The European Commission has granted an additional indication for GlaxoSmithKline's Tyverb (lapatinib) to be used in combination with 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.

“Today’s announcement is important for women with this specific type of metastatic breast cancer, who will have now a new treatment option. The combination of Tyverb and trastuzumab, which is chemotherapy-free, has the potential to make a positive impact on the care and survival of these patients,” said Paolo Paoletti, president, GlaxoSmithKline Oncology.

The combination was evaluated in the EGF104900 trial, a randomised, open-label, phase III study of lapatinib + 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 + trastuzumab was associated with an 8.3 month increase in median OS versus lapatinib monotherapy (17.2 months vs. 8.9 months; n=150; HR=0.62; 95 per cent Confidence Interval 0.42, 0.90).

Within the EGF104900 trial, the incidence of AEs was similar in both treatment groups (94 per cent vs. 90 per cent). The most frequent adverse reactions (> 25 per cent) during the trial were diarrhoea and nausea. Additional adverse events which affected > 10 per cent of patients included fatigue, vomiting, rash, dyspnoea, anorexia and headache. Serious adverse events, including diarrhoea, decreased cardiac function and hepatobiliary disorders, were experienced by 26 per cent of patients.

Adverse events led to treatment discontinuation in 17 patients (11 per cent) treated with lapatinib + 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.1

The combination’s (dual) targeting of the same HER2 receptor at different points – ‘above’ and ‘below’ the cell membrane (vertical) – is known as vertical dual blockade:

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

Lapatinib, in contrast, inhibits 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.

Lapatinib is an orally administered small molecule that inhibits the tyrosine kinase components of the HER1 (ErbB1 or EGFR) and HER2 (ErbB2) receptors. Stimulation of HER1 and HER2 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.

Lapatinib was first approved for use in combination with capecitabine in the metastatic setting in 2007 and is currently approved in 107 countries including the U.S., Europe, Australia, India, Brazil, Russia, Turkey, South Korea and other countries around the world.

Lapatinib plus trastuzumab is approved for use in countries in the EU, Philippines, Russia and Thailand only.

Metastatic breast cancer—breast cancer that has spread from the breast to other parts of the body—is the most common invasive cancer in women. It comprises more than one-fifth of invasive cancers in women and 16 per cent of all female cancers. The prognosis of metastatic breast cancer is often poor; distant metastases are the cause of about 90 per cent of deaths due to breast cancer. Around 15 to 30 per cent of breast cancers are HER2-positive, and amplification of the HER2 gene is associated with aggressive biological behaviour and a poorer prognosis. Clinically, HER2-positive disease often features poorly differentiated, high-grade tumours, lymph node involvement, increased rates of cell proliferation and a relative resistance to certain types of chemotherapy. As a result, HER2 is an important target for therapy.