Data from Tykerb investigational phase III studies in neo-adjuvant HER2-positive breast cancer presented at breast cancer symposium

Issued: London, UK and Philadelphia, US

Topline results were presented today from two Phase III studies examining the effect of Tykerb (lapatinib) in the neo-adjuvant setting of HER2-positive breast cancer.^{i, ii} The combination of lapatinib and trastuzumab, with standard chemotherapy, was compared to standard chemotherapy plus either lapatinib or trastuzumab in a trial called NeoALTTO. In another trial, known as GeparQuinto, lapatinib plus standard chemotherapy was compared to trastuzumab plus standard chemotherapy. The studies were conducted and presented by international cooperative groups, with research being funded in part by GlaxoSmithKline. Data findings from both trials were presented at the 33rd annual meeting of the CTRC-AACR San Antonio Breast Cancer Symposium (SABCS), held in San Antonio, Texas (8-12 December 2010).

The primary endpoint for NeoALTTO and GeparQuinto was pathological complete response (pCR) defined as the absence of invasive cancer cells in the breast at surgery.

“In NeoALTTO, a higher level of complete pathological response was obtained by the dual inhibition of the HER2 pathway using an antibody, trastuzumab, and a small molecule tyrosine kinase inhibitor, lapatinib, compared with either agent alone. This is an important scientific finding,” said Paolo Paoletti, M.D., Head of Oncology Research and Development, GSK. “Although lapatinib is not currently approved in this setting, we are committed to further researching the potential of this combination in this aggressive form of breast cancer.”

NeoALTTO

The Neo-Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation Trial (NeoALTTO) randomised 455 patients with HER2-positive primary breast cancer to receive lapatinib (L) plus paclitaxel or trastuzumab (T) plus paclitaxel or a combination of lapatinib and trastuzumab (L+T) plus paclitaxel. The study was led by the Breast International Group (BIG) - in particular by its partners the SOLTI cooperative group and the Breast European Adjuvant Study Team (BrEAST) - and was funded by GlaxoSmithKline.

The primary endpoint for NeoALTTO was pathological complete response defined as the absence of invasive cancer cells in the breast at surgery or only non-invasive in-situ cancer in the breast. Topline results showed the pCR rate was 51.3 percent in the lapatinib plus trastuzumab combination arm compared to a rate of 24.7 percent for the lapatinib arm and 29.5 percent for the trastuzumab arm. The difference in pCR between the lapatinib plus trastuzumab arm compared to the trastuzumab arm was statistically significant, p=0.0001. The pCR difference between the lapatinib and trastuzumab arms was not statistically significant, p=0.34.

Grade 3 adverse events presented for L,T and L+T respectively were: diarrhoea (23 percent, 2 percent and 21 percent), neutropenia (16 percent, 3 percent and 9 percent), hepatic (13 percent, 1 percent and 9 percent), and skin disorders (7 percent, 3 percent, and 7 percent). No deaths occurred during the treatment phase of the neo-adjuvant setting of the study, and no major cardiac dysfunction occurred during the neo-adjuvant phase of the study. There was one patient death immediately after the end of treatment.

Results presented at SABCS 2010 reflect findings from the 18 weeks of therapy prior to surgery, a very important window in the treatment of early breast cancer. Analysis of primary endpoint efficacy and safety findings is ongoing. The study is continuing for secondary endpoints, which include overall survival, disease-free survival and safety.

GeparQuinto

GeparQuinto is an open-label Phase III trial led by the German Breast Group which evaluated patients with HER2-negative and HER2-positive breast cancer. In the HER2-positive setting 620 patients were randomised to receive neo-adjuvant treatment with epirubicin/cyclophosphamide followed by docetaxel in combination with either trastuzumab or lapatinib. The lapatinib dosing used in the study was lower than the dose in the currently approved label for lapatinib. The study employed pathological complete response as the primary endpoint defined as the absence of tumour residuals (invasive and non-invasive) in the breast and lymph nodes at the time of surgery.

Study results show that both the lapatinib and trastuzumab therapies demonstrated an ability to reduce the presence of tumour residuals in breast and nodes at the time of surgery. The pCR rate in the trastuzumab arm was 31.3 percent compared to the lapatinib arm of 21.7 percent, p<>

The topline presentation of the results at SABCS contained limited safety data. Categories of frequently occurring serious adverse events, all grades, included: gastrointestinal, blood disorders and infections. Analysis of primary endpoint efficacy and safety findings is ongoing. The study is ongoing for secondary endpoints, which include overall survival, disease-free survival and safety.

