Data from GlaxoSmithKline’s pivotal study of Tykerb in women with advanced breast cancer, whose disease has progressed despite earlier treatment with Roche’s Herceptin, suggest that the drug should be considered part of a new standard of care in these patients, according to the principle investigator in the study.

The results were presented on the same day that GSK announced an expanded access programme for the drug, and says it now plans to press on with seeking approval in the second half of the year in this indication.

Charles Geyer of Allegheny General Hospital told the American Society of Clinical Oncology conference that the results of the Phase III study - which was terminated early in March because it met its primary endpoint of extending the time to disease progression - provided clear evidence that Tykerb was effective as part of a combination regimen in advanced HER2-positive breast cancer.

In the open label, Phase III study, Tykerb (lapatinib ditosylate) was combined with Roche’s Xeloda (capecitabine) and compared to Xeloda alone in 321 patients with advanced, metastatic breast cancer that had progressed despite earlier treatment with Herceptin (trastuzumab) and chemotherapy, including taxanes or anthracyclines.

Tykerb is an orally-active small molecule blocking both HER-2 – the same target as Herceptin – and the epidermal growth factor receptor via its inhibition of the ErbB1 and ErbB2 pathways.

Median time to progression with Tykerb plus Xeloda was just under 37 weeks, while for those receiving Xeloda alone the delay was a little under 20 weeks, which was a statistically significant difference. However, there was no difference in survival or response rate, said Geyer.

Adding Tykerb to Xeloda treatment did not seem to increase the side effect burden of treatment either, he noted, with most adverse reactions mild and manageable. The most common side effects were diarrhoea, fatigue and skin rashes.

Cardiotoxicity not seen

Meanwhile, Geyer said Tykerb does not appear to have the risk of cardiotoxicity that has been ascribed to Herceptin, on the assumption that HER-2 may have a cardioprotective effect that is blocked by the antibody. For this reasoning, Herceptin is used with caution in patients with heart disease.

Although there was an increase in the absolute number of cases of reduced cardiac function with the combination group - with four cases compared to one with Xeloda alone - this was not a significant difference, all the cases were asymptomatic and returned to normal once treatment was stopped.

However, the population could be considered to be favourable to Tykerb in this regard, as all the patients would have received Herceptin and undergone the cardiac stress testing demanded to qualify for treatment with Roche’s drug.

Treating brain metastases

Crucially, there was also evidence presented at ASCO that Tykerb could treat cancer that had spread to the central nervous system, a quality that Herceptin is thought to lack because as a larger monoclonal antibody drug it is unable to penetrate the blood brain barrier.

Roughly a third of metastases in patients with HER2-positive breast cancer are in the brain, and are currently treated with radiotherapy. The hope is that a systemic agent such as Tykerb could provide a new treatment option for patients who do not respond to radiotherapy, as well as potentially stopping new CNS lesions forming.

While the 39-patient study did not meet the statistical threshold required to show efficacy, there was a ‘glimmer of activity’ with Tykerb that was encouraging and should be followed up, according to Eric Winer of the Dana-Farber Cancer Institute.

Paolo Paoletti, head of oncology research at GSK, said the Tykerb data and other cancer developments at the company reinforce his view that cancer will, in time, be treated as a chronic disease, with directed combination treatment controlling progression.

And Paoletti’s view was also backed up by Francisco Esteva of the University of Wisconsin, who suggested while chairing a symposium looking at the treatment prospects for breast cancer patients beyond Herceptin that “in 5 to 10 years we will have the tools needed to eliminate mortality in HER2-positive breast cancer.”

GSK is testing Tykerb in a number of combination studies, including alongside Herceptin, taxanes and hormonal therapies, in order to expand its role as a treatment for refractory disease and advance its use into the first-line setting.