Trametinib Plus Dabrafenib Gains FDA Approval for Advanced Melanoma

Paolo Paoletti, MD

The FDA has approved the first-ever targeted therapy combination for patients with unresectable or metastatic melanoma who harbor a BRAF V600E or V600K mutation, based on results from an open-label phase I/II trial.

The combination of the MEK inhibitor trametinib (Mekinist) and the BRAF inhibitor dabrafenib (Tafinlar) nearly doubled the duration of response and significantly improved overall response rates (ORR) when compared with dabrafenib alone. The agents were individually approved by the FDA in May 2013 along with a companion diagnostic.

"This approval marks another key moment in what continues to be a rapid evolution of the treatment landscape for metastatic melanoma patients. Combining agents that target different mechanisms regulating the growth of cancer cells is one of the promising areas in cancer research," said Paolo Paoletti, MD, President of Oncology at GSK, the company that developed the combination, in a press release. "We are proud that the first approved combination of targeted therapies in metastatic melanoma is Mekinist and Tafinlar, and our hope is that it will become part of the new standard of care for appropriate patients with BRAF V600E or V600K mutation-positive metastatic melanoma."

On average 50% of patients who are treated with a single-agent BRAF or MEK inhibitor develop resistance within 6 to 7 months following initial treatment. Moreover, secondary skin cancers are common with single-agent BRAF inhibition.

The phase II portion of the open-label phase I/II study that was the basis for the approval of dabrafenib plus trametinib enrolled 162 patients with advanced melanoma and BRAF V600E/K mutations. These patients were randomized in a 1:1:1 ratio, with 54 patients in each arm who had not previously received BRAF or MEK inhibitors.

The recommended dosing for the combination is 150 mg of dabrafenib twice daily plus 2 mg of trametinib once daily (150/2). For the combination and dabrafenib monotherapy, respectively, the ORR was 76% versus 54% (P = .03) and the median duration of response was 10.5 months compared with 5.6 months. The investigator-assessed median PFS with the combination was 9.4 months compared with 5.8 months for dabrafenib monotherapy (hazard ratio [HR] = 0.39; 95% CI, 0.25 - 0.62; P < .001).

After 1 year, 41% of patients in the 150/2 group were alive and progress-free compared with only 9% in the monotherapy arm (P < .001). Overall, approximately 80% of patients crossed over from the monotherapy group to the combination arm following disease progression.

The BRAF and MEK inhibitor combination was found to significantly reduce the incidence of secondary cutaneous squamous cell carcinoma, which occurred in 19% of patients receiving dabrafenib monotherapy compared with 2% with combination 150/1 (P = .004) and 7% for combination 150/2 (P = .09).

For all types of skin rashes, 36% of patients in the monotherapy arm developed a rash compared with 27% for the combination. The most frequent all grade side effects associated with the combination were pyrexia (71%) and chills (58%). On average, severe pyrexia occurred in 25% in the combination group and in 2% for dabrafenib alone.

To support the accelerated approval, the combination of dabrafenib and trametinib is being explored in a number of phase III trials for patients with metastatic melanoma.

Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK Inhibition in Melanoma with BRAF V600 Mutations. N Engl J Med. 2012; 367:1694-1703.