About NeoALTTO

NeoALTTO is a multinational, randomised, Phase III study in primary breast cancer. In the study, 455 patients with HER2 -positive primary breast cancer were randomised to one of three treatment arms; Patients were randomised to receive either lapatinib 1500 mg/d, or trastuzumab four mg/kg IV loading dose followed by two mg/kg IV weekly, or lapatinib 1000 mg/d with trastuzumab four mg/kg IV loading dose followed by two mg/kg IV weekly for a total of six weeks.

After this biological window, patients continued on the same targeted therapy plus weekly paclitaxel 80 mg/m² for a further 12 weeks, until definitive surgery (total neo-adjuvant therapy duration of 18 weeks). Paclitaxel was initiated at week four if there was evidence of disease progression at that time. In NeoALTTO, the primary endpoint was pCR defined as no invasive cancer in the breast or only non-invasive in-situ cancer in the breast specimen.

About GeparQuinto

GeparQuinto is a neo-adjuvant Phase III study, planned to include more than 2,500 patients that were HER2-positive and HER2-negative. The HER2-positive cohort of the study included 620 HER2-positive breast cancer patients and compared lapatinib versus trastuzumab given concomitantly with anthracycline–taxane-based therapy. Both groups received trastuzumab post surgery.

The primary end point was pathological complete response defined as no invasive or non-invasive tumour residuals in breast and nodes, i.e. patients with some residual disease. The trial was led and presented by the GBG (German Breast Group) who are responsible for data management and the trial database. The trial was supported by GSK, Roche, Novartis and Sanofi.

About Tykerb (lapatinib)

In the United States, lapatinib is indicated in combination with letrozole for the treatment of postmenopausal women with hormone receptor positive metastatic breast cancer that over expresses the HER2 receptor for whom hormonal therapy is indicated. Tykerb in combination with an aromatase inhibitor has not been compared to a trastuzumab-containing chemotherapy regimen for the treatment of metastatic breast cancer. Lapatinib is also FDA approved in combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumours over express HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab.3
In Europe, lapatinib, in combination with an aromatase inhibitor (AI), is indicated for the treatment of post-menopausal women with hormone receptor (HR)-positive, HER2 (ErbB2) over-expressing metastatic breast cancer and for whom chemotherapy is currently not intended. In Europe, lapatinib is also approved in combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumours over-express HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab.

Lapatinib is approved in 91 countries including the U.S., Europe, Australia, India, Brazil, Russia, Turkey, South Korea and other countries around the world. Registration dossiers have been filed in Canada, China, Japan, Mexico and a number of countries in Asia, Latin America and the Middle East.

US FDA boxed warning and important safety information for Tykerb

Hepatotoxicity has been observed in clinical trials and postmarketing experience. The hepatotoxicity may be severe and deaths have been reported. Causality of the deaths is uncertain.

Patients with known severe hypersensitivity to TYKERB or any of its components should not take TYKERB. Also, patients may experience decreased left ventricular ejection fraction, hepatotoxicity, diarrhoea, interstitial lung disease/pneumonitis, QT prolongation, and risk of fetal harm in pregnant women. If TYKERB is to be administered to patients with severe hepatic impairment, dose reduction should be considered. The most common adverse reactions (=20%) during therapy with TYKERB plus letrozole compared to letrozole were diarrhoea (64%, 20%), rash (44%, 13%), nausea (31%, 21%), and fatigue (20%, 17%). The most common adverse reactions (>20%) during therapy with TYKERB plus capecitabine versus capecitabine alone were diarrhoea (65%, 40%), palmar-plantar erythrodysesthesia (53%, 51%), nausea (44%, 43%), rash (28%, 14%), vomiting (26%, 21%), and fatigue (23%, 25%).

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 further information please visit www.gsk.com.

Notes to editors

TYKERB® and TYVERB® are registered trademarks of the GlaxoSmithKline group of companies.

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 2009.

References

(i) Jose Baselga, Ian Bradbury, Holger Eidtmann, Serena Di Cosimo, Claudie Aura et al. Final Results of the NeoALTTO Trial (BIG01-06 / EGF106903): A Phase III, randomized, open-label, neo-adjuvant study of lapatinib, trastuzumab, and their combination plus paclitaxel in women with HER2-positive primary breast cancer, 2010 CTRC-AACR San Antonio Breast Cancer Symposium, S3-3
(ii) Untch M, Loibl S, Bischoff J, Eidtmann H, Kaufmann M, Blohmer J-U, Hilfrich J, et al. Lapatinib vs Trastuzumab in combination with neo-adjuvant anthracycline-taxane-based chemotherapy: Primary efficacy endpoint analysis of the GEPARQUINTO STUDY (GBG 44), 2010 CTRC-AACR San Antonio Breast Cancer Symposium, S3-1