Posted on June 18th, 2012 by
Two new targeted therapies—trametinib and dabrafenib—show promise in the treatment of advanced melanoma, either improving survival or delaying disease progression, according to the results of two studies 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. Melanoma is dangerous because it is more likely than other types of skin cancer to spread (metastasize) to other parts of the body.
Much new cancer research has been focused on targeted therapies, which are anticancer drugs that interfere with specific pathways involved in cancer cell growth or survival. Targeted therapies provide an opportunity to deliver more individualized and more effective cancer therapy.
Zelboraf, another targeted therapy, has been shown to improve outcomes among patients with advanced melanoma with a BRAF gene mutation, but it has also been shown to accelerate the development of secondary skin cancers in some patients. Furthermore, most patients eventually develop resistance to the drug. Thus, new targeted therapies could mean improved treatment options for advanced melanoma.
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. This mutation produces an abnormal version of the BRAF protein that stimulates cancer growth. Zelboraf inhibits this protein, and researchers are exploring other BRAF-targeted drugs as well. It may also be possible to control the effects of an abnormal BRAF protein by blocking other proteins that work with it. MEK is one of these proteins, and drugs that inhibit MEK are also being explored for the treatment of melanoma.
Two new targeted therapies have shown promise in the treatment of advanced melanoma—dabrafenib targets BRAF, while trametinib targets MEK.
Results from a phase III study presented at ASCO showed that trametinib delayed tumor growth and extended survival in patients with advanced melanoma with BRAF mutations, compared with standard chemotherapy. The study included 420 patients with advanced melanoma and BRAF mutations who were randomized to receive trametinib or standard chemotherapy. The results showed a benefit in the trametinib group—overall 22 percent of patients receiving trametinib responded to treatment compared with 8 percent of those who received chemotherapy. Furthermore, patients in the trametinib group experienced improved progression-free survival (PFS)—4.8 months compared to 1.5 months in the chemotherapy group. This represented a 55 percent reduction in the risk of progression. At interim analysis, overall survival was also improved with trametinib—81 percent of patients in the trametinib group were alive at 6 months compared to 67 percent in the chemotherapy group—which translated to a 46 percent reduced risk of death. Side effects of trametinib were generally manageable.
The results of another study presented at ASCO indicated that dabrafenib reduced the risk of disease progression by 70 percent compared to standard chemotherapy in patients with previously untreated, advanced melanoma with BRAF mutations. The study included 250 patients with previously untreated, inoperable stage III or IV melanoma who were randomly assigned to receive dabrafenib or standard chemotherapy. The results were overwhelming—50 percent of patients in the dabrafenib group responded to treatment, compared to 6 percent in the chemotherapy group. The estimated median progression-free survival was significantly longer in the dabrafenib group—5.1 months compared to 2.7 months in the chemotherapy group. There were fewer cases of serious skin toxicity in the dabrafenib group; however, more patients in the dabrafenib group experienced drops in blood cell counts, pain, and fever.
Both of these new targeted therapies show promise for the treatment of advanced melanoma—and may offer effective treatment with a better safety profile than the currently available targeted treatment for melanoma.
 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.
 Robert C, Flaherty KT, Hersey P, et al. METRIC Phase 3 Study: Efficacy of Trametinib (T), a potent and selective MEK inhibitor (MEKi), in progression-free survival (PFS) and overall survival (OS), compared with chemotherapy (C) in patients (pts) with BRAFV600E/K mutant advanced or metastatic melanoma (MM). Presented at the 2012 annual meeting of the American Society of Clinical Oncology, June 1-5, 2012, Chicago, IL. Abstract LBA8509.
 Hauschild A, Grob JJ, Demidov LV, et al. Phase III, randomized, open-label, multicenter trial (BREAK-3) comparing the BRAF kinase inhibitor dabrafenib (GSK2118436) with dacarbazine (DTIC) in patients with BRAFV600E-mutated melanoma. Presented at the 2012 annual meeting of the American Society of Clinical Oncology, June 1-5, 2012, Chicago, IL. Abstract LBA8500.
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