GSK Announces Results of First Phase III Trial Evaluating Tykerb/Tyverb (lapatinib) Plus Herceptin (trastuzumab)

LONDON, PHILADELPHIA, May 15, 2008 – GlaxoSmithKline today announced positive data from the first-ever randomised, multi-centre, open label Phase III trial of the combination of two targeted agents, lapatinib and trastuzumab, in women with HER2-positive metastatic breast cancer.¹  HER2-positive breast cancer is a particularly aggressive form of cancer that affects approximately 25 to 30 percent of breast cancer patients.²  The study results demonstrated a benefit from the combination.  Both treatments target the HER2 protein but work in different ways.¹ Trastuzumab attaches to the outside of the HER2 protein, while lapatinib goes inside the cell to block signals from the HER2 protein for the cancer to grow.³  GlaxoSmithKline Oncology will present these and other new data in breast cancer at the annual American Society of Clinical Oncology (ASCO) meeting in Chicago beginning Friday 30th May.

 “Many women with HER2 positive breast cancer are still very active and living full lives, yet when their disease progresses after trastuzumab and chemotherapy, we have had limited treatment options. Therefore it is important to study options that may eventually help women in their fight against this disease,” said lead investigator Joyce O’Shaughnessy, M.D., Baylor-Sammons Cancer Center, Texas Oncology, PA, US Oncology, Dallas, TX.  “Effectively attacking HER2 from multiple angles is an exciting and innovative approach, and demonstrates the significant advances being achieved in treating this complex form of breast cancer.”

Despite receiving multiple prior lines of anti-cancer therapy, patients who received lapatinib plus trastuzumab in this study experienced:
? A statistically significant increase in median progression-free survival versus TYKERB alone (12 weeks vs. 8.1 weeks)¹
? A 27 percent reduction in the risk of disease progression [Hazard Ratio: 0.73; p=0.008]¹
? A response rate of 10.3 percent versus 6.9 percent.  Response rate is a clinical term that is calculated by complete and partial disappearance of the tumour.
? Double the overall clinical benefit rate versus lapatinib alone (24.7 percent vs. 12.4 percent; p=0.01).¹  Clinical benefit rate is calculated by the response rate and the rate of durable stable disease (greater than or equal to 6 months).
? A trend in improved overall survival [Hazard Ratio: 0.75; p=0.106]1

The study also demonstrated the activity of lapatinib as a single agent in this patient population, with patients on this arm achieving a median progression free survival of 8.1 weeks and an overall clinical benefit rate of 12.4 percent.¹ 

The clinical synergy of lapatinib and trastuzumab confirms previous observational findings in preclinical studies and previously reported data from a Phase I study. These latest findings confirm the rationale for further research of this combination in earlier lines of therapy in the metastatic setting and in early stage disease. Additional analysis is underway to explore the benefit that lapatinib plus trastuzumab can offer to less heavily pre-treated patients.¹

Study Background
In this study, 296 patients with HER2 (ErbB2) positive breast cancer who had documented progression on trastuzumab treatment in the metastatic setting were eligible to be randomised to receive lapatinib (1000 mg QD) plus trastuzumab (2 mg/kg weekly after 4 mg/kg loading dose) or lapatinib alone (1500 mg QD). Patients were heavily pre-treated and had received a median of six prior anti-cancer regimens.  Patients had received a median of three prior lines of trastuzumab.¹

The primary endpoint of the study was progression-free survival, and secondary endpoints included clinical benefit rate (CR+PR+SD ?24 weeks), response rate, and overall survival.  If patients progressed on the lapatinib monotherapy arm after four weeks of therapy, they could cross over to receive the combination of lapatinib + trastuzumab.  Adverse events were similar in both arms, with Grade 1/2 diarrhoea significantly higher in the lapatinib + trastuzumab arm (53 percent vs. 41 percent; p=0.03).  Two patients in the combination arm and one patient in the lapatinib monotherapy arm experienced symptomatic decreases in left ventricle ejection fracture (LVEF); one patient in the lapatinib + trastuzumab arm died due to a pulmonary thromboembolism with progressive malignant pleural effusions; two patients with LVEF decrease later recovered.  Isolated cases of asymptomatic transient decreases in LVEF were noted in both treatment arms.¹

Additional Breast Cancer Data for Investigational Uses of Lapatinib to be Presented at ASCO
GSK Oncology will also be presenting for the first time results of two studies evaluating lapatinib in combination with other targeted therapies, including lapatinib +  pazopanib, GSK's investigational, oral, multikinase angiogenesis inhibitor, and lapatinib + bevacizumab.  Final results from a trial evaluating lapatinib monotherapy in inflammatory breast cancer (IBC) will also be presented on-site.  For more information on date and time of presentation, visit www.asco.org.

“The breadth of data to be presented at ASCO this year is truly remarkable and signifies the commitment of GSK Oncology to being at the forefront of cancer research,” said Paolo Paoletti, M.D., Senior Vice President of the Oncology Medicine Development Center at GSK.  “We are excited by all of the results that will be presented and the promise they hold for the cancer community.”

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.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 (ErbB2) 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 from the Committee for Medical Products for Human Use (CHMP) of Europe.  Marketing authorisation in Europe is pending.

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 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.
HERCEPTIN® is a registered trademark of Genentech, Inc.

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. O’Shaughnessy J, et. al. Final presentation for abstract #1015 – A randomized study of lapatinib (TYKERB®) in combination with trastuzumab vs. lapatinib monotherapy in heavily pretreated HER2-positive metastatic breast cancer progressing on trastuzumab therapy. To be presented at the 2008 American Society of Clinical Oncology annual meeting.
2. “Glossary.” American Cancer Society. http://www.cancer.org/docroot/gry/gry_0.asp?txtSearch=her2&dictionary=. Accessed May 7, 2008.
3. Geyer C, et. al.  Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006;355:2733-43.

Posted: May 2008

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