Breast Cancer Treatment Tykerb

NEW BREAST CANCER TREATMENT APPROVED BY THE TGA

New therapy for women with ErbB2 (HER2)-positive metastatic breast cancer that has progressed despite treatment with other therapies including Herceptin® (1)

GlaxoSmithKline Australia (GSK) today announced that its new breast cancer treatment TYKERB® (lapatinib ditosylate) has been approved by the Therapeutic Goods Administration (TGA) and will be commercially available in Australia for the first time.

Lapatinib is a treatment for patients with ErbB2 (HER2) positive advanced / metastatic breast cancer, whose disease has progressed despite treatment with other therapies including Herceptin® (trastuzumab).(2)

A submission for lapatinib to be listed on the Pharmaceutical Benefits Scheme (PBS) was recently rejected.# GSK is considering the issues leading to the rejection in evaluating future steps.

Since the inception of the Medicare Herceptin Program, 59 per cent of patients with metastatic ErbB2 (HER2) positive breast cancer have either withdrawn from treatment or died.(3) This highlights the need for Australian women to access new TGA approved HER2 targeted therapies that may help them to continue fighting their disease.

In recognising the importance of timely access to lapatinib, GSK will provide lapatinib free of charge to eligible patients who are enrolled in the Tykerb Access Program (TAP) before 30 November 2007.

"It is essential that Australian women have access to this treatment which may help them to continue fighting their disease. GSK has made the decision to provide the treatment at no charge, as an interim measure, to ensure that Australian women are not subject to an additional financial burden at what is already a difficult time for them and their families." said Dr Michael Elliott, VP and Medical Director, GSK.

Lapatinib is a small molecule, once-daily targeted therapy that is taken in tablet form.(4) Lapatinib is taken in combination with Xeloda® (capecitabine), a type of chemotherapy that is also taken in tablet form. It is estimated that between 300-500 women a year would be suitable for the treatment.

The most common side effects during therapy with the combination of lapatinib and Xeloda are diarrhoea, nausea and vomiting, hand-foot syndrome, fatigue and rash(.6,7) These side effects are generally manageable. People with heart, lung and liver problems should take the drug with caution. Lapatinib may also interact with other drugs and patients should review with their doctor the medicines they are currently taking to make sure they are not taking something that cannot be taken with Tykerb.*

As a small molecule, lapatinib penetrates and works inside the tumour cells to target ErbB2 (HER2) receptors.(8)

Lapatinib was recommended by Australian Drug Evaluation Committee (ADEC) for approval by the TGA on 1st June 2007. From 26th June 2007, lapatinib has been approved for use in Australia.

Medical Oncologist, Associate Professor Fran Boyle,University of Sydney, today commented on the registration of lapatinib in Australia, saying: "The TGAs approval of lapatinib in Australia is the next step forward in treating and managing advanced ErbB2 (HER2) positive breast cancer in this country."

"The registration of lapatinib is welcome news to Australian women with ErbB2 (HER2) positive advanced / metastatic breast cancer. This particular group of women in Australia now have another viable treatment option available."

Breast cancer is the most common invasive cancer diagnosed in females in Australia and is the leading cause of death in females, accounting for about 2,600 deaths each year(.9,10) While breast cancer can also be found in men, it is extremely rare.(11)

In 2006, the number of estimated new breast cancer cases was approximately 13,261.(12) This number is expected to increase to 14,800 by 2011.(13) Of these, it is estimated that 25-30 per cent will have ErbB2 (HER2) positive breast cancer.(14 )

About the submission for PBS listing

GSKs submission for PBS listing of lapatinib has been rejected on the basis of unacceptable incremental cost effectiveness.(15) Lapatinibs cost effectiveness was supported in GSKs submission by a comparison to Herceptin. However, as Herceptin is still not considered cost effective by the PBAC in the metastatic setting and as such is not PBS listed for this use, the PBAC did not accept Herceptin as a cost-offset.

This makes it very difficult to demonstrate the cost effectiveness of lapatinib, which is indicated for use in patients whose disease has progressed despite treatment with Herceptin, even in light of the fact that lapatinib costs less than Herceptin.(16)

About the TYKERB Access Program (TAP)

With lapatinib now registered in Australia, GSK will provide lapatinib free of charge to eligible patients who are enrolled in the TYKERB Access Program (TAP) before 30 November 2007.

