The U.S. Food and Drug Administration has approved Mekinist (trametinib) in combination with Tafinlar (dabrafenib) for the treatment of patients with unresectable melanoma or metastatic melanoma with the BRAF V600E or V600K mutations, as detected by an FDA-approved test. The drugs are oral agents used to block signaling in different sites of the same molecular pathway that promotes cancer cell growth.
“Mekinist and Tafinlar are the first drugs approved for combination treatment of melanoma,” Richard Pazdur, MD, Director of the FDA's Office of Hematology and Oncology Products, said in a news release. “Their development for combination use is based on the strong understanding of the biological pathways of the disease. This approval illustrates the value of continuing to study drugs in combination for clinical development.”
Both drugs were approved last summer as single agents, along with the THxID BRAF test, a companion diagnostic to determine mutation status (OT 6/25/13 issue). The combination was approved through the FDA's Accelerated Approval program, which allows the FDA to approve a drug to treat a serious disease based on clinical data showing that the drug has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients.
The drug combination was also reviewed under a Priority Review designation because they demonstrated the potential to significantly improve the safety or effectiveness in the treatment of a serious condition (OT 10/10/13 issue).
The safety and effectiveness of the drug combination were demonstrated in a clinical trial of 162 patients with unresectable or metastatic melanoma with the BRAF V600E or V600K mutation, most of whom had not received prior therapy. The patients received either the drug combination or Tafinlar as a single agent until their melanoma progressed or side effects became intolerable.
The results showed that the cancer shrank or disappeared in 76 percent of the patients treated with the drug combination for an average duration of 10.5 months, while 54 percent of patients treated with Tafinlar as a single agent had the same response for an average of 5.6 months. Clinical trials are still ongoing to determine whether the drug combination improves survival.
The most common side effects included fever, chills, fatigue, rash, nausea, vomiting, diarrhea, abdominal pain, peripheral edema, cough, headache, arthralgia, night sweats, decreased appetite, constipation, and myalgia. The incidence and severity of fever was found to increase when Mekinist was used in combination with Tafinlar in the clinical trial.
Serious side effects reported in the trial included bleeding, clot formation, heart failure, skin problems, and eye problems. One of the serious side effects of Tafinlar—the development of a new squamous cell carcinoma of the skin—was reduced when the drug was used in combination with Mekinist, which is consistent with the biology of the effects of these two drugs on the targeted molecular pathway, a news release notes.
In the trial, when the drug combination was used, the incidence of squamous cell carcinoma on the skin was seven percent compared with 19 percent when Tafinlar was used a single agent. Other clinically significant side effects include kidney injury.
Mekinist and Tafinlar are both marketed by GlaxoSmithKline.