GSK receives marketing authorisation from the European Commission for additional indication: Tyverb™ (lapatinib)

GlaxoSmithKline announced today that the European Commission has granted an additional indication for Tyverb™ (lapatinib) to be used in combination with trastuzumab.

Issued: London UK

GlaxoSmithKline announced today that the European Commission has granted an additional indication for 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.[1]

“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.[2]a The primary endpoint of the trial was progression-free survival (PFS), with overall survival (OS) as the secondary endpoint.2

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:3

  • 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).1

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

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.1

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

About Vertical Dual Blockade of the HER2 receptor

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.4
  • Lapatinib, in contrast, inhibits kinase activity of the same HER2 receptor intracellularly (‘below’).4

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.4

About Tyverb™ (lapatinib)

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.1

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.

Safety Information

Cardiac toxicity: Lapatinib has been associated with reports of decreases in LVEF. Lapatinib has not been evaluated in patients with symptomatic cardiac failure. Caution should be taken if lapatinib is to be administered to patients with conditions that could impair left ventricular function (including co-administration with potentially cardiotoxic medicinal products). There has been no dedicated study to assess the potential for lapatinib to prolong the QT interval. A small, concentration dependent increase in QTc interval was observed in an uncontrolled, open-label dose escalation study of lapatinib in advanced cancer patients, such that an effect on QT interval cannot be ruled out.1

Interstitial lung disease and pneumonitis: Lapatinib has been associated with reports of pulmonary toxicity including interstitial lung disease and pneumonitis.1

Hepatotoxicity: Hepatotoxicity has occurred with lapatinib use and may in rare cases be fatal. The hepatotoxicity may occur days to several months after initiation of treatment. 1

Diarrhoea: Diarrhoea, including severe diarrhoea, has been reported with lapatinib treatment. Diarrhoea can be potentially life-threatening if accompanied by dehydration, renal insufficiency, neutropenia and/or electrolyte imbalances and fatal cases have been reported.1

Detailed information on the use of lapatinib in combination with trastuzumab and its safety profile, including routine monitoring and other management requirements, are described in the Summary of Product Characteristics, which can be accessed on the EMA website, together with the European Public Assessment Report ( and in the Community Register of Medicinal Products on the European Commission’s website (

About Metastatic and HER2-Positive Breast Cancer

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.5 It comprises more than one-fifth of invasive cancers in women and 16 per cent of all female cancers.5 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.6 Around 15 to 30 per cent of breast cancers are HER2-positive,7 and amplification of the HER2 gene is associated with aggressive biological behaviour and a poorer prognosis.8 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.9

Notes to editors:

Tykerb is the registered trade mark of the GlaxoSmithKline group of companies in the United States and the countries outside Europe.

Tyverb is a registered trademark of the GlaxoSmithKline group of companies in the European Union.

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 further information please visit

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Cautionary statement regarding forward-looking statements
GSK cautions investors that any forward-looking statements or projections made by GSK, including those made in this announcement, are subject to risks and uncertainties that may cause actual results to differ materially from those projected. Factors that may affect GSK' s operations are described under Item 3.D 'Risk factors' in the company's Annual Report on Form 20-F for 2012.


[1]    Tyverb™ EU Label.

[2]   Blackwell KL, Burstein HJ, Storniolo AM, et al. (2010) Randomized study of Lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol. 28:1124–1130.

3    Blackwell KL, Burstein HJ, Storniolo AM, et al. Overall Survival Benefit with lapatinib in Combination with Trastuzumab for patients with Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer: Final Results From the EGF 104900 Study.

4   Scaltriti M, Verma C, Guzman M, et al. Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity. Oncogene. 2009;28(6):803-814

5    The World Health Organization. Breast Cancer: Prevention and Control. Retrieved May 16, 2012.

6   Wang, Yingqun. Breast cancer metastasis driven by ErbB2 and 14-3-3. Cell Adh Migr. 2010 Jan-Mar; 4(1): 7-9.

7   American Cancer Society. Breast Cancer Facts & Figures 2011-2012. Atlanta: American Cancer Society, Inc. Downloaded from on July 17, 2013.

8 HER2Status. Retrieved July 11, 2013.

9    Burstein, HJ. The distinctive nature of HER2-positive breast cancers. N Engl J Med. 2005;353(16).

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