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 22nd August 2013 GlaxoSmithKline

GSK receives EMA approval for new Tyverb® (lapatinib) indication in combination with trastuzumab for patients with relapsed HER2-positive, HR-negative metastatic breast cancer.

The European Medicines Agency (EMA) has granted an update to the marketing authorisation for Tyverb® (lapatinib) to be used in combination with Herceptin® (trastuzumab). This combination is indicated for adult patients with breast cancer whose tumours overexpress HER2 (ErbB2) with hormone receptor-negative (HR-) metastatic disease that has progressed on prior trastuzumab therapy(ies) in combination with chemotherapy.

"We are proud to bring a new chemotherapy-free option to metastatic breast cancer patients. Through vertical dual blockade of the HER2 receptor, the combination of lapatinib and trastuzumab achieves a clinically significant improvement in overall survival for patients with HER2-positive, HR-negative metastatic breast cancer,” said Dr Pim Kon, UK Medical Director, GlaxoSmithKline. “We believe this new combination therapy has the potential to make a meaningful impact on the care and survival of women in this breast cancer population.”

The combination works by targeting the same HER2 receptor at different points - ‘above’ and ‘below’ the cell membrane (vertical) thereby enhancing blockade – these agents subsequently produce a vertical dual blockade of the HER2 receptor:

• Trastuzumab is a monoclonal antibody that binds to the extracellular (‘above’) domain of the HER2 receptor.

• Lapatinib, in contrast, inhibits tyrosine kinase activity of the same HER2 receptor intracellularly (‘below’).

By targeting both extracellular and intracellular domains of the same receptor [vertical dual HER2 blockade] complementary mechanisms of action may be realised, potentially achieving better pathway inhibition than could be accomplished with either compound alone.

The EMA approval is based on findings from the EGF104900 study – a randomised, open-label, Phase III study of lapatinib plus trastuzumab versus lapatinib monotherapy in patients with HER2-positive metastatic breast cancer whose disease had progressed on a trastuzumab-containing regimen. The primary endpoint of the trial was progression-free survival (PFS), with overall survival (OS) as the secondary endpoint.

The authorisation for the new indication is based on overall survival (OS) results in the HER2-positive, HR-negative metastatic breast cancer population within the EGF104900 trial. This post-hoc subgroup analysis showed that:

The combination of lapatinib plus trastuzumab was associated with an 8.3 month increase in median OS versus lapatinib monotherapy (17.2 months vs. 8.9 months; n=150; Hazard Ratio=0.62; 95% Confidence Interval 0.42, 0.90).

Please note that lapatinib is not licensed for use as a monotherapy in Europe or elsewhere.

Approximately 25% to 30% of women with metastatic breast cancer have tumours which over-express ErbB2, a protein commonly referred to as HER2 (human epidermal growth factor). HER2-positive tumours are associated with a worse prognosis and reduced overall survival compared to HER2-negative tumours. Patients with HER2 advanced or metastatic breast cancer have limited targeted therapy options available to them after trastuzumab-based therapy has failed to halt disease progression. GlaxoSmithKline is working with the National Health Service (NHS) to support decision-making about the most appropriate funding route for this new treatment combination of lapatinib and trastuzumab.

Within the EGF104900 trial, the incidence of AEs was similar in both treatment groups (94% vs. 90%). The most frequent adverse reactions (> 25 per cent) in the combination arm were diarrhoea, and nausea. Additional adverse events which affected > 10 per cent of patients who received the combination arm, included rash, fatigue, vomiting, dyspnoea, anorexia and headache. Serious adverse events were experienced by 26 per cent of patients in the combination arm vs. 16% in the monotherapy arm.

Adverse events led to treatment discontinuation in 17 patients (11 per cent) treated with lapatinib plus trastuzumab compared with nine patients (6 per cent) treated with lapatinib monotherapy. In total, six patients had fatal serious adverse events; of these, one – probable but unconfirmed pulmonary embolism in the combination therapy arm – was considered to be related to study treatment. There was an increased incidence of cardiac toxicity, but these events were comparable in nature and severity to those reported from the lapatinib clinical programme. These data are based on exposure to this combination in 149 patients in the pivotal trial.


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