TGA approves GSK’s combination of TAFINLAR®(dabrafenib) and MEKINIST® (trametinib)

GSK Australia announced today that the Therapeutics Goods Administration (TGA) has approved the combination of two oral targeted therapies, MEKINIST (trametinib) and TAFINLAR (dabrafenib), for the treatment of patients with BRAF V600 mutation positive unresectable Stage III or metastatic (stage IV) melanoma.^1,2

MEKINIST has also been approved as a single agent (monotherapy) in the same patient population where BRAF inhibitors cannot be used.¹ Before taking MEKINIST as monotherapy or in combination with TAFINLAR, patients must have confirmation of a BRAF V600 mutation using a validated test.¹ Among those with metastatic melanoma, approximately 40% have a BRAF mutation, which is an abnormal change in a gene that can enable some melanoma tumours to grow and spread.³

The approval of the combination is based on a Phase I/II study which included four parts.⁴ In one part of the Phase II, patients were treated with TAFINLAR + MEKINIST.⁴ The Australian approval for MEKINIST as a single agent was granted based on results from the Phase III METRIC study.⁵

“The approval of these two targeted therapies in combination gives physicians a new treatment option for appropriate patient,” said Dr Andrew Yeates Medical Director GSK Australia.

“The focus for GSK now is to ensure that Australians with unresectable stage III or metastatic melanoma receive reimbursed access to combination therapy as soon as possible and we are working closely with the Australian Government to achieve this,” Dr Andrew Yeates said.

According to Associate Professor Georgina Long who is a medical oncologist and translational clinical researcher at Melanoma Institute Australia in Sydney, the registration of a combination therapy for metastatic melanoma is “another significant step forward in the effort to find therapies for patients with metastatic melanoma, Australia's Cancer.”

“Building on the single agent BRAF inhibitor, we now have a combination of two targeted drugs - a BRAF inhibitor and MEK inhibitor – that when given together inhibit the BRAF mutation for patients with metastatic melanoma,” said Associate Professor Long.

About TAFINLAR and MEKINIST

BRAF and MEK are key components of the MAPK pathway, which regulates the normal growth and death of cells, including skin cells.6 In approximately 40% of melanomas, a mutated BRAF protein in the MAPK pathway disrupts normal cellular regulation and stimulates tumour cell growth.³
TAFINLAR and MEKINIST target mutated BRAF and MEK in the MAPK pathway which may lead to an inhibition of oncogenic signalling, thereby inhibiting the proliferation of tumour cells.^1,2

About Metastatic Melanoma
Melanoma is the most serious type of skin cancer and causes 75% of skin cancer-related deaths.^7,8
Australia has the highest incidence of melanoma in the world and melanoma is often referred to as Australia's national cancer.⁸ More than 12,500 new cases of melanoma are diagnosed in Australia every year and more than 1,500 Australians die from melanoma each year.⁸ Typically, less than 5% of all newly incident melanoma patients present with metastatic disease.⁹

For further information about metastatic melanoma please speak with your healthcare professional. For Consumer Medicine Information (CMI) on MEKINIST or TAFINLAR, please see www.gsk.com.au

Please review MEKINIST^® (trametinib) and TAFINLAR^® (dabrafenib) Product Informations before prescribing, available from www.gsk.com.au

MEKINIST (trametinib dimethyl sulfoxide) in combination with TAFINLAR (dabrafenib mesilate) Minimum Product Information.

Contraindications: hypersensitivity to trametinib dimethyl sulfoxide or dabrafenib mesilate or excipients. Precautions - MEKINIST: Efficacy and safety not established in patients with wild-type BRAF melanoma. Non-cutaneous malignancies, haemorrhage, cardiomyopathy, ocular adverse events, retinal pigment epithelial detachment, retinal vein occlusion, pneumonitis, pyrexia, serious skin toxicity, hepatic events, effects on fertility, pregnancy (category D), lactation, paediatric use and use in elderly.

Precautions -TAFINLAR: Efficacy and safety not established in patients with wild-type BRAF melanoma. Patients should be routinely monitored for ophthalmologic reactions during therapy. Pyrexia and serious non-infectious febrile events, cutaneous squamous cell carcinoma (cuSCC), new primary melanoma, non-cutaneous malignancy, uveitis, pancreatitis, hyperglycaemia, renal failure, effects on fertility, pregnancy (category D), lactation, paediatric use and use in elderly.

Interactions - TAFINLAR: Strong inhibitors or inducers of CYP2C8 or CYP3A4, proton pump inhibitors, medicinal products affected by induction of CYP3A4, CYP2C9, CYP2B6, CYP2C8, CYP2C19, UGT and transporters, hormonal contraceptives, warfarin, statins and OATP1B1 or OATP1B3 substrates.

