GlaxoSmithKline plc announced late-breaking results from a large, randomized, pivotal phase III study of its small molecule dual kinase inhibitor, Tykerb (lapatinib ditosylate).

In this study, the combination of Tykerb and capecitabine (Xeloda) versus capecitabine alone nearly doubled time to progression (36.9 weeks [8.5 months] in the combination arm versus 19.7 weeks [4.5 months] with capecitabine alone, p=0.00032) in women with refractory advanced or metastatic ErbB2 positive breast cancer whose disease had progressed following treatment with trastuzumab (Herceptin) and other cancer therapies. In April 2006, GSK stopped enrolment of the study based on the unanimous recommendation of an Independent Data Monitoring Committee (IDMC) because it had met its primary endpoint of time to disease progression, and exceeded the predetermined stopping criteria outlined in the committee charter.

Tykerb is an investigational drug and is not yet approved for marketing by any regulatory body.

Results of this, and several other important Tykerb studies, are being presented at the 2006 American Society of Clinical Oncology (ASCO) annual meeting in Atlanta, Georgia. GSK plans to file for regulatory approval of Tykerb in the United States and Europe in the second half of 2006.

"Because ErbB2 positive breast cancer may eventually progress during or following treatment with trastuzumab, there has been a need for an effective alternative treatment that can successfully block the function of ErbB2 in another way," said Charles Geyer, M.D., Director of Breast Medical Oncology at Allegheny General Hospital (Pittsburgh, Pennsylvania) and principal investigator for this trial. "These results indicate that lapatinib [Tykerb] can provide a needed alternative when trastuzumab no longer appears to be helping to control the disease."

Tykerb, a small molecule that is administered orally, inhibits the tyrosine kinase components of ErbB1 and ErbB2 receptors. Stimulation of ErbB1 and ErbB2 is associated with cell proliferation and with multiple processes involved in tumour progression, invasion, 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.

"These results suggest that Tykerb has significant potential as an essential component of the treatment regimen for women with advanced breast cancer," said Paolo Paoletti, M.D., Senior Vice President of the Oncology Medicine Development Center at GSK. "Worldwide, more than one million women are diagnosed with breast cancer every year and it is a leading cause of cancer related deaths. The data presented at ASCO clearly demonstrates GSK's continued commitment to changing the treatment paradigm for these women, in hopes of one day making cancer a chronic disease."

The international, multicenter, open-label study (EGF100151) enrolled 392 patients who had advanced or metastatic breast cancer with documented ErbB2 overexpression and whose disease progressed following treatment with trastuzumab and other cancer therapies. The interim analysis included 321 patients (160 in the Tykerb -capecitabine arm and 161 in the capecitabine monotherapy arm).1

Adverse events (AEs) leading to discontinuation were similar in the Tykerb -capecitabine combination arm (14 per cent) versus capecitabine alone (11 per cent), as were overall AEs. AEs in the Tykerb -capecitabine arm included diarrhoea, hand-foot syndrome and rash. An asymptomatic relative decrease of = 20 per cent in left ventricular ejection fraction (LVEF), a measure of the strength of the heart observed through electrocardiogram, occurred in 2.5 per cent of patients on the combination arm and less than 1 per cent of patients on capecitabine; all patients recovered normal LVEF.

Another abstract being presented on June 4th (Abstract #583) shows a low incidence of cardiac events in patients treated with Tykerb . Results of an analysis of cardiac function in women treated with Tykerb in all trials to date showed that 37 of 2,812 women (1.3 per cent) who have received Tykerb have experienced a decrease in LVEF (33 events were asymptomatic and 4 were symptomatic).

Treatment for brain metastases is an area of significant unmet medical need as one-third of women with ErbB2 overexpression and metastatic breast cancer develop central nervous system (CNS) or brain metastases. Once the disease advances to this stage, overall disease prognosis is poor with the average one-year survival from diagnosis estimated at about 20 per cent.4Additional analysis from the EGF100151 study (Late-Breaking Abstract) suggests that Tykerb may play a role in decreasing the occurrence of brain metastases. Indeed, in the interim analysis, only 4 patients experienced CNS relapse in the Tykerb -capecitabine arm versus 11 in the capecitabine alone arm.

Another study (abstract #503) being presented today at ASCO provides preliminary evidence suggesting that Tykerb may be effective in treating brain metastases associated with breast cancer. The Phase II trial was conducted by investigators at the Dana-Farber/Harvard Cancer Center, the University of North Carolina, and Georgetown University and was sponsored by the National Cancer Institute's Cancer Therapeutic Evaluation Program (CTEP). The trial evaluated Tykerb in 39 patients with ErbB2 positive breast cancer who had developed CNS metastases while on trastuzumab. As reported in the abstract, two patients achieved partial response as measured by RECIST, a linear measure of solid tumours. An additional five patients achieved stable disease for = 16 weeks. Volumetric analysis, which is a more precise three dimensional measure of tumour volume, was performed in 20 patients. Eight of the patients (40 per cent) showed volumetric decline in CNS lesions - five patients showed = 30 per cent volumetric decline and an additional three patients showed 15-30 per cent volumetric decline. Although the trial did not demonstrate the hypothesized level of activity as assessed by RECIST, the study concludes that there is sufficient evidence of preliminary clinical effect to suggest that Tykerb can penetrate the CNS.2 The most common adverse events with Tykerb were diarrhoea (grade 3, 21 per cent), fatigue (grade 3, 16 per cent), and rash (grade 3, 5 per cent).

Tykerb is being developed by GSK as an orally administered therapy for breast cancer and other solid tumours. GSK is using advanced technologies, including pharmacogenetics, to better define patient populations that may respond to Tykerb.

GSK plans to submit Tykerb regulatory filings in the U.S. and Europe in the second half of 2006.The compound already has been granted Fast Track status by the FDA for the treatment of refractory advanced or metastatic breast cancer in women who have documented ErbB2 overexpression and who have failed previous therapy.