Lapatinib demonstrates activity in combination with other targeted therapies and as monotherapy across a range of breast cancer settings

Data in this release to be presented on SUNDAY, JUNE 1, 2008; 9:30 – 9:45 AM (CDT), TUESDAY, JUNE 3, 2008; 11:00 AM –
12:00 PM (CDT), and MONDAY, JUNE 2; 2:00 – 6:00 PM (CDT), respectively.

• First Phase II data investigating the dual inhibition of HER2 (ErbB2) and VEGF pathways with two oral, small molecule tyrosine-kinase inhibitors (lapatinib and pazopanib) demonstrates activity in first-line HER2 positive breast cancer¹
• Phase II results combining lapatinib and bevacizumab, a monoclonal antibody, shows activity in recurrent metastatic HER2 positive breast cancer²
• Final results from the largest prospective trial evaluating lapatinib monotherapy as a treatment for relapsed inflammatory breast cancer (IBC) demonstrates activity in this highly aggressive and difficult to treat disease³

London, UK, Philadelphia, PA, 1 June 2008

GlaxoSmithKline today announced the results of three studies evaluating lapatinib - 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 lapatinib 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 tumours, which is thought to be related to the ability of cancer cells to develop primary or acquired resistance. It is believed that targeted inhibition of several tumour cell signalling 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 Development 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 tumours are the HER family of tyrosine kinase receptors and vascular endothelial growth factors (VEGF).⁴ HER2 overexpression is associated with poor prognosis and reduced overall survival while VEGF is linked to formation of new blood vessels (angiogenesis).

Lapatinib and pazopanib in HER2 positive advanced or metastatic breast cancer: abstract 1016¹

DATA PRESENTATION: SUNDAY, JUNE 1, 2008; 9:30 – 9:45 AM (CDT)

Lapatinib 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 lapatinib plus pazopanib experienced disease progression versus 38.9 percent of patients who received lapatinib alone (p=0.37).

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

- By investigator assessment, patients receiving the combination had a 44.9 percent response rate (90% CI 35.1-54.8) vs. a 27.8 percent response rate (90% CI 19.1-36.5) for those in the monotherapy arm.

- By independent assessment patients receiving the combination had a 36.2 percent response rate (90% CI 26.7-45.8) at 12 weeks vs. a 22.2 percent response rate (90% 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% CI 46.7 – 66.3) vs. a 31.9 percent response rate (90% 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% CI 33.7 – 53.3) at 12 weeks vs. a 23.6 percent response rate (90% CI 15.4 – 31.8) for those in the monotherapy arm.

“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 Centre. “In addition both drugs are taken orally once daily.“

Treatment continued until tumour progression, patients withdrew due to an adverse event (AE) or withdrawal of consent.¹ Three patients in the combination arm had an asymptomatic decrease (≥ 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 diarrhoea (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 one death in the combination arm due to dyspnoea.

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

Lapatinib and bevacizumab in HER2 positive metastatic breast cancer: abstract 1042²

DATA PRESENTATION: TUESDAY, JUNE 3, 2008; 11:00 AM – 12:00 PM (CDT)

This single-arm, Phase II trial evaluated the efficacy of oral lapatinib plus intravenous (IV) bevacizumab, a monoclonal antibody against VEGF. Similar to the study with pazopanib, results from this study demonstrate that lapatinib combined with bevacizumab provided patients with a 34.4 percent clinical benefit rate (complete response + partial response + stable disease ≥ 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 lapatinib administered orally daily and 10 mg/kg bevacizumab IV every two weeks. The most common adverse events (AEs) were diarrhoea (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 haemorrhage and one Grade 3 hypertensive event were reported.²

“In this study, blocking the HER2 and VEGF pathways with the combination of lapatinib 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 Centre. “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 636³

DATA PRESENTATION: MONDAY, JUNE 2; 2:00 – 6:00 PM (CDT)

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

This Phase II study of lapatinib monotherapy in IBC is the largest prospective clinical trial ever conducted in relapsed/refractory HER2 positive IBC. Final analysis showed lapatinib 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 and taxanes were enrolled in this study. Patients were treated continuously and received one dose of 1500 mg of lapatinib daily. Diarrhoea was the most frequent adverse event, occurring in approximately 60 percent of patients. The most common serious adverse events (SAEs) reported for patients were dyspnoea (6%), pleural effusion (4%), and pyrexia (2%). 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 www.us.gsk.com/media. This information will be updated throughout the ASCO annual meeting. Please also see onsite contact information listed at the end of this release.

About lapatinib

Lapatinib 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 tumour progression and metastases. Overexpression of this receptor has been reported in a variety of human tumours and is associated with poor prognosis and reduced overall survival.

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 tumours overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab. Lapatinib 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 www.gskoncology.com

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 www.gsk.com/media. For more information about GSK Oncology, visit www.gskoncology.com

Notes to editors:

TYKERB® is a registered trademark of the GlaxoSmithKline group of companies in the United States.

TYVERB® 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.

Lapatinib 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 lapatinib have been filed in Canada and a number of countries in Asia, Latin America and the Middle East.

For on-site contact at ASCO May 30 – June 3, 2008:

U.S media only: Sarah Alspach – +1 215 287 6354
Global media: Gregory Clarke – +1 317 694 3545
European media: Sonja Luz – +44 7920 568 625

 

Enquiries: US Media enquiries:	Mary Anne Rhyne	+1 919 483 2839
UK Media enquiries:	Philip Thomson	+44 20 8047 5502
	Gwenan White	+44 20 8047 5502
	Alice Hunt	+44 20 8047 5502
European Analyst/Investor enquiries:	David Mawdsley	+44 20 8047 5564
	Sally Ferguson	+44 20 8047 5543
	Gary Davies	+44 20 8047 5503
US Analyst/ Investor enquiries:	Frank Murdolo	+1 215 751 7002
	Tom Curry	+1 215 751 5419

References

[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 Jan 2008.

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