combination had a

56.5 percent response rate (90 percent CI 46.7 - 66.3) vs. a 31.9

percent response rate (90 percent CI 22.9 - 41.0) for those in the

monotherapy arm.

-- By independent assessment patients receiving the combination had a 43.5

percent response rate (90 percent CI 33.7 - 53.3) vs. a 23.6 percent

response rate (90 percent CI 15.4 - 31.8) for those in the monotherapy


"Data outcomes from this study are important because they demonstrate that these two targeted therapies can be combined and may provide a potential, future treatment option for HER2-positive breast cancer," said Dr. Dennis Slamon, UCLA Jonsson Comprehensive Cancer Center. "In addition, both drugs are taken orally once daily."

Treatment continued until tumor progression, patients withdrew due to an adverse event (AE) or withdrawal of consent.(1) Three patients in the combination arm had an asymptomatic decrease (greater than or equal to 20 percent) in left ventricular ejection fraction (LVEF) that was below the lower limit of normal. One patient had a smaller decline (< 20 percent) in LVEF that was symptomatic. The most common adverse events (AEs) in the combination arm versus the monotherapy arm were diarrhea (67 percent vs. 58 percent), rash (28 percent vs. 29 percent), AST increase (32 percent vs. 16 percent), ALT increase (30 percent vs. 16 percent), nausea (29 percent vs. 16 percent), hypertension (26 percent vs. 4 percent), respectively (all grades).(1) There was one death in the monotherapy arm due to hepatic failure and one death in the combination arm due to dyspnea.

Further evaluation of the combination of TYKERB and pazopanib first-line therapy in patients with HER2-positive metastatic breast cancer is warranted.

Lapatinib and bevacizumab in HER2+ metastatic breast cancer: abstract 1042(2)


This single-arm Phase II trial evaluated the efficacy of oral TYKERB plus intravenous (IV) bevacizumab, a monoclonal antibody against VEGF. Similar to the study with pazopanib, results from this study demonstrate that TYKERB combined with bevacizumab provided patients with a 34.4 percent clinical benefit rate (complete response + partial response + stable disease greater than or equal to 24 weeks), and 62.5 percent of patients were progression free at week 12.(2)

To date, 32 patients enrolled in this trial had received a median of five prior metastatic breast cancer therapies (range, 0-15) and 28 out of 32 patients enrolled had received prior treatment with trastuzumab (median duration 19.7 months). The dosing regimen for this study was 1500 mg of TYKERB administered orally daily and 10 mg/kg bevacizumab IV every two weeks. The most common adverse events (AEs) were diarrhea (81 percent), rash (66 percent), nausea (56 percent), fatigue (56 percent), and vomiting (46 percent). The majority of patients experienced adverse events of Grade 1 or 2. Two Grade 2 asymptomatic left ventricular ejection fraction decreases, one Grade 3 gastrointestinal hemorrhage and one Grade 3 hypertensive event were reported.(2)

"In this study, blocking the HER2 and VEGF pathways with the combination of TYKERB and bevacizumab translated to anti-cancer activity for even heavily pretreated patients with metastatic breast cancer that could potentially advance the treatment of this high risk disease," said lead investigator, Dr. Hope Rugo, University of California San Francisco Helen Diller Family Comprehensive Cancer Center. "The approval of targeted therapies that focus on specific pathways has changed how we treat patients. We are in an exciting time where this study and others are now demonstrating the promise of combination targeted therapy regimens that block multiple interrelated pathways that cause cancer growth."

Lapatinib monotherapy in HER2+ relapsed/refractory inflammatory breast cancer (IBC): abstract 636(3)


In addition to the combination of targeted therapies, TYKERB has shown positive results as a monotherapy in HER2-positive inflammatory breast cancer (IBC).(8) Although IBC is rare, it is the most aggressive form of primary breast cancer and is associated with lower overall survival.(9)

This Phase II study of TYKERB monotherapy in IBC is the largest prospective clinical trial ever conducted in relapsed/refractory HER2-positive IBC. Final analysis showed TYKERB is clinically active, demonstrating a 38.9 percent response rate (in skin lesions or RECIST) (95 percent C.I. 30-48 percent) and a 36 percent response rate was noted in refractory patients previously treated with trastuzumab. The median duration of response was 20.9 weeks. Overall progression-free survival (PFS) was 14.6 weeks.(3)

One hundred and twenty six patients with HER2-positive (IHC 3+ or FISH positive) IBC that was refractory to anthracyclines, taxanes were enrolled in this study. Patients were treated continuously and received one dose of 1500 mg of TYKERB daily. Diarrhea was the most frequent adverse event, occurring in approximately 60 percent of patients. The most common serious adverse events (SAEs) reported for patients were dyspnea (6 percent), pleural effusion (4 percent), and pyrexia (2 percent). Thirteen patients had fatal SAEs; five of the fatal SAEs were considered possibly related to treatment.

