BRAF/MEK Combo Active in BRAF-Resistant Melanoma

Melanoma with diameter change

Combined treatment with a BRAF inhibitor and a MEK inhibitor resulted in modest clinical efficacy in a group of patients whose melanoma had progressed after prior treatment with a BRAF inhibitor, results of a new study published in the Journal of Clinical Oncology show.

The open-label phase I/II study examined combination treatment with dabrafenib and trametinib. The combined used of BRAF and MEK inhibitors has also been explored in patients who are treatment-naive, with study results published recently in Lancet Oncology and presented at the 2014 ESMO Congress.

“BRAF inhibitors are a highly active therapy in the 50% of melanomas that harbor BRAF mutations,” said Douglas B. Johnson, MD, of Vanderbilt-Ingram Cancer Center. “Acquired resistance and tumor growth occur in almost all patients, which limits the long-term benefit of these agents.”

In this study, Johnson and colleagues examined a possible treatment strategy for patients with melanoma that has become resistant to BRAF inhibitors. They studied the pharmacology, safety, and efficacy of combination treatment with dabrafenib and trametinib, administering the drug combination in patients with progression on a BRAF inhibitor prior to study enrollment (Group B; n = 26), and in patients who crossed over to combination treatment after progression on dabrafenib monotherapy (Group C; n = 45).

“We found that in patients who have developed resistance to BRAF inhibitors, the combination of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) has modest clinical activity and is a potential treatment strategy,” Johnson told Cancer Network.

Patients in Group B had an overall response rate of 15%. The four responding patients had partial response and 13 additional patients (50%) had stable disease at 8 weeks. Patients in Group C had an overall response rate of 13%, including one complete response and five partial responses. Twenty additional patients (44%) had stable disease.

Patients in Group C had a median progression-free survival of 3.6 months and a median overall survival of 11.8 months from cross-over.

The researchers also explored whether those patients with a longer benefit from initial BRAF inhibition had a better response from subsequent combination therapy.

“We found that patients who had previously benefited for an extended interval on a BRAF inhibitor in turn benefited more from the combination,” Johnson said.

In Group C, 22 patients were considered to have rapid resistance (resistance < 6 months from beginning dabrafenib monotherapy) and 23 patients had delayed resistance (resistance ≥ 6 after initiation). Patients with rapid resistance had an overall response rate of 0% and a median progression-free survival of 1.8 months compared with an overall response rate of 26% and a progression-free survival of 3.9 months in the delayed-resistance group.

“This study shows that dabrafenib and trametinib should not necessarily be given to every patient who develops disease progression on a single agent BRAF inhibitor,” Johnson said. “However, patients who are on treatment for greater than 6 months have the chance to have a real benefit from this FDA-approved combination. In this setting, this combination can be considered as an active treatment option.”