Combatting Treatment Resistance in Metastatic Melanoma Therapy

Two drugs under review by the FDA—dabrafenib and trametinib—seem to slow development of treatment resistance in patients with metastatic malignant melanoma.

Approximately half of metastatic melanoma patients who are treated with BRAF inhibitors develop treatment resistance to them. BRAF inhibitors have been able to suspend and reverse tumor growth in most patients, but tumor growth usually resumes within 6 or 7 months. Treatment resistance probably results from mutations that activate the MEK protein, leading to reactivation of the mitogen-activated protein kinase pathway, a pathway that includes BRAF.

Two drugs under review by the FDA—dabrafenib and trametinib—seem to slow development of treatment resistance in patients with metastatic malignant melanoma. To test their ability to do so, researchers conducted a multicenter study in the United States and Australia. They published their results in the September 29, 2012, edition of the New England Journal of Medicine.

This 2-stage trial found no drug-to-drug interactions between the 2 agents in phase I. In phase II, the researchers enrolled 162 patients and randomized them to different dose combinations:

• Combination 150/2: twice daily dabrafenib 150 mg plus once daily trametinib 2 mg
• Combination 150/1: twice daily dabrafenib 150 mg plus once daily trametinib 1 mg
• Monotherapy: twice daily dabrafenib 150 mg alone

The results showed that combination 150/2 outperformed combination 150/1 on all measures. Median progression-free survival (PFS) in the combination 150/2 group was 9.4 months, compared with 5.8 months in the monotherapy group. The rate of complete or partial response was 76% with combination 150/2 therapy and 54% with monotherapy—a significant and encouraging difference. At 1 year, PFS was 41% for combination 150/2 patients, but only 9% among monotherapy patients. Patients in the monotherapy group were allowed to cross over to the combination 150/2 treatment if their cancer returned or progressed.

Dose-limiting toxicities were low in the combination 150/2 group. Cutaneous squamous cell carcinoma, papillomas, and hyperkeratosis occurred in 7%, 4%, and 9%, respectively, of combination 150/2 patients, and 19%, 15%, and 30%, respectively, of monotherapy patients. The incidence of pyrexia (abnormally elevated body temperature) was significantly higher in the combination 150/2 group (71%) than in the monotherapy group (26%). The incidence of acneiform dermatitis, trametinib’s most common and dose-limiting toxicity, was reduced when dabrafenib and trametinib were administered in combination.

The researchers conclude that dabrafenib and trametinib were safely combined at full monotherapy doses. They also conclude that combination therapy significantly improved PFS, nonsignificantly reduced the rate of proliferative skin lesions, and increased the rate of pyrexia among patients with metastatic melanoma with BRAF mutations. They could not explain the mechanism by which these changes occurred.

Ms. Wick is a visiting professor at the University of Connecticut School of Pharmacy and a freelance writer from Virginia.