Tyverb®/Tykerb® (lapatinib) plus letrozole significantly delayed disease progression in post-menopausal women with ErbB2 positive metastatic breast cancer

Findings from one of the largest studies in hormone receptor positive women determined clinical benefit with first-line oral treatment regimen

New results from a study in metastatic breast cancer showed that the combination of Tyverb®/Tykerb®(lapatinib) plus letrozole as a first line treatment regimen provided a significant improvement in delaying disease progression when compared to treatment with Femara® (letrozole) alone. [1] In the study, women diagnosed with post-menopausal, hormone receptor positive (HR+) and ErbB2 positive metastatic breast cancer experienced a 5.2 month increase in median progression free survival (PFS) compared to women treated with letrozole alone. These data were unveiled at the 31stAnnual CTRC-AACR San Antonio Breast Cancer Symposium, December 10th-14th, 2008.

This double blind, placebo controlled study (EGF30008) included 1,286 post-menopausal women with HR+ breast cancer who were randomised to treatment with lapatinib plus letrozole or to letrozole alone. Letrozole, an aromatase inhibitor (AI), is a recognised therapy in the treatment of HR+ breast cancer. The ErbB2 status of patients was not required for randomisation into the study, however PFS was the primary endpoint in the HR+ and ErbB2 positive patient post study analysis.

Via independent central testing 219 patients were deemed ErbB2 positive.Current treatment regimens for woman who are HR+ and ErbB2 positive include chemotherapy with monoclonal antibody.In the study, women in this patient population who received combination therapy with lapatinib and letrozole experienced a significantly increased median PFS, compared to treatment with letrozole alone (8.2 months versus 3.0 months respectively, HR=0.71, p=0.019)1 - an improvement of 41 percent.

“The encouraging positive results seen in women who are HR+ and ErbB2 positive shows that the lapatinib and letrozole combination has the potential to become a first-line, oral treatment option for clinicians and patients in this setting in the future, says Paolo Paoletti, SVP Oncology R&D, GSK. “We plan to discuss these data with regulators in the near future.”

Results from the intent to treat group (ITT; all patients, irrespective of ErbB2 status) showed that lapatinib plus letrozole provided, on average, an additional month before disease progression compared to letrozole treatment alone (11.9 months versus 10.9 months, HR=0.86, p=0.026).1 Within the ITT group there was therefore a small subset of HR+ ErbB2 negative women who benefited from this treatment combination and further investigations into this specific group of women are warranted.

The combination of letrozole and lapatinib was manageable, and no new safety issues were identified. Grade 3 / 4 adverse events that occurred in more than 2 percent of patients in either the combination arm or monotherapy arm included diarrhoea (9 percent vs. less than 1 percent, respectively); back pain (2 percent vs. 2 percent, respectively); fatigue (2 percent vs. less than 1 percent, respectively); increased ALT (2 percent vs. less than 1 percent, respectively) and increased AST (2 percent vs. less than 1 percent, respectively).

Growth factor receptors such as those in the ErbB family play a key role in cell growth and survival.[2] Targeting these protein receptors is a way in which cancer cells can be killed and tumour growth curtailed. Approximately 70 percent of all breast cancer cases are HR+[3] and only a third of all HR+ tumours respond to first-line treatment with AIs. Furthermore, tumours that initially respond to AIs can become resistant, leading to disease progression and ultimately, patient death.[4] Recent studies have revealed interactions between HR and ErbB receptors as a primary contributor to the development of resistance, and served as the hypothesis basis for this study.[5]

About EGF30008

EGF30008 is a Phase III, randomised, double-blind, placebo-controlled trial in 1,286 post-menopausal women with HR+ metastatic breast cancer. Women in the study were randomised to compare the efficacy of first-line therapy with lapatinib, a small molecule dual tyrosine kinase inhibitor, and the aromatase inhibitor letrozole versus letrozole monotherapy. At randomisation patients received either letrozole 2.5 mg once daily (QD) plus lapatinib 1500 mg QD, or letrozole 2.5 mg QD plus placebo. The primary endpoint of EGF30008 was PFS in the HR+/ErbB2 positive population, and secondarily in the overall ITT population. Secondary endpoints included overall response rate (ORR), clinical benefit rate (CBR), time to response, duration of response, overall survival, safety assessments, and quality of life. Hormonal therapy was allowed in the adjuvant setting only (1 year prior to study entry) and crossover was not permitted.

