Two drugs that target mutations on the BRAF gene have been approved for treating metastatic or unresectable melanomas that express the mutations – along with a companion test to detect the mutations, the Food and Drug Administration announced on May 29.
Dabrafenib and trametinib are the third and fourth drugs to be approved by the FDA for metastatic or unresectable melanoma since 2011, when vemurafenib (Zelboraf) and ipilimumab (Yervoy) were approved.
Dabrafenib, a BRAF inhibitor, was approved for patients with unresectable or metastatic melanoma with the BRAF V600E mutation as detected by an FDA-approved test. It will be marketed as Tafinlar and is taken twice a day, by mouth.
Trametinib, a MEK inhibitor, was approved to treat patients with unresectable or metastatic melanomas that express the BRAF V600E or V600K mutations, as detected by the test. It will be marketed as Mekinist, and is taken by mouth once a day.
The two drugs are not approved as combination treatment, according to a statement from the FDA.
The just-approved THxID BRAF test will be used to determine if the mutations are present. About half of melanomas have a BRAF mutation, according to the FDA.
"Advancements in our understanding of the biological pathways of a disease have allowed for the development" of these two drugs, Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA Center for Drug Evaluation and Research (CDER), said in the statement. The approval of the drugs and the diagnostic test, the second that tests for the BRAF mutation, "demonstrates the commitment of pharmaceutical and diagnostic partners to develop products that detect and target the molecular drivers of cancer," added Alberto Gutierrez, Ph.D., director of the CDER Office of In Vitro Diagnostic Devices and Radiological Health.
In a study of 250 people with previously untreated BRAF V600E mutation–positive, unresectable or metastatic melanoma, the median progression-free survival (PFS) was 5.1 months among those randomized to treatment with dabrafenib vs. 2.7 months among those randomized to chemotherapy with dacarbazine, a statistically significant difference (hazard ratio, 0.33).
The most common adverse events associated with dabrafenib were hyperkeratosis, headache, fever, joint pain, noncancerous skin tumors, alopecia, and hand-foot syndrome. The most serious adverse events associated with dabrafenib treatment were an increased risk of cutaneous squamous cell carcinoma, fevers complicated by hypotension, severe rigors, dehydration, kidney failure, and hyperglycemia requiring an increased dose or initiation of treatment with glucose-lowering drugs, according to the FDA.
In a study of 322 patients with metastatic or unresectable melanoma positive for the BRAF V600E or V600K mutation, the median PFS was 4.8 months among those on trametinib vs. 1.5 months among those on chemotherapy (paclitaxel or dacarbazine), a significant difference (HR, 0.47). Those patients who had been treated with dabrafenib or another BRAF inhibitor "did not appear to benefit" from trametinib treatment, according to the FDA.
Rash, diarrhea, peripheral edema, and acneiform skin breakouts were the most common adverse effects associated with trametinib. Among the most serious adverse events associated with trametinib were heart failure, lung inflammation, skin infections, and loss of vision.
The labels for both drugs warn that the drugs can cause fetal harm.
Dabrafenib and trametinib are marketed by GlaxoSmithKline (GSK), and the THxID BRAF Kit is manufactured by bioMérieux, a French company.
The two drugs are expected to be available no later than the "early third quarter" of 2013, according to a GSK statement. The company worked with bioMérieux to develop the test, and it is the only FDA-approved test that detects the V600K mutation.
Serious adverse events associated with these drugs should be reported to the FDA’s MedWatch program at 800-332-1088 or www.fda.gov/medwatch/.