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Glaxosmith­kline Reports Positive New Data on Tykerb(R)(­Lapatinib)­ at the 2007 American Society of Clinical Oncology (Asco) Annual Meeting
Sunday June 3, 10:00 am ET  
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 /PRNewswir­e-FirstCal­l/ -- 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.
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"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.

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