Drug Combination More Effective than Single Drug for Advanced MelanomaThe combination of two targeted drugs—dabrafenib and trametinib—may delay the progression of advanced melanoma longer than dabrafenib alone, a new study suggests. These results, presented September 29 at the 2012 European Society for Medical Oncology Congress (ESMO) and published concurrently in the New England Journal of Medicine, add to a growing body of evidence that combinations of targeted drugs for melanoma are more effective and less toxic than a single targeted drug.
Dabrafenib and trametinib target different parts of a cell signaling pathway altered in melanoma by a mutation called BRAF V600. Single drugs that block BRAF activity shrink melanoma, but the tumors inevitably develop resistance. Researchers hoped that adding a second drug with a different target would slow the development of resistance and disease progression.
In the first part of the randomized phase II trial, which enrolled 85 patients, the researchers determined the combination’s safety and the doses to be used in the trial. The researchers then randomly assigned 162 patients to one of three treatment groups: dabrafenib alone, dabrafenib plus a low dose of trametinib, or dabrafenib plus a higher dose of trametinib. Patients whose disease progressed with dabrafenib alone were allowed to add the higher dose of trametinib to their treatment.
Patients receiving the higher dose of trametinib plus dabrafenib had a median progression-free survival of 9.4 months compared with 5.8 months for patients receiving dabrafenib alone. After 1 year of follow-up, 41 percent of patients receiving the higher-dose of trametinib plus dabrafenib had no disease progression, compared with 9 percent of those who received dabrafenib alone.
Overall, 79 percent of patients in the higher-dose combination group were alive after 1 year, explained Dr. Georgina Long of the Melanoma Institute Australia, one of the study’s authors, at an ESMO press conference. “We have never, ever seen a 12-month survival of that level in metastatic melanoma to date,” she said.
Side effects differed among the treatment groups, and patients in all arms of the trial frequently required temporary or permanent dose reductions. More patients receiving dabrafenib alone (19 percent) developed a secondary squamous-cell skin cancer than patients receiving the higher-dose combination (7 percent), though this difference was not statistically significant. Most patients in the higher-dose combination group (71 percent) experienced a fever compared with a minority of those receiving dabrafenib alone (26 percent).
The trial was funded by GlaxoSmithKline, the drugs’ manufacturer. Two company-sponsored phase III trials of the drug combination are currently under way (here and here).
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