Posted on June 6th, 2012 by
The combination of two investigational targeted drugs, dabrafenib and trametinib, stalls cancer progression and has less toxicity than current standard single-agent targeted therapy with Zelboraf® (vemurafenib), according to the results of a phase IB study presented at the 2012 annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago, Illinois.
Of the more than one million new diagnoses of skin cancer each year, roughly 68,000 involve melanoma. More than 8,000 people die of melanoma each year in the United States. What makes melanoma so dangerous is that it is more likely than other types of skin cancer to spread (metastasize) to other parts of the body.
In order to provide more individualized and more effective cancer therapy, much research has been focused on determining specific pathways involved in cancer cell growth or survival. The BRAF gene is known to play a part in cell growth, and mutations in BRAF are common in several types of cancer. Approximately half of all melanomas carry a specific BRAF mutation known as V600E and in those patients, the nearby MEK pathway is also highly active. Currently, Zelboraf is the only BRAF inhibitor approved for treating melanoma. Zelboraf has been shown to improve outcomes among patients with advanced melanoma with a BRAF gene mutation, but also accelerates the development of secondary skin cancers in some patients. Furthermore, most patients eventually develop resistance to the drug.
Dabrafenib targets the BRAF gene, while trametinib targets MEK. The combined use of the drugs simultaneously targets the BRAF and MEK pathways and researchers hope this will provoke a stronger anti-cancer response.
This analysis included 77 patients with advanced melanoma who had a V600 BRAF mutation and who had no previous BRAF-targeted treatment. The median progression-free survival (PFS) was 7.4 months—meaning patients lived for a median of 7.4 months before their disease got worse. This was comparable to what has been observed in the use of Zelboraf; however, patients receiving this combination therapy experienced fewer secondary skin cancers—2 percent of patients developed squamous cell carcinomas and another two percent developed actinic keratoses (small pre-malignant lesions). Other side effects included fever, fatigue, and dehydration.
The researchers concluded that the combination of dabrafenib and trametinib shows promising results with an acceptable safety profile. They speculated that the drug combination causes cancer shrinkage and that the second drug may actually suppress the side effects of the first. The combination will be further studied in a phase III trial.
 Weber JS, Flaherty KT, Infante JR, et al. Updated safety and efficacy results from a phase I/II study of the oral BRAF inhibitor dabrafenib (GSK2118436) combined with the oral MEK 1/2 inhibitor trametinib (GSK1120212) in patients with BRAFi-naive metastatic melanoma. Presented at the 2012 annual meeting of the American Society of Clinical Oncology, June 1-5, 2012, Chicago, IL. Abstract 8510.
 Su F, Viros A, Milagre C et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. New England Journal of Medicine. 2012;366:207-15.
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