About Tyverb®/Tykerb® (lapatinib)

Lapatinib is an oral small-molecule inhibitor of the EGFR and ErbB2 tyrosine kinase receptors. Stimulation of EGFR and ErbB2 is associated with cell proliferation and with multiple processes involved in tumour progression 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 is approved for patients who have received prior trastuzumab in 63 countries. On March 13, 2007, the United States Food and Drug Administration (FDA) approved lapatinib in combination with capecitabine, for the treatment of patients with advanced or metastatic breast cancer whose tumours overexpress ErbB2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab. On June 10, 2008, the European Commission adopted a decision to grant a conditional marketing authorisation for lapatinib in all 27 European Union (EU) member states. Other countries include Australia, India, Brazil, Russia, Turkey, South Korea, Taiwan and others around the world. Registration dossiers for lapatinib have been filed in Canada, China, Japan, Mexico and a number of countries in Latin America, Middle East, Africa and Asia Pacific.

Lapatinib has been associated with hepatotoxicity. The hepatotoxicity may be severe and deaths have been reported. Causality is uncertain. Patients should receive liver function tests before initiation of treatment, every 4 to 6 weeks during treatment, and as clinically indicated. A dose reduction in patients with severe pre-existing hepatic impairment should be considered. Discontinue and do not restart lapatinib if patients experience severe changes in liver function tests. Lapatinib has been associated with reports of decreased left ventricular ejection fraction. Patients’ left ventricular ejection fraction should be evaluated before and during treatment.

GSK in Oncology

GSK Oncology is dedicated to producing innovations in cancer that will make profound differences in the lives of patients. Through GSK’s revolutionary ‘bench to bedside’ approach, we are transforming the way treatments are discovered and developed, resulting in one of the most robust pipelines in the oncology sector. Our worldwide research in oncology includes collaborations with more than 160 cancer centres. GSK is closing in on cancer from all sides with a new generation of patient focused cancer treatments in prevention, supportive care, chemotherapy and targeted therapies.

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Notes to Editors:

To access the latest GSK Oncology media materials, visit www.gskcancermedia.com

TYKERB® is a registered trademark of the GlaxoSmithKline group of companies in the United States and the countries outside of Europe.

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

FEMARA® is a registered trademark of Novartis in the United States and the European Union.

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References

[1] Johnston, S et al. Lapatinib Combined with Letrozole vs. Letrozole Alone for Front Line Postmenopausal Hormone Receptor Positive (HR+) Metastatic Breast Cancer (MBC): First Results from the EGF30008 Trial. Abstract #46, presented at 16.45 – 17.00 CT, Friday 12th December, 2008, at the 31st Annual CTRC-AACR San Antonio Breast Cancer Symposium.

[2] Normanno N, Bianco C, De Luca A, Maiello MR, Salomon, DS. Target-based agents against ErbB receptors and their ligands: a novel approach to cancer treatment. Endocrine-Related Cancer 2003; 10;1-21.

[3] BedardPE, Freedman OC, Howell A et al. Overcoming endocrine resistance in breast cancer – are signal transduction inhibitors the answer. Breast Cancer Res Treat. 2008 108:307-317

[4] Prat, A and Baselga, J. The role of hormonal therapy in the management of hormonal-receptor-positive breast cancer with co-expression of HER2. Nature Clinical Practice Oncology. 2008;5:531-542

[5] Arpino G, Wiechmann L, Osborne CK, et al. Crosstalk between the Estrogen Receptor and the HER Tyrosine Kinase Receptor Family: Molecular Mechanism and Clinical Implications for Endocrine Therapy Resistance. Endocrine Reviews. 2008; 29(2): 217-233

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