• 2/26/2007
  • Barcelona, Spain
  • press release
  • PRNewswire (www.prnewswire.com)

GlaxoSmithKline (GSK) today announced the start of an international Phase III trial of its investigational cancer treatment TYKERB(lapatinib) in squamous cell carcinoma of the head and neck (SCCHN). This announcement coincided with the International Meeting on Innovative Approaches in Head & Neck Oncology, Barcelona, Spain, February 22-24 supported by the European Society for Therapeutic Radiology and Oncology (ESTRO), where GSK presented results from a Phase I study of lapatinib in SCCHN. Lapatinib is an investigational
drug that is not yet approved for marketing by any regulatory body.

This large adjuvant trial will compare the effectiveness of oral lapatinib versus placebo given in high-risk patients following surgery.

SCCHN is the sixth most common cancer worldwide (1): 600,000 people are diagnosed with SCCHN annually (1), 40,000 in the United States (2) and 100,800 in Europe alone.(3) 40,000 people die from the disease every year.(3)

The design of this Phase III trial was based on recent results from two large-scale, independent randomized studies which have established the addition of chemotherapy to radiation therapy as the new standard of care in the post-operative treatment of high-risk SCCHN patients with additional use of chemotherapy.(4, 5) However, 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, 5)

“The initiation of this trial represents another exciting step towards understanding the role of lapatinib in other tumor types beyond breast cancer,” says Professor Jean Bourhis, Head of Radiation-Oncology Department, Institute Gustave Roussy, France and principal investigator for this trial. “There is a significant group of patients who are at high-risk of disease recurrence following surgery, and they need new treatments that can be combined with standard chemoradiation therapy.”

This global, Phase III study will enroll 680 high-risk patients with locally advanced head and neck cancer (stages II, III and IVa) that have undergone surgery. Patients will receive, within four to seven weeks after surgery, either lapatinib (1500 mg) or placebo tablets once-daily with radiotherapy and cisplatin for seven weeks. After this time, patients will continue with either lapatinib or placebo treatment for one year. The principal objective will be to investigate the length of time without disease symptoms, and overall survival with other clinical factors will also be measured. Side effects will be assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE).

Results from a Phase I dose-escalation study of lapatinib (doses ranged from 500 mg to 1500 mg) plus chemoradiation in 31 head and neck cancer patients were also presented at the conference. Results identified 1500 mg of lapatinib taken once-daily with chemotherapy and radiotherapy as the optimal dose for this combination, and this dose was selected for the Phase III study. Additionally, 89% of patients had a tumor response to this combination treatment. The most common side effects in the Phase I study were mouth ulcers (87%), radiation skin injury (65%), nausea (61%), swallowing difficulties (52%) and vomiting (52%).(6)

“Having already shown promise as a breast cancer treatment, we are very excited to continue investigating lapatinib in SCCHN,” said Paolo Paoletti, MD, Senior Vice President, Oncology Medicine Development Centre, GSK. “We recognize the importance of developing a new treatment approach to difficult- to-treat tumor types, such as head and neck cancer, which may offer hope to patients in need of a further treatment option.”

Lapatinib blocks the activation of two key receptors, EGFR (ErbB1) and HER2 (ErbB2), associated with increased growth and development of this type of head and neck tumor. Stimulation of these receptors is associated with multiple processes involved in tumor growth. An excessive presence of these receptors has been reported in a variety of human tumors and is associated with poor outcome and reduced survival.

About SCCHN:
SCCHN is the most common form of cancer of the head and neck, and approximately two-thirds of all patients are diagnosed with advanced disease. EGFR and HER2 are two types of receptors found on tumors which play a key role in the development of this type of head and neck cancer. Researchers have found that the excessive expression of EGFR receptors is nearly universal in SCCHN disease, with large numbers of HER2 receptors present in 20 to 40 percent of tumors.(7, 8)

About Lapatinib:
Lapatinib was discovered and developed by GSK as an oral once daily therapy, and is currently being investigated in breast cancer and other solid tumors. Phase III results of lapatinib plus capecitabine show superior efficacy to capecitabine alone in women with HER2 positive advanced breast cancer who have progressed following prior therapy, including trastuzumab.(9)

The most frequent side effects related to lapatinib from clinical trials to date are mild to moderate (grade 1 or 2) diarrhea, nausea, vomiting, fatigue and rash.(10)

GSK is using advanced technologies, including pharmacogenomics, to better define patient populations that may respond to lapatinib.

Lapatinib, in combination with capecitabine, has been submitted for marketing approval in the United States, European Union and Switzerland for the treatment of advanced or metastatic HER2 positive breast cancer in women who have progressed despite prior therapy, including trastuzumab. Registration dossiers have also been filed in Australia, Canada and New Zealand.

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 “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 partnerships with more than 160 cancer centres. GSK is developing a new generation of patient focused cancer treatments in prevention, supportive care, chemotherapy and targeted therapies.

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 http://www.gsk.com. For further information on the trial please visit http://www.clinicaltrials.gov.

REFERENCES
(1) Study EGF102988 protocol.
(2) Wang J, Xi L, Hunt J, et al. American Association for Cancer Research. “Expression Pattern of Chemokine Receptor 6 (CCR6) and CCR7 in Squamous Cell Carcinoma of the Head and Neck Identifies a Novel Metastatic Phenotype,” citing Greenlee, R. T., Hill-Harmon, M. B., Murray, T., and Thun, M. Cancer statistics, 2001. CA Cancer J. Clin., 51: 15- -36, 2001.
(3) Mouth Cancer Foundation. Initiative of the Restorative Dentistry Oncology Clinic: http://www.rdoc.org.uk/ accessed 3rd Jan 2007.
(4) 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.
(5) 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.
(6) El-Hariry, I., Harrington K. et al. A phase I, open label study (EGF100262) of lapatinib plus chemoradiation in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). Oral st presentation, 1 International Meeting on Innovative Approaches in nd th Head & Neck Oncology, Barcelona, Spain. 22 – 24 February 2007.
(7) Khademi B, Shirazi FM, Vasei M, et al. The expression of p53, cerbB-1 and cerbB-2 molecules and their correlation with prognostic markers in patients with head and neck tumors. Cancer Letters 2002;184:223-230.
(8) O-Charoenrat P, Modjtahedi H, Rhys-Evans P et al. Epidermal Growth Factor-like Ligands Differentially Up-Regulate Matrix Metalloproteinase 9 in Head and Neck Squamous Carcinoma Cells. Cancer Research, 2000; 60:1121-1128.
(9) Geyer C, Forster J, Lindquist D, Chan S, Romieu C et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006; 355;2733-43. (10) GSK data on file. Ongoing studies to 15 November 2005.