GSK receives marketing authorisation from the European Commission for Tafinlar™

GSK announced today that the European Commission has granted marketing authorisation for Tafinlar™ (dabrafenib).

Issued: London, UK

GlaxoSmithKline plc announced today that the European Commission has granted marketing authorisation for Tafinlar (dabrafenib) as an oral targeted treatment indicated in monotherapy for unresectable melanoma (melanoma that cannot be removed by surgery) or metastatic melanoma (melanoma which has spread to other parts of the body) in adult patients with a BRAF V600 mutation.1 Dabrafenib is not indicated for the treatment of patients with wild-type BRAF melanoma. Before taking dabrafenib, patients must have confirmation of a BRAF V600 mutation using a validated test.1

“Today’s authorisation of Tafinlar™ represents an important step in GSK's ongoing effort to bring new treatment options to cancer patients, especially as we have brought it to market in less than five years after our initial testing,” said Paolo Paoletti, M.D., President, GlaxoSmithKline Oncology. “With this new personalised medicine, we hope to make a meaningful difference in the lives of appropriate patients with metastatic melanoma; a devastating disease and a cancer with one of the lowest survival rates.”

Dabrafenib is a kinase inhibitor that targets BRAF, a key component of a biological pathway in the body that regulates the normal growth and death of cells, including skin cells.2 Theavailability of a diagnostic test allows the identification of patients with unresectable or metastatic melanoma who have the BRAF V600 mutation, and therefore are eligible to receive this therapy.

About Melanoma and Metastatic Melanoma

Melanoma is the most serious type of skin cancer and causes 75 per cent of skin cancer-related deaths. 3 If found early and confined to the skin, melanoma can usually be removed with surgery, but sometimes it can spread to other parts of the body, a process referred to as metastasis.4 Typically, less than 5 per cent of all newly incident melanoma patients present with metastatic disease. A BRAF gene mutation is seen in 50-70 per cent of cutaneous melanoma cases.5

According to the World Health Organisation, 200,000 people worldwide were diagnosed with melanoma in 20086, a figure that is predicted to increase to 233,000 by 2015.6 The median and one-year survival rates of patients with metastatic melanoma, treated with chemotherapy, are 12 months and 49 per cent, respectively. 7

Tafinlar™ (dabrafenib) Clinical Data

The marketing authorisation for dabrafenib is based on results from several multicentre global trials. One of these trials was a Phase III study, BREAK-3, in which treatment with dabrafenib was compared to dacarbazine (chemotherapy) in 250 previously untreated patients with BRAF V600E mutation-positive unresectable or metastatic melanoma. At the pre-specified analysis of BREAK-3, from December 2011, dabrafenib reduced the relative risk of disease progression or death by 70 per cent compared to dacarbazine (95 per cent CI: 0.18, 0.51, p<0.0001). Study data showed a median progression-free survival of 5.1 months with dabrafenib (95 per cent CI; 4.9, 6.9) compared to 2.7 months for dacarbazine (95 per cent CI: 1.5, 3.2) (2011 cut-off data).

In a post-hoc analysis from June 2012, dabrafenib reduced the relative risk of disease progression or death by 63 per cent compared to dacarbazine (95 per cent CI: 0.24, 0.58, P<0.0001). The data showed a median progression free survival of 6.9 months (95 per cent CI: 5.2, 9.0) compared to 2.7 months for dacarbazine (95 per cent CI: 1.5, 3.2). A further post-hoc analysis, from December 2012, showed overall survival at 12 months was 70 per cent with dabrafenib, compared with 63 per cent for dacarbazine (HR = 0.76, 95 per cent CI: 0.48, 1.21).1

Patients with melanoma driven by BRAF mutations other than V600E were excluded from the BREAK-3 trial and with respect to patients with the V600K mutation in single arm studies, the activity appears lower than in V600E tumours. 1

Other trials included:

·         A Phase II study, BREAK-2, a multicentre, single-arm, open-label study of 92 patients with BRAF V600E or V600K mutation-positive metastatic melanoma who had not received prior treatment or were previously untreated or failed at least one prior systemic therapy.8

·         A Phase II trial, BREAK-MB, a prospective open-label study of 172 BRAF V600 mutation-positive melanoma patients with brain metastases, with and without prior local therapy. Brain metastasis, which occurs when cancer has spread to the brain,is one of the most common and challenging complications for metastatic melanoma patients.9 More than 60 per cent of late-stage melanoma patients will develop brain metastases.9

About Tafinlar (dabrafenib)

Tafinlar™ (dabrafenib) targets BRAF, a key component of the MAPK (mitogen-activated protein kinase) pathway. In many types of melanoma, a mutated BRAF protein on the MAPK pathway disrupts normal cellular regulation and promotes increased cell production.2 Dabrafenib binds to the mutated BRAF protein, which may lead to an inhibition of oncogenic signalling, thus inhibiting the proliferation of tumour cells.

In the European Union (EU), dabrafenib is now licensed in monotherapy for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation as detected by a validated test.1 Dabrafenib is also licensed in the U.S, Canada and Australia.

Safety Information

Toxicities with precautions for use include pyrexia (fever, including severe fever), cutaneous squamous cell carcinoma, new primary melanoma, non-cutaneous malignancy, renal failure, pancreatitis, uveitis (an inflammation of the middle, pigmented, vascular structure of the eye), and QT prolongation (a disorder of the heart's electrical system).