To access the TAP patients must meet certain criteria, including the TGA approved indication for lapatinib:
In combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumours overexpress HER2 (ErbB2) and whose tumours have progressed after treatment with an anthracycline, a taxane and trastuzumab.

The TAP program will continue until 30 November 2007, when it will be reviewed for its continuing viability. GSK will continue to fund the treatment for patients enrolled before 30 November until their oncologist determines that there is no longer clinical benefit from the treatment. Oncologists will be provided with notification of any proposed changes to the program. About ErbB2 (HER2) positive breast cancer

ErbB2 (HER2) receptors play a key role in cell growth and survival.(17) People with ErbB2 (HER2) positive metastatic breast cancer have a form of cancer which tends to be highly aggressive(18) and is associated with a greater risk for disease progression and death if not recognised and treated.(19,20)

Also known as advanced breast cancer, metastatic breast cancer is the term used to describe cancer that has spread from the original site in the breast to other organs or tissues in the body.(21)

Continuing drug development aims to provide effective treatment options with limited toxicity.(22) The main aim of treatment for metastatic breast cancer is to improve the patients quality of life by reducing symptoms and to slow disease progression.(23)

About GlaxoSmithKline Oncology

GlaxoSmithKline is one of the world's leading research-based pharmaceutical and healthcare companies committed to improving the quality of human life by enabling people to do more, feel better and live longer.

*Patients should seek advice from their oncologist to discuss the suitability of lapatinib for them. A copy of the Tykerb Consumer Medicine Information can be accessed online at http://www.gsk.com.au/products_prescription-medicines_detail.aspx?view=407 PBS Information: This product is not listed on the PBS

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MINIMUM PRODUCT INFORMATION. TYKERB: lapatinib ditosylate Indication: Tykerb, in combination with capecitabine, is indicated for the treatment of patients with advanced/metastatic breast cancer whose tumours overexpress HER2 (ErbB2) and whose tumours have progressed after treatment with an anthracycline, a taxane and trastuzumab. Contraindications: No known contraindications. Precautions: Decreases in left ventricular ejection fraction (LVEF); conditions that could impair left ventricular function; interstitial lung disease and pneumonitis; diarrhoea including severe diarrhoea -proactive management with anti-diarrhoeal agents is important; concomitant treatment with CYP3A4 inhibitors (e.g. ketoconazole, itraconazole or grapefruit juice) or inducers (e.g. rifampin, carbamazepine or phenytoin ); moderate or severe hepatic impairment; pregnancy (category C); lactation. For more details, refer to full PI. Interactions: Inhibitors or inducers of the CYP3A4 enzymes may alter Tykerb pharmacokinetics - co-administration should proceed with caution, and clinical response and adverse events should be closely monitored. Tykerb inhibits CYP3A4 and CYP2C8 in vitro at clinically relevant concentrations caution should be exercised when dosing Tykerb concurrently with medications that are substrates of these enzymes. Inhibitors or inducers of Pgp, BCRP and OATP1B1 may alter exposure and/or distribution of Tykerb. Tykerb may affect the pharmacokinetics of substrates of Pgp (e.g. digoxin), BCRP (e.g. topotecan) and OATP1B1 (e.g. rosuvastatin). Bioavailability of Tykerb is affected by food. For more details, refer to full PI. Adverse Events: Tykerb monotherapy: Very common: anorexia, diarrhoea, nausea, vomiting, hyperbilirubinaemia, rash (including dermatitis acneform), fatigue. Common: decreased left ventricular ejection fraction. Uncommon: interstitial lung disease/pneumonitis. Tykerb in combination with capecitabine, frequency difference of >5% compared to capecitabine alone: Very common: dyspepsia, dry skin. Similar frequency to capecitabine alone: Very common: stomatitis, constipation, abdominal pain, palmar-plantar erythrodysaesthesia, mucosal inflammation, pain in extremity, back pain, insomnia. Common: headache. For more details, refer to full PI. Dosage and Administration: Adults: 1250mg (five tablets) once daily continuously. Tykerb should be taken at least 1h before or at least 1h after food. Tykerb is taken in combination with capecitabine. The recommended dose of capecitabine is 2000mg/m/day taken in 2 doses 12h apart on days 1-14 in a 21 day cycle. Capecitabine should be taken with food or within 30min after food. A positive HER2 protein overexpression/gene amplification is necessary for selection of patients. Treatment with Tykerb should continue until disease progression or unacceptable toxicity. Children: Efficacy and safety has not been evaluated. Elderly: No overall differences in safety of Tykerb were observed between the elderly and younger subjects. Cardiac events: Evaluate LVEF in all patients prior to treatment to ensure baseline LVEF within institutional limits of normal. Evaluate LVEF at 8-12wk intervals. Discontinue Tykerb in patients with symptoms associated with decreased LVEF
Grade 3 (NCI CTCAE) or if LVEF drops below lower limit of normal. Restart at a reduced dose (1000mg/day) after a minimum of 2wk if the LVEF recovers to normal and the patient is asymptomatic. Pulmonary symptoms: Monitor patients for pulmonary symptoms. Discontinue Tykerb in patients with pulmonary symptoms indicative of interstitial lung disease/pneumonitis
Grade 3 NCI CTCAE. Other toxicities: Consider dose adjustment if
Grade 2 (NCI CTCAE) toxicity occurs for other adverse events. Restart Tykerb at 1250mg/d when the toxicity improves to Grade 1. If the toxicity recurs, then Tykerb should be restarted at a lower dose (1000mg/d). CYP3A4 enzymes: Dose adjustment is recommended during co-administration of Tykerb with inducers/inhibitors of CYP3A4. PLEASE REVIEW PRODUCT INFORMATION BEFORE PRESCRIBING. Full Product Information is available from the Medical Affairs and Pharmacovigilance Department at GlaxoSmithKline ph 1800 033 109.

