In two large-scale trials, new drugs made by GlaxoSmithKline extended the lives of patients with advanced melanoma longer than standard chemotherapy. The drugs work by blocking the effect of the BRAF gene mutation, which is present in about half of melanoma cases and triggers tumor growth.
The two drugs tested by GlaxoSmithKline are trametinib and dabrafenib. The first drug blocks a protein known as MEK, which is believed to be a key protein in the chain of signaling pathways that allow BRAF mutations to stimulate the growth of tumors. The second drug inhibits BRAF directly.
In the trial for trametinib, 322 patients with advanced or metastatic melanoma received trametinib, taken as a pill, or one of two chemotherapy drugs. Patients given trametinib lived for an average of 4.8 months before the disease worsened, compared with 1.5 months for melanoma patients treated with chemo.
The researchers found trametinib was also associated with a 55% reduction in death risk. After six months, about 80% of those taking trametinib were alive compared with the 67% in the chemotherapy group.
“Importantly, trametinib is the first MEK inhibitor to demonstrate clinical benefit in a late-phase melanoma trial,” said Dr. Rafael Amado, head of oncology R&D for GlaxoSmithKline, in a statement.
In the trial of dabrafenib, the BRAF inhibitor, the researchers looked at 250 patients and found that those on the drug lived for an average of 5.1 months before their disease worsened, compared with 2.7 months for chemotherapy patients. Dabrafenib treatment reduced the risk of disease progression or death by 70%.
Currently, the only BRAF inhibitor approved by the Food and Drug Administration for the treatment of advanced melanoma is Zelboraf, made by Roche Holding AG and Daiichi Sankyo Co. That drug, approved last year, targets the mutant BRAF gene, similar to dabrafenib. In the latest trial results, Zelboraf was shown to improve survival by an average of four months. However, tumors can eventually become resistant to the drug and its mechanism can trigger secondary, less deadly skin cancers. According to Reuters, 19% of patients on Zelboraf developed a less-deadly form of skin cancer known as cutaneous squamous cell carcinoma and 10% developed another type of non-malignant lesion.
Blocking MEK instead of BRAF could be a way to treat melanoma without causing secondary skin cancers, Dr. Caroline Robert, lead researcher in the Glaxo studies and a consultant to Glaxo and other companies told the New York Times. The two drugs could be used in tandem.
Glaxo is now conducting a trial combining the treatments. The combination “is where we have the most enthusiasm right now,” the author of the trametinib study, Keith Flaherty, director for developmental cancer therapeutics at Massachusetts General Hospital, told Bloomberg. It “looks better in terms of efficacy, and better in terms of safety.”
Results from both trials were presented at the American Society of Clinical Oncology meeting in Chicago. The trametinib study was also published in the New England Journal of Medicine.