The FDA has granted an accelerated approval to the combination of the MEK inhibitor trametinib and the BRAF inhibitor dabrafenib as a treatment for patients with unresectable or metastatic melanoma that harbors a BRAF V600E or V600K mutation.
Richard Pazdur, MD
The FDA has granted an accelerated approval to the combination of the MEK inhibitor trametinib (Mekinist) and the BRAF inhibitor dabrafenib (Tafinlar) as a treatment for patients with unresectable or metastatic melanoma who harbor a BRAF V600E or V600K mutation.
The approval for the combination was based on results from an open-label phase I/II trial, which showed that trametinib combined with dabrafenib nearly doubled the duration of response and significantly improved overall response rates (ORR) when compared with dabrafenib alone. Dabrafenib and trametinib were each approved as single agents in May 2013 along with a companion diagnostic. The approval of the agents in combination marks the first for a targeted therapy combination in advanced melanoma.
"Mekinist and Tafinlar are the first drugs approved for combination treatment of melanoma,” said Richard Pazdur, MD, the director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “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."
On average, 50% of patients treated with a single-agent BRAF or MEK inhibitor develop resistance within 6 to 7 months following initial treatment. To address this concern, it was believed that a more complete inhibition of the MAPK pathway was required, providing the preclinical rational for the combination of a BRAF and MEK inhibitor.
The phase I/II study was conducted in four segments. The phase II component of the study provided the majority of information regarding clinical activity. In this segment of the trial, 162 patients with advanced melanoma and BRAF V600E/K mutations were randomized in a 1:1:1 ratio, with 54 patients in each arm who had not previously received BRAF or MEK inhibitors. Patient characteristics were balanced between arms, with an ECOG performance status of 0 or 1.
In the first arm, patients received 150 mg of dabrafenib twice daily (BID) plus 1 mg of trametinib once daily (combination 150/1). In arm 2, patients received 150 mg of dabrafenib BID plus 2 mg of once-daily trametinib (combination 150/2). In the control arm, patients received single-agent dabrafenib at 150 mg BID.
The primary endpoints of the study included progression-free survival (PFS), ORR, and duration of response. Overall survival (OS) was assessed as a secondary endpoint; however, crossover between arms following progression was allowed in the trial.
Based on results from the trial, the 150/2 combination was shown to be superior and was chosen as the FDA-approved dose. For the 150/2 group 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 150/2 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). Slight differences in the PFS HR were noted by an independent review committee that was attributed to variations in the definition of progression. The HR for PFS by independent review was less pronounced at 0.55 (95% CI, 0.33-0.93; P = .02)
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 150/2 study 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 20% and 27% for the 150/1 and 150/2 groups, respectively. The most frequent all grade side effects associated with the combination were pyrexia (71%) and chills (58%). On average, severe pyrexia occurred in 19% of patients in the 150/1 group, 25% in the 150/2 group, and in 2% for dabrafenib alone.
"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."
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. In the phase III placebo-controlled COMBI-AD study, dabrafenib in combination trametinib in being explored as an adjuvant treatment for patients with high-risk melanoma with a BRAF V600 mutation following surgical resection.
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.