Dabrafenib/Trametinib Combo Granted EU Approval for Advanced Melanoma

Bruno Strigini

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 = .002).

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&shy;—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.