Tyverb Demonstrates Encouraging Results in Phase II Study in Advanced Head and Neck Cancer
Results support GSK’s confidence in the ongoing Phase III study for Tyverb® (lapatinib) in advanced head and neck cancer
Data on ESMO abstract #688O. Del Campo, et al. Effect of lapatinib monotherapy on apoptosis and proliferation: Results of a Phase II randomised study in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN).
LONDON, Sept. 14, 2008-GlaxoSmithKline’s (GSK) oral targeted agent Tyverb® (lapatinib) demonstrated single agent activity and improvement in clinical response to the subsequent standard chemoradiation compared to placebo in a Phase II study of advanced squamous cell carcinoma of the head and neck (SCCHN). These encouraging results, presented during the 33rd Congress of the European Society for Medical Oncology (ESMO), represent an important step in the development of lapatinib for head and neck cancer. Lapatinib is already being investigated further for head and neck cancer; an innovative Phase III adjuvant study (MAINTYNANCE) is currently recruiting across the world.
Lapatinib is the first oral, small molecule, dual targeted therapy that works intracellularly (from inside the cell) to inhibit both EGFR and ErbB2 (HER2), two receptor proteins which are involved in tumour growth. EGFR expression has been demonstrated to occur with high frequency in the majority of cancers including head and neck, ovarian, bladder and lung  and typically presents a more aggressive clinical course of the cancer.  
“These results show that the use of a dual tyrosine-kinase inhibitor like lapatinib may be clinically relevant not just in breast cancer, but maybe in other tumours such as head and neck cancer where EGFR is overexpressed,” said Paolo Paoletti, M.D., Senior Vice President, Oncology Research and Development, GSK. “We are committed to developing lapatinib in head and neck cancer through our global Phase III trial, which is extremely exciting and aims to set a new standard of care and improve patient survival. The trial is the largest ever conducted in the resectable locally advanced setting. It is currently open and enrolling.”
“The Phase II study results demonstrated clear clinical activity with monotherapy lapatinib in patients with squamous cell carcinoma of the head and neck,” said Josep Maria Del Campo, M.D., Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain, and primary investigator of the study. “Interestingly, it was also observed that treatment with lapatinib appeared to improve response to chemoradiation.”
In the Phase II study, 107 therapy-naïve patients with locally advanced SCCHN were randomised (2:1) to receive 1500 mg of oral lapatinib or placebo. Patients were treated with lapatinib for a duration of two to six weeks, after which all patients received standard treatment with concurrent platinum-based chemotherapy and radiation therapy. Patients were followed-up for 12 weeks after completion of chemoradiation. Tumour biopsies were taken at time of study enrolment (Day 0) and after two weeks of study participation (Day 14) for biomarker analysis.
During the short duration (14 days) of lapatinib treatment there was a modest, but statistically significant reduction in mean tumour cell proliferation in patients who had received lapatinib compared to the placebo arm (-8% vs. -2.7% respectively, p=0.039). In addition, a trend towards inducing death of cancer cells was observed in some patients.
In a subset of 40 patients who had radiological scans following a short duration of lapatinib monotherapy (approximately one month), four patients (17%, n=24) had a complete or partial response, compared with no responders on the placebo arm (n=16).
88 patients were determined to be evaluable for radiological analysis following their complete course of chemoradiation, i.e., they had radiology scans at baseline (enrolment) and post-chemoradiation (~weeks 8-12 after treatment). The results showed an improvement in response rate (complete response and partial response) for patients who had received lapatinib compared to the placebo arm (86 vs. 63% respectively. A difference in complete response rate between the two groups after they received chemoradiation was also observed; 28% of patients in the lapatinib arm achieved complete response compared to 7% of patients in the placebo arm;1suggesting lapatinib may enhance the effect of subsequent chemoradiation. The most common adverse events (AEs) observed after lapatinib followed by chemoradiation treatment included mucositis (70%), asthenia (58%), odynophagia (33%), dysphagia (30%), rash (10%), nausea (29%) vomiting (25%) and diarrhoea (4%) compared to 67%, 47%, 36%, 33%, 14%, 22%, 36% and 6% for the placebo arm respectively.
