The U.S. Food and Drug Administration approved two new oral agents, Tafinlar (dabrafenib) and Mekinist (trametinib), for patients with metastatic or unresectable melanoma.
Tafinlar, a BRAF inhibitor, is approved to treat patients with melanoma whose tumors express the BRAF V600E gene mutation. Mekinist, a MEK inhibitor, is approved to treat patients whose tumors express the BRAF V600E or V600K gene mutations.
The FDA approved both drugs as single agents, not combination treatment, along with a genetic test, the THxID BRAF test, which is a companion diagnostic that will help determine if a patient's melanoma cells have the V600E or V600K mutation in the BRAF gene. Approximately 76,690 Americans will be diagnosed with melanoma in 2013, according to the National Cancer Institute, and approximately half of skin melanomas have a BRAF mutation.
“Advancements in our understanding of the biological pathways of a disease have allowed for the development of Tafinlar and Mekinist, the third and fourth drugs the FDA has approved for treating metastatic melanoma in the past two years,” Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research, said in a news release. Both vemurafenib (OT, 9/10/11 issue) and ipilimumab (OT, 4/25/13 issue) were approved in 2011 for the treatment of patients with metastatic or unresectable melanoma.
The approval for tafinlar is based on a study of 250 previously untreated adult patients with BRAF V600E gene mutation-positive metastatic or unresectable melanoma. Patients were randomly assigned to receive tafinlar or the chemotherapy drug dacarbazine. The study demonstrated a statistically significant increase in progression-free survival for patients receiving tafinlar compared with patients taking dacarbazine—median progression-free survival was 5.1 months compared with 2.7 months, respectively.
The most serious side effects reported were: increased risk of cutaneous squamous cell carcinoma, fevers that may be complicated by hypotension, shaking chills, dehydration, kidney failure, and increased blood sugar levels requiring medication. The most common side effects reported in patients receiving the drug were hyperkeratosis, headache, fever, joint pain, non-cancerous skin tumors, hair loss, and hand-foot syndrome.
The approval for mekinist is based on a study of 322 patients with metastatic or unresectable melanoma with the BRAF V600E or V600K gene mutation, who had no more than one prior chemotherapy regimen for advanced or metastatic disease and no prior BRAF or MEK inhibitor treatment. Patients were randomly assigned to receive either mekinist or chemotherapy.
Median progression-free survival in patients treated with mekinist was 4.8 months compared with 1.5 months for the chemotherapy group. Patients who previously used tafinlar or other inhibitors of BRAF did not appear to benefit from mekinist. The most serious side effects reported in patients receiving the drug included heart failure, lung inflammation, skin infections, and loss of vision. Common reported side effects were rash, diarrhea, peripheral edema, and acne-like skin breakouts.
Women of childbearing years should be advised that tafinlar and mekinist carry the potential to cause fetal harm. Men and women should also be advised that both agents also carry the potential to cause infertility.
The FDA's approval of the THxID BRAF test is based on data from clinical studies that support the tafinlar and mekinist approvals. Samples of patients' melanoma tissue were collected to test for the mutation.
Both drugs are marketed by GlaxoSmithKline. The THxID BRAF Kit is manufactured by bioMérieux of Grenoble, France.
Tim Turnham, Executive Director of the Melanoma Research Foundation, said in a statement that the organization celebrates the approvals, as there is a dire need for new treatment options for people with the disease. “This is positive news for the melanoma community. We still have much work to do in terms of providing additional treatments for people fighting advanced melanoma, but this is an important step forward.”