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Pair of gene-targeted melanoma drugs show promise in late-stage clinical trials

11 June 2012
Appeared in BioNews 660

Two drugs targeting advanced melanoma linked to a mutation in the BRAF gene are more effective than current chemotherapy at slowing the progress of the skin cancer, clinical trial results indicate.

Dabrafenib and trametinib were both produced by pharmaceuticals company GSK and may represent a further advance in personalised medicine for cancer, where drugs are targeted specifically against the genetic underpinnings of the disease. Results from the final series of clinical trials before the drugs could become widely available (phase III trials) were presented at the Annual Meeting of the American Society of Clinical Oncology in Chicago last week.

The BRAF mutation has been identified in around half of all cases of melanoma, and patients were selected for eligibility based on the BRAF mutation status of their cancer in both trials.

Patients given dabrafenib lived for 5.1 months before their disease worsened (a measure called progression-free survival, or PFS) compared to 2.7 months with standard chemotherapy. In a separate trial, trametinib showed a PFS of 4.8 months compared to 1.5 months following chemotherapy.

For a long time melanoma was considered nearly untreatable. Dr Caroline Robert, head of Dermatology at the Institute Gustave Roussy in Paris, and lead investigator of the trametinib study told the New York Times, that now, thanks to recent advances, 'In melanoma, we are living something incredible'.

Roche currently market a BRAF inhibitor which improves survival in advanced melanoma but can result in a less severe form of skin cancer known as cutaneous squamous cell carcinoma. These tumours can be removed surgically but are clearly undesirable and trametinib does not appear to induce them. The drug works by blocking a protein called MEK, which is just downstream of BRAF in the chain of signals that prompt tumor growth.

The trametinib trial enlisted 322 patients and the survival rate was 81 percent in the trametinib group compared to 67 percent in the chemotherapy group after 6 months. The drug's clear benefits meant that patients in the chemotherapy cohort were later allowed to crossover to receive trametinib therapy. Meanwhile the dabrafenib study enrolled 250 patients and the drug, which is a BRAF inhibitor, reduced the risk of disease progression or death by 70 percent.

Dr Rafael Amado, head of oncology research and development at GSK said that trametinib was 'the first MEK inhibitor to demonstrate clinical benefit in a late phase melanoma trial'.

He added: 'We are planning regulatory submissions for dabrafenib and trametinib as single agent therapies and have recently started a phase III programme to further investigate the effect of the combination in this disease'.

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