About MAINTYNANCE (Phase III adjuvant study)
The MAINTYNANCE trial will evaluate the effects of lapatinib in combination with standard concurrent cisplatin and radiation therapy. Patients with resected head and neck cancer will be randomised post-surgery to treatment with chemoradiation with or without lapatinib followed by one year of lapatinib monotherapy. MAINTYNANCE is currently open and recruiting in a total of 21 countries (13 in European Union, 2 in North America and 6 in Rest of World) and is expected to recruit patients through late 2009. Further details can be found on www.clinicaltrials.gov (identifier NCT00424255).
About Head and Neck Cancer
Head and neck cancer arises in the nasal cavity, paranasal sinuses, lips, mouth, salivary glands, pharynx (throat), or larynx.  There are over 640,000 cases of head and neck cancer diagnosed annually worldwide, and over 350,000 deaths from the disease.6 In Europe there are over 140,000 cases diagnosed annually. 
Most head and neck cancers begin in the moist tissues lining hollow organs and cavities (mucosal surfaces). Normal mucosal cells look like scales (squamous) under a microscope so this type of head and neck cancer is collectively known as squamous cell carcinoma of the head and neck (SCCHN).  The most common therapy forms of treatment for SCCHN include surgery, radiotherapy and chemotherapy.
Research suggests that approximately one quarter to one third of advanced head and neck cancers that are primarily treated with surgery and radiation therapy come back following treatment.4 Approximately half of high-risk patients treated with surgery and chemoradiation therapy die within 5 years. ,
About Tyverb® (lapatinib)
Lapatinib is an oral small-molecule inhibitor of the EGFR and ErbB2 (HER2) tyrosine kinase receptors. Stimulation of EGFR and ErbB2 is associated with cell proliferation and with multiple processes involved in tumour progression and metastases. Overexpression of these receptors
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 ErbB2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab. On June 10, 2008, the European Commission adopted a decision to grant a conditional marketing authorisation for lapatinibin all 27 European Union (EU) member states. Lapatinib is approved for sale in 55 countries including Australia, India, Brazil, Russia, Turkey, South Korea and other countries around the world. Registration dossiers for lapatinib have been filed in Canada, China, Japan, Mexico and a number of countries in Latin America, Middle East, Africa and Asia Pacific.
Lapatinib has been associated with hepatotoxicity. The hepatotoxicity maybe severe and deaths have been reported. Causality is uncertain. Patients should receive liver function tests before initiation of treatment, every 4 to 6 weeks during treatment, and as clinically indicated. A dose reduction in patients with severe pre-existing hepatic impairment should be considered. Discontinue and do not restart lapatinib if patients experience severe changes in liver function tests.
GSK in Oncology
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Notes to Editors:
To access the latest GSK Oncology media materials, visit www.gskcancermedia.com
TYKERB ® is a registered trademark of the GlaxoSmithKline group of companies in the United States and the countries outside of Europe.
TYVERB ® is a registered trademark of the GlaxoSmithKline group of companies in Europe pending regulatory approval.
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 Del Campo, JM., Sebastian, P. et al. Effect of lapatinib monotherapy on apoptosis and proliferation: Results of a phase II randomised study in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). Abstract #6880
 Konecny GE, Pegram MD, Venkatesan N, et al. Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumab-treated breast cancer cells. Cancer Res. 2006 Feb 1;66(3):1630-9
 Normanno N, Bianco C, De Luca A, Maiello MR, Salomon, DS. “Target-based agents against ErbB receptors and their ligands: a novel approach to cancer treatment.” Endocrine-Related Cancer 2003; 10;1-21.
 Ang KK, Berkey BA, et al. Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res. 2002; 62(24): 7350-7356
 Head and Neck Cancer - Definition of Head and Neck Cancer. National Cancer Institute. Accessed August 6, 2008.
 Cancer Mondial. Accessed 2nd September 2008.
 National Cancer Institute. Accessed 3rd Jan 2007
 Bernier J, Domenge C et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. NEJM; 2004 May 6;350(19):1945-52
 Cooper J, Pajak TF et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. NEJM; 2004 May 6;350(19):1937-44.
Posted: September 2008