"Inflammatory breast cancer is one of the most misunderstood and aggressive forms of breast cancer. In fact, often the disease is so advanced in many patients by the time of diagnosis that there are few effective therapies available," said investigator Dr. Bella Kaufman, The Chaim Sheba Medical Center, Tel Hashomer, Israel. "We are very excited to see these results as they provide the promise of future options for these patients."

Available online

For additional information on GSK's Oncology portfolio or the data being presented at ASCO, including detailed product fact sheets and press releases, visit This information will be updated throughout the ASCO annual meeting. Please also see onsite contact information listed at the end of this release.


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

On March 13, 2007, the United States Food and Drug Administration (FDA) approved TYKERB, in combination with capecitabine, for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab. TYKERB recently received a positive opinion for conditional approval from the Committee for Medical Products for Human Use (CHMP) of Europe. Marketing authorization for the European Union is granted by the European Commission and is expected within approximately two months of the CHMP's positive opinion.

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. For more information about GSK Oncology, visit

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. To access the latest GSK Oncology media materials, visit For more information about GSK Oncology, visit

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.

Important Safety Information

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 percent of patients) and postmarketing experience. The hepatotoxicity may be severe and deaths have been reported. The 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 retreated with TYKERB.

As with other therapies for HER2 overexpression, TYKERB has been associated with reports of decreases in left ventricular ejection fraction (LVEF). Caution should be taken if TYKERB is to be administered to patients with pre-existing cardiac conditions, including uncontrolled or symptomatic angina, arrhythmias, or congestive heart failure. LVEF should be evaluated in all patients prior to and during treatment with TYKERB.

Diarrhea was the most common adverse event resulting in discontinuation of study medication. 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.

TYKERB has been associated with interstitial lung disease and pneumonitis. Discontinue TYKERB if patients experience severe pulmonary symptoms.

TYKERB prolongs the QT interval in some patients. Consider ECG and electrolyte monitoring.

Fetal harm can occur when administered to a pregnant woman. Women should be advised not to become pregnant when taking TYKERB.

The most common adverse events (>20 percent) during treatment with TYKERB plus capecitabine were diarrhea, vomiting, nausea, fatigue, palmar-plantar erythrodysesthesia, and rash.
Please see full prescribing information.

Notes to editors:

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

TYVERB(R) is a registered trademark of the GlaxoSmithKline group of companies in Europe and is the proposed trade name in certain markets, pending regulatory approval. TYVERB is currently not licensed in Europe.

TYKERB is approved for sale in more than 20 countries including the United States, Australia, New Zealand, Switzerland, South Korea and certain countries in South America and the Middle East.

Registration dossiers for TYKERB have been filed in Canada and a number of countries in Asia, Latin America and the Middle East.

(1) Slamon D, Gomez H, Kabbinawar F, et al. Randomized study of pazopanib and lapatinib versus lapatinib alone in patients with HER2-positive advanced or metastatic breast cancer. J Clin Oncol. 2008; 26: 2008 (May 20 suppl; abstr 1016)

(2) Rugo HS, S. Franco S, Munster P, et al. A phase II evaluation of lapatinib (L) and bevacizumab (B) in HER2+ metastatic breast cancer (MBC). J Clin Oncol. 2008; 26:(May 20 suppl; abstr 1042).

(3) Kaufman B, Trudeau M, Johnston S et al. Clinical activity of lapatinib monotherapy in patients with HER2+ relapsed/refractory inflammatory breast cancer (IBC): Final results of the expanded HER2+ cohort in EGF103009. J Clin Oncol. 2008; 26: 2008 (May 20 suppl; abstr 636)

(4) Tabernero J. The role of VEGF and EGFR inhibition: Implications for combining anti-VEGF and anti-EGFR agents. Mol Cancer Res. 2007 ;5(3) :203-220

(5) Olayioye, M. Update on HER-2 as a target for cancer therapy Intracellular signaling pathways of ErbB2/HER-2 and family members. Breast Cancer Res 2001; 3;385-389.

(6) Bianchi S, et al. ErbB-receptors expression and survival in breast carcinoma: A 15-year follow-up study. Journal of Cellular Physiology. 2005; 206;702-708.

(7) McMahon G. VEGF receptor signaling in tumor angiogenesis. The Oncologist. 2000; 5 (1):3-10

(8) Johnston S, Trudeau M et al. Phase II study of predictive biomarker profiles for response targeting human epidermal growth factor receptor 2 (HER- 2) in advanced inflammatory breast cancer with lapatinib monotherapy. J Clin Oncol. 2008;26(7):1066-72. Epub Ja

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