The combination of dabrafenib (Tafinlar) plus trametinib (Mekinist) has been approved by the European Commission for the treatment of patients with unresectable or metastatic BRAF V600
–positive melanoma, according to a statement from the drugs’ developer, Novartis.
The approval is based on results from the phase III COMBI-d and COMBI-v studies, in which BRAF/MEK inhibition with dabrafenib/trametinib improved overall survival (OS) versus single-agent BRAF inhibition, which is the current standard of care in Europe.
“We look forward to making the Tafinlar and Mekinist targeted combination treatment, which demonstrated a significant overall survival benefit in two robust clinical trials, available across Europe as soon as possible," said Bruno Strigini, President, Novartis Oncology, in a statement. “Today's EU approval further demonstrates our ongoing commitment to deliver medicines that can further enhance outcomes for patients with metastatic melanoma.”
The COMBI-d trial randomized 423 patients with BRAFV600E/K
-mutant melanoma to dabrafenib plus trametinib (n = 211) or placebo (n = 212). The median patient age was approximately 56 years and approximately one-third of those in each arm had elevated LDH levels. Investigator-assessed progression-free survival (PFS) was the primary outcome measure, and secondary endpoints included OS, overall response rate (ORR), duration of response, and safety.
The combination of dabrafenib and trametinib demonstrated a median OS of 25.1 months compared with 18.7 months with dabrafenib alone (HR, 0.71; 95% CI, 0.55-0.92; P
= .011). The 2-year OS rate with the combination was 51% versus 42% with the single-agent.
Median PFS was 11.0 months with the combination compared with 8.8 months in the control arm (HR, 0.67; 95% CI, 0.53-0.84; P
<.001). ORR was 69% versus 53%, for the combination and single-agent, respectively. The complete response rate was 16% in the combination arm compared with 13% for dabrafenib. Duration of response was 12.9 and 10.6 months in the combination and monotherapy arms, respectively.
All-grade adverse events (AEs) occurred in 97% of patients in each arm; however, treatment-related AEs were lower in the combination arm (87% vs 90%). Treatment-related grade 3 AEs occurred in 30% of patients with the single-agent versus 32% with the combination. Discontinuation of treatment due to AEs occurred in 11% of patients with the combination versus 7% for the monotherapy
The most common AE with the combination was pyrexia (57% vs 33%). Grade 3 pyrexia occurred in 7% (n = 15) versus 2% (n = 4) of the combination versus control arms, respectively.
The incidence of cutaneous squamous cell carcinoma and keratoacanthoma was 10% with single-agent dabrafenib and 3% with the combination. Additionally, other skin-related AEs were lower with the combination.
COMBI-v randomized 704 patients to receive the combination of trametinib and dabrafenib (n = 352) or monotherapy with the BRAF inhibitor vemurafenib (Zelboraf; n = 352). The primary endpoint of the trial was OS with secondary endpoints focused on PFS, response, and safety. Crossover was not allowed; however, the study was stopped early, following a positive interim analysis.
The median PFS with the combination was 11.4 versus 7.3 months with vemurafenib (HR, 0.56; P
<.001). ORR was 64% with the combination versus 13% for vemurafenib alone. The median duration of response was 13.8 months compared with 7.5 months with vemurafenib.
The 1-year OS rate was 72% versus 65% for the combination and monotherapy, respectively. The median OS in the combination arm was not reached compared with 17.2 months with vemurafenib (HR, 0.69; P
The most frequently reported AEs with the combination compared with vemurafenib, respectively, were pyrexia (53% vs 21%) and bleeding events (18% vs 7%). Discontinuation of treatment due to AEs was similar between the treatment groups.
A number of events were lower with the combination, particularly the incidence of rash (22% vs 43%). Additionally, AEs were less frequent with the combination versus single-agent for photosensitivity reaction (4% vs 22%), hand-foot syndrome (4% vs 25%), skin papillomas (2% vs 23%), squamous-cell carcinomas and keratoacanthomas (1% vs 18%), and hyperkeratosis (4% vs 25%).
In the United States, the dabrafenib/trametinib combination received an accelerated approval in January 2014 for patients with BRAF V600E/K
–positive melanoma. The FDA is currently reviewing an application for full approval of the BRAF/MEK regimen based on data from the COMBI-d and COMBI-v studies. A final decision on the application is scheduled by November 2015.