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Tafinlar, an oral treatment for unresectable or metastatic melanoma in adult patients with a BRAF V600 mutation, approved by European Commission

The European Commission has granted marketing authorisation for Tafinlar ( Dabrafenib ) as an oral targeted treatment indicated in monotherapy for unresectable melanoma or metastatic melanoma in adult patients with a BRAF V600 mutation.
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.

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. The availability 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.

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% compared to Dacarbazine ( p less than 0.0001 ).
Study data showed a median progression-free survival of 5.1 months with Dabrafenib compared to 2.7 months for Dacarbazine ( 2011 cut-off data ).
In a post-hoc analysis from June 2012, Dabrafenib reduced the relative risk of disease progression or death by 63% compared to Dacarbazine ( P less than 0.0001 ). The data showed a median progression free survival of 6.9 months compared to 2.7 months for Dacarbazine.

A further post-hoc analysis, from December 2012, showed overall survival at 12 months was 70% with Dabrafenib, compared with 63% for Dacarbazine ( HR = 0.76 ).

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.

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. 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 ), Tafinlar is 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.

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 ) ( greater than or equal to 15% ) reported with Dabrafenib were hyperkeratosis, headache, pyrexia ( fever ), arthralgia , fatigue, nausea, skin papilloma, alopecia, rash and vomiting.

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.

Melanoma is the most serious type of skin cancer and causes 75% of skin cancer-related deaths. 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. Typically, less than 5% of all newly incident melanoma patients present with metastatic disease. A BRAF gene mutation is seen in 50-70% of cutaneous melanoma cases. ( Xagena )

Source: GlaxoSmithKline, 2013