BRAF and MEK Inhibitors Offer Good News in Melanoma Free

Phase III study findings show increases in progression-free survival for patients with advanced disease.

Until recently, patients with advanced melanoma suffered from a lack of effective treatment options. Approval came only last year for the first targeted therapy, vemurafenib (Zelboraf; Genentech), which blocks a mutated form of the BRAF protein present in about half of these patients.

Fortunately, the list may soon grow, given the positive results of 2 phase III trials for 2 targeted agents, trametinib and dabrafenib, reported at the 2012 Annual Meeting of the American Society of Clinical Oncology in Chicago, June 1–5.

“For 50 years, we had nothing,” said Caroline Robert, MD, PhD, head of dermatology at the Institut Gustave Roussy in Paris, France, who presented the results of the trametinib study. “Now hopefully we will have others.”

The 2 investigational drugs both affect signal transduction in the RAS–RAF–MAPK pathway: dabrafenib inhibits BRAF and trametinib inhibits MEK1/2.

In the BREAK-3 study, 250 untreated patients with advanced BRAF^V600E-mutated melanoma were randomly assigned to receive dabrafenib or the standard chemotherapy dacarbazine. Half of the patients in the dabrafenib group responded to therapy, compared with just 6% of patients treated with dacarbazine. Median progression-free survival time was significantly longer in the dabrafenib group: 5.1 months versus 2.7 months.

Overall survival data are not yet available. However, principal investigator Axel Hauschild, MD, professor of dermatology at the University Hospital in Kiel, Germany, noted that overall survival might be difficult to assess because patients whose disease progressed on dacarbazine were allowed to cross over to the dabrafenib arm of the trial.

In most cases, dabrafenib was well tolerated, Hauschild said. Some patients experienced mild to moderate skin reactions on their hands and feet. However, the rate of serious skin problems was relatively low, with about 6% of patients developing squamous cell carcinoma and 3% developing photosensitivity. In a phase III study of vemurafenib, 12% of patients developed squamous cell carcinoma and 12% developed sun sensitivity.

“These findings represent another advance for melanoma and form the foundation for further studies to evaluate the role of dabrafenib in combination with other drugs,” said Hauschild. He noted that some early research gives “very good indications that progression-free survival is much longer” when dabrafenib is combined with trametinib.

In the trametinib study, called METRIC, 322 patients with advanced disease harboring either a V600E or V600K BRAF mutation were randomly assigned to receive trametinib or chemotherapy—either dacarbazine or paclitaxel. Overall, 22% of the patients who received trametinib responded to treatment, compared with 8% of those who received chemotherapy. Median progression-free survival was significantly greater in the trametinib group than in the chemotherapy group—4.8 months compared with 1.5 months.

An interim analysis of overall survival showed that 81% of patients in the trametinib group were alive after 6 months of follow-up, versus 67% in the chemotherapy group. Nearly half of the patients whose disease progressed while they were on chemotherapy were permitted to take trametinib, so the overall survival advantage may ultimately prove to be greater if this crossover effect is taken into account, Robert explained.

“This is the first in a new class of targeted drugs that could benefit patients with melanoma who have BRAF mutations. The findings show that targeting the MEK molecular pathway is a viable strategy for treating many people with the disease,” said Robert.

She also noted that because most patients taking vemurafenib develop resistance to it, a drug that targets a different part of the pathway will be particularly beneficial. Another potential benefit of trametinib: None of the patients who took it developed squamous cell carcinoma.

When asked how physicians would decide which one of the growing number of drugs to prescribe, Robert said that molecular testing and additional clinical trials will be needed. “Really, this is not a problem,” she added, referring to the need to choose a treatment. “It's very good news.”