Healthcare Industry News:  lapatinib 

Biopharmaceuticals Oncology

 News Release - June 3, 2007

Glaxosmithkline Reports Positive New Data on Tykerb(R)(Lapatinib) at the 2007 American Society of Clinical Oncology (ASCO) Annual Meeting

KEY TYKERB STUDIES:

- Activity demonstrated for the first time in the treatment of first-line metastatic HER2-(ErbB2) positive breast cancer in combination with paclitaxel (Taxol(R)) one of the most commonly used chemotherapies(1)

- Activity in brain metastases associated with HER2-positive breast cancer, an area of significant unmet medical need(2,3)

- 19% of patients on TYKERB monotherapy had reduction in brain metastases

- In trial extension, reduction in brain metastases found in 40% of patients on TYKERB + capecitabine combination


CHICAGO, June 3 (HSMN NewsFeed) -- GlaxoSmithKline today announced positive data from three key studies on its first-in-class, oral small molecule HER2 kinase inhibitor, TYKERB® (lapatinib). Results of these and other important TYKERB studies are being presented this week at the 2007 American Society of Clinical Oncology (ASCO) annual meeting in Chicago, Illinois. The use of TYKERB in these settings is investigational.

"The robust clinical data presented for TYKERB at ASCO further demonstrate the great potential of this drug as an essential component of treatment regimens for women with HER2-positive breast cancer," said Paolo Paoletti, M.D., Senior Vice President of the Oncology Medicine Development Center at GSK. "GSK is dedicated to an ongoing TYKERB clinical program to identify additional treatment regimens, as well as patient populations that may respond to TYKERB. The data presented at ASCO this week underscore our unrelenting commitment to improving treatment for these patients."

TYKERB in Combination with Paclitaxel as First-Line Treatment for Patients with Metastatic or Relapsed Advanced Breast Cancer (Abstract #1011, Embargoed until June 3, 9:00 AM, CDT)(1)

Paclitaxel is one of the most commonly used chemotherapies in breast cancer. Therefore, the evaluation of TYKERB in combination with this treatment is of high importance.

This large, randomized, multicenter, prospective trial evaluated a total of 580 patients either negative or untested for HER2 overexpression. While the combination therapy did not demonstrate an incremental benefit for patients with HER2-negative disease, an analysis of 91 patients who were retrospectively identified as having HER2-positive disease showed that TYKERB plus paclitaxel increased progression-free survival in patients with HER2-positive breast cancer not previously treated with trastuzumab. Results as follows represent the combination of TYKERB plus paclitaxel (n=52) versus paclitaxel alone (n=39), respectively, in patients with HER2-positive disease:

-- Median progression-free survival was 7.9 months versus 5.2 months (p=0.007)

-- Median duration of response was 7.4 months versus 5.5 months

-- Complete or partial response occurred in 60 percent of patients versus 36 percent (p = 0.027)

-- There was a trend towards improvement in overall survival after 39 deaths had been reported. Data presently available indicate a median survival of 24 months versus 19 months (p=0.160), but data are not yet fully mature

Data from this trial of TYKERB plus paclitaxel versus paclitaxel alone as first-line treatment in patients with newly diagnosed metastatic breast cancer have provided the first evidence of activity in the HER2-positive subgroup that the combination significantly improves progression-free survival of the disease compared with the chemotherapy alone.

"These results have the potential to directly impact clinical practice and may benefit patients in the first-line treatment setting," said Dr. Angelo Di Leo, Director of the Medical Oncology Unit, Hospital of Prato (Italy) and lead investigator of this trial. "TYKERB in combination with paclitaxel is a step in the right direction as the oncology community explores potential combination therapies to individualize treatment for breast cancer patients."

The most common adverse events (AEs) included rash, diarrhea, nausea, vomiting, neutropenia and mucositis. The addition of TYKERB to paclitaxel resulted in an increase in diarrhea and rash. SAE-related deaths were higher in the combination arm (2.7% vs 0.6%).

Several additional Phase III trials combining TYKERB with taxanes are being conducted in patients with HER2-positive disease.

TYKERB Activity in Brain Metastases Associated with Breast Cancer (Abstract #1012, Embargoed until June 3, 9:00 AM, CDT), (Abstract #1035, Embargoed until June 2, 8:00 AM, CDT) One-third of women with HER2-positive metastatic breast cancer currently develop central nervous system (CNS) or brain metastases.(4) Limited treatment options clearly demonstrate that brain metastases is an area of significant unmet medical need. Once the disease advances to this stage, overall disease prognosis is poor with the average one-year survival from diagnosis estimated at about 20 percent.(5)

Results from an ongoing, multicenter Phase II study suggest that TYKERB has clinical activity in heavily pretreated patients with CNS metastases from HER2-positive breast cancer. Patients (n=241) enrolled in this study had radiographically documented progressive brain lesions following prior therapy with trastuzumab and cranial radiotherapy. Results from an independent radiology review show that 19 patients (7%) treated with TYKERB monotherapy experienced a partial response, defined by a greater than or equal to 50% volumetric reduction in brain lesions with no progression of tumor outside the brain, no increase in steroid requirements or worsening of neurological symptoms. Forty-six patients (19%) experienced a greater than or equal to 20% volumetric reduction in brain lesions.