Adverse Events – MEKINIST+TAFINLAR: Very common Urinary tract infection, neutropenia, dizziness, night sweats, muscle spasms, rash, dry skin, acneiform dermatitis, actinic keratosis, erythema, pruritis, decreased appetite, dehydration, headache, haemorrhage, cough, oropharyngeal pain, diarrhoea, nausea, vomiting, constipation, abdominal pain, dry mouth, pyrexia, chills, fatigue, peripheral edema, arthralgia, myalgia, back pain, muscle spasm, pain in extremity, anemia, insomnia, increased ALT/AST, increased alkaline phosphatase and hyperbilirubinemia. Common Thrombocytopenia, hyponatraemia, hypotension, gamma-glutamyltransferase increase, hyperhidrosis, rhabdomyolysis and QT prolongation. Dosage and Administration: Confirmation of BRAF V600 mutation with approved/validated test required.

Recommended dose of TAFINLAR is 150mg (two 75mg capsules) twice daily (total daily dose 300mg) at least one hour before or at least two hours after a meal, approximately 12 hours between doses, at similar times every day. Recommended dose of MEKINIST is 2mg orally once daily with a full glass of water, without food, at least one hour before or at least two hours after a meal. When taken in combination, MEKINIST should be taken at same time each day with either the morning or evening dose of TAFINLAR. Dose adjust TAFINLAR and MEKINIST according to product informations. TAFINLAR dose adjustments below 50mg twice daily not recommended. MEKINIST dose adjustments below 1mg not recommended. TAFINLAR daily dose should not exceed 150mg twice daily.

Refer to TAFINLAR full product information and MEKINIST full product information for detailed information on precautions, interactions, adverse events and dosage and administration. Min PI v1mt

MEKINIST^® (trametinib dimethyl sulfoxide) monotherapy Minimum Product Information

Contraindications: hypersensitivity to trametinib dimethyl sulfoxide or excipients. Precautions: Efficacy and safety not established in patients with wild-type BRAF melanoma. Cardiomyopathy, ocular adverse events, retinal pigment epithelial detachment, retinal vein occlusion, pneumonitis, pyrexia, serious skin toxicity, hepatic events, effects on fertility, pregnancy (category D), lactation, paediatric use and use in elderly.

Adverse Events: Very common Hypertension, haemorrhage, cough, dyspnoea, diarrhoea, nausea, vomiting, constipation, abdominal pain, dry mouth, rash, acneiform dermatitis, dry skin, pruritis, alopecia, fatigue, peripheral oedema, paronychia and pyrexia. Common Folliculitis, cellulitis, pustular rash, anaemia, hypersensitivity, dehydration, blurred vision, periorbital oedema, visual impairment, left ventricular dysfunction, decreased ejection fraction, lymphoedema, epistaxis, pneumonitis, stomatitis, AST increase, ALT increase, blood alkaline phosphatase increase, chapped skin, erythema, palmar-plantar erythrodysaethesia, skin fissures, increased blood creatine phosphokinase, face oedema, mucosal inflammation and asthenia.

Dosage and Administration: Confirmation of BRAF V600 mutation with approved/validated test required. Recommended dose of MEKINIST is 2mg orally once daily with a full glass of water, without food, at least one hour before or at least two hours after a meal. Dose adjust MEKINIST according to product information. MEKINIST dose adjustments below 1mg not recommended. Refer to MEKINIST full product information for detailed information on precautions, interactions, adverse events and dosage and administration. Min PI v1m

For full product information, information on GSK products or to report an adverse event involving a GSK product, please contact GSK Medical Information on 1800 033 109. GlaxoSmithKline Australia Pty Ltd. ABN 47 100 162 481. Melbourne, VIC. MEKINIST^® is a registered trade mark of the GSK Group of Companies.


For full product information, information on GSK products or to report an adverse event involving a GSK product, please contact GSK Medical Information on 1800 033 109. GlaxoSmithKline Australia Pty Ltd. ABN 47 100 162 481. Melbourne, VIC.

Tafinlar and Mekinist are registered trade marks of the GSK group of companies. AUS/MEK/0020/14; Date of Approval February 2014

Additional Notes

GSK is 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 more information please visit www.gsk.com.au

A/Prof Long has served on advisory boards sponsored by GSK for which compensation was received and has been involved in clinical trials sponsored by GSK. In relation to this media announcement, no compensation was provided to A/Prof Long, and the opinions expressed are her own. A/Prof Long has been briefed by GSK on the approved use of this product.

References
1. MEKINIST Approved Product Information
2. TAFINLAR Approved Product Information
3. Lee JH et al, Br J Dermatol, 2011;164(4):776-84
4. Flaherty KT et al, N Engl J Med, 2012; 367(18):1694-703
5. Flaherty KT et al, N Engl J Med, 2012; 367(2):107-14
6. National Library of Medicine. “Genetics Home Reference” Available at http://ghr.nlm.nih.gov/gene/BRAF (accessed Aug 2013)
7. Jerant AF et al, Am Fam Physician, 2000:62:357-68
8. Australian Institute of Health and Welfare & Australasian Association of Cancer Registries 2012. Cancer in Australia: an overview, 2012. Cancer series no. 74. Cat. no. CAN 70. Canberra: AIHW.