®GlaxoSmithKline Australia Pty Ltd. ABN 47 100 162 481. 1061 Mountain Highway, Boronia, VIC 3155. Tykerbis a registered trade mark of the GlaxoSmithKline group of companies.

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1 Geyer CE et al N Engl J Med 2006; 355: 2733-2743

2 Tykerb Approved Product Information, Issue 1

3 Australian Government Medicare Australia. Accessed on 14 August 2007
http://www.medicareaustralia.gov.au/providers/programs_services

4 Tykerb Approved Product Information, Issue 1

5 GSK submission to the Pharmaceutical Benefits Advisory Committee

6 Geyer CE et al N Engl J Med 2006; 355: 2733-2743

7 Tykerb Approved Product Information, Issue 1

8 Montemurro F et al Expert Opin Biol Ther 2007; 7: 257-268

9 Australian Institute of Health and Welfare & National Breast Cancer Centre 2006. Breast cancer in Australia: an overview, 2006. Cancer series no. 34. cat. no. CAN 29. Canberra: AIHW

10 National Health and Medical Research Centre (NHMRC) & National Breast Cancer Centre. Clinical Practice Guidelines: Management of advanced breast cancer. Canberra: Commonwealth of Australia, 2001

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13 Australian Institute of Health and Welfare & National Breast Cancer Centre 2006. Breast cancer in Australia: an overview, 2006. Cancer series no. 34. cat. no. CAN 29. Canberra: AIHW

14 Meric F et al J Am Coll Surg 2002;194: 488-501

15 Australian Government. Department of Health and Ageing. PBAC Outcomes by Meeting. Accessed on 20 August 2007.
http://www.health.gov.au/internet/wcms/publishing.nsf/Content/pbac-outcomes-by-meeting

16 GSK submission to the Pharmaceutical Benefits Advisory Committee

17 Hynes NE, Lane HA Nat Review Cancer 2005; 5: 341-54

18 Meric F et al. J Am Coll Surg. 2002;194(4):488-501

19 Carney WP et al Clin Chem 2003; 49(10): 1579-1598

20 Slamon DJ et al Science 1987; 235(4785): 177-182

21 National Breast Cancer Centre. Clinical Practice Guidelines: Management of advanced breast cancer. Canberra: Commonwealth of Australia, 2001

22 Cristofanilli M Semin Oncol 2006; 33 (3 Suppl 9): S9-S14

23 Kataja VV et al. Ann Oncol 2005; 16 (Suppl 1):i10-i12