An additional 102 patients (42%) achieved stable disease for at least eight weeks based on a protocol defined composite response criteria. Twenty- two percent of all patients had no disease progression within the first six months on TYKERB monotherapy.(2)

An exploratory analysis in a previous, Phase III study found that numerically fewer patients on TYKERB plus capecitabine developed brain metastases as compared to capecitabine alone. As a result, this Phase II study was amended to allow patients whose disease progressed in the brain and/or non-CNS on monotherapy TYKERB to then receive the combination of TYKERB and capecitabine. In patients (n=40) treated with TYKERB in combination with capecitabine, 8 (20%) experienced a greater than or equal to 50% volume reduction in brain metastases, and 16 (40%) experienced greater than or equal to 20% volume reduction.(2)

"There is a significant need for effective alternatives to prevent and treat brain metastases arising from breast cancer as there are no currently approved systemic treatments for these patients. These data suggest that TYKERB may cross a compromised blood brain barrier and suggest the CNS activity of TYKERB," said Nancy U. Lin, M.D., Harvard Medical School (Boston,

Massachusetts) and principal investigator for this trial. "TYKERB has promise in the treatment of brain metastases."

The most common AEs included diarrhea (13% Grades 3 and 4), skin rash (3% Grades 3 and 4), nausea (3% Grade 3), vomiting (4% Grade 3), fatigue (3% Grade 3) and anorexia (1% Grade 3).(2)

In addition, updated brain metastases data (abstract #1035) from an unplanned, retrospective subset analysis of the pivotal trial of TYKERB plus capecitabine versus capecitabine alone in patients with HER2-positive, trastuzumab-exposed advanced breast cancer showed a reduction in the number of patients developing CNS metastases as a first site of relapse (4 versus 13 patients, p=0.0445).(3) Original data were presented at ASCO 2006.

Ongoing Trials

GSK has a comprehensive clinical trial program that is actively studying TYKERB in other breast cancer settings and other cancers to better identify patient populations that may respond to therapy. The landmark Phase III study TEACH (Tykerb® Evaluation After CHemotherapy), trial has reached a key milestone, enrolling more than 1,000 patients. TEACH is designed to investigate whether adjuvant treatment with TYKERB will improve disease-free survival in women with early-stage HER2-positive breast cancer, including those with positive and negative node involvement.(6)

About TYKERB/TYVERB

TYKERB/TYVERB (lapatinib) is a first-in-class 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.

TYVERB was approved in Switzerland in May 2007. Marketing applications for TYKERB/TYVERB have been filed around the world, including the European Union, Canada, Brazil, Australia and South Korea.

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 GlaxoSmithKline at www.gsk.com.

Important Safety Information

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 preexisting 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.

Caution should be taken if TYKERB is to be administered to patients with severe hepatic impairment due to increased systemic exposure to the drug.

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

Diarrhea, including severe diarrhea, has been reported during treatment with TYKERB. Proactive management of diarrhea with antidiarrheal 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.

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

The most common AEs during treatment with TYKERB plus capecitabine were diarrhea, hand-foot syndrome, nausea, rash, vomiting and fatigue.

*Please see full prescribing information.

Cautionary statement regarding forward-looking statements

Under the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995, the company cautions investors that any forward-looking statements or projections made by the company, 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 the Group's operations are described under 'Risk Factors' in the 'Business Review' in the company's Annual Report on Form 20-F for 2006.

References

1. Di Leo et al. Abstract #1011 - lapatinib (L) with paclitaxel compared to paclitaxel as first-line treatment for patients with metastatic breast cancer: A phase III randomized, double-blind study of 580 patients. Presented at the 2007 American Society of Clinical Oncology annual meeting.

2. Lin et al. Abstract # 1012 - EGF105084, a phase II study of lapatinib for brain metastases in patients (pts) with HER2+breast cancer following trastuzumab (H) based systemic therapy and cranial radiotherapy (RT). Presented at the 2007 American Society of Clinical Oncology annual meeting.

3. Geyer et al. Abstract # 1035 - lapatinib (L) plus capecitabine © in HER2+ advanced breast cancer (ABC): Genomic and updated efficacy data. Presented at the 2007 American Society of Clinical Oncology annual meeting.

4. Lin et al. Phase II trial of lapatinib for brain metastases in patients with HER2+ breast cancer. Presented at the 2006 American Society of Clinical Oncology annual meeting.

5. R. Weil et al. Breast Cancer Metastasis to the Central Nervous System. American Journal of Pathology. 2005;167:913-920.

6. Tykerb Evaluation After Chemotherapy (TEACH): lapatinib Versus Placebo In Women With Early-Stage Breast Cancer http://www.clinicaltrials.gov/ct/show/NCT00374322?order=4. Accessed May 2007.


Source: GlaxoSmithKline

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