The safety profile of dabrafenib is based on data from five clinical monotherapy studies and included 578 patients with melanoma. The most frequently occurring adverse drug reactions (ADRs) (= 15 per cent) reported with dabrafenib were hyperkeratosis (a condition causing benign skin thickening or lesions), headache, pyrexia (fever), arthralgia (joint pain), fatigue, nausea, skin papilloma (a condition causing benign skin growths), alopecia (hair loss), rash and vomiting.1

·            Pyrexia: Fever has been reported in clinical trials. In 1 per cent of patients in clinical trials, serious non-infectious febrile events were identified defined as fever accompanied by severe rigors, dehydration, hypotension and/or acute renal insufficiency.1

·            Cutaneous Squamous Cell Carcinoma (cuSCC): Cases of cuSCC (which include those classified as keratoacanthoma or mixed keratoacanthoma subtype) have been reported in patients treated with dabrafenib.1

·            New primary melanoma: New primary melanomas have been reported in clinical trials. 1

·             Non-cutaneous secondary/recurrent malignancy: In vitro experiments have demonstrated paradoxical activation of MAP-kinase signalling in BRAF wild type cells with RAS mutations when exposed to BRAF inhibitors. This may lead to increased risk of non-cutaneous malignancies with dabrafenib exposure when RAS mutations are present. Cases of RAS-associated malignancies have been reported.1

·            Renal failure: Renal failure has been identified in < 1 per cent of patients treated with dabrafenib. Observed cases were generally associated with pyrexia and dehydration. Granulomatous nephritis has been reported. Dabrafenib has not been studied in patients with renal insufficiency (defined as creatinine > 1.5 x ULN) therefore caution should be used in this setting. 1

·            Uveitis: Ophthalmologic reactions including uveitis and iritis have been reported.1

·            Pancreatitis: Pancreatitis has been reported in < 1 per cent="" of="" dabrafenib-treated="">1

·            QT prolongation: Worst-case QTc prolongation of > 60 millisecond (msec) was observed in 3 % of dabrafenib-treated subjects (One > 500 msec in the integrated safety population). Treatment with dabrafenib is not recommended in patients with uncorrectable electrolyte abnormalities (including magnesium), long QT syndrome or who are taking medicinal products known to prolong the QT interval. Initiation of treatment with dabrafenib is not recommended in patients with QTc > 500 msec. 1

·            Drug Interactions: Dabrafenib is a substrate of CYP2C8 and CYP3A4. Potent inducers of these enzymes should be avoided when possible as these agents may decrease the efficacy of dabrafenib. Agents that increase gastric pH might decrease the bioavailability of dabrafenib and should also be avoided when possible. Concomitant use of dabrafenib with medicinal products that are sensitive substrates of CYP3A4, CYP2C8, CYP2C9, CYP2C19, or CYP2B6 enzymes or transporters may result in loss of efficacy of many commonly used medicinal products and should generally be avoided if monitoring for efficacy and dose adjustment is not possible. Concomitant administration of dabrafenib with warfarin or digoxin may result in decreased warfarin or digoxin exposure respectively.1

Detailed information on the use of Tafinlar™ and its safety profile, including routine monitoring and other management requirements, are described in the Summary of Product Characteristics, which will be published on the European Medicines Agency website, together with the European Public Assessment Report (EPAR, http://www.ema.europa.eu/) and in the Community Register of Medicinal Products on the European Commission’s website (http://ec.europa.eu/health/documents/community-register/html/index_en.htm).

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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.

References

1       Tafinlar EU Summary of Product Characteristics, 30 August 2013

2       Cantwell-Dorris, E., O'Leary, J. et al. BRAFV600E: Implications for Carcinogenesis and Molecular  Therapy. Mol Cancer Ther. March 2011; 10: 385.

3       Jerant AF, et al. Early detection and treatment of skin cancer. Am Fam Physician 62(2):357–368                 (2000).

4     Melanoma Research Foundation. “Staging Melanoma.” Available at http://www.melanoma.org/learn-more/melanoma-101/staging-melanoma.

5       Romano E, Schwartz GK, Chapman PB, et al. Treatment implications of the emerging molecular classification system for melanoma. Lancet Oncol. 2011;12(9):913-22.

6       Ferlay, J, Shin HR, Bray, F, Forman, D, Mathers, C, Parkin, DM GLOBOCAN 2008 v1.2. Cancer Incidence and Mortality Worldwide: IARC Cancerbase No.10 [Internet] Lyon, France: International Agency for Research on Cancer; 2010. Available from: http://globocan.iarc.fr. Accessed March 2013

7       Faruk Tas, Journal of Oncology. 2012.

8       Trefzer U. BREAK-2: A phase IIA trial of the selective BRAF kinase inhibitor GSK 2118436 in patients with BRAF (V600E/K) positive metastatic melanoma (LBA1 1). 8th International Congress for the Society of Melanoma Research; Tampa, Fla.. November 9–13, 2011.

9       AIM at Melanoma. “Brain Metastases.” Available at https://www.aimatmelanoma.org/en/aim-for-answers/stages-of-melanoma/brain-metastates.html.