The FDA has assigned a priority review to an application for the full approval of dabrafenib (Tafinlar) plus trametinib (Mekinist) in patients with unresectable or metastatic BRAFV600
mutation-positive melanoma, according to a statement from the drug's developers, Novartis.
The application for the combination was based on data from the phase III COMBI-d and COMBI-v studies, which showed an improvement in overall survival (OS) with dabrafenib plus trametinib versus single-agent BRAF inhibition. Under this review program, the FDA will make a decision on the application in November 2015. The combination was initially granted an accelerated approval for patients with BRAF
-mutant melanoma in January 2014.
In addition to the FDA designation, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency has issued a positive opinion on the combination. Based on this opinion, the European Commission will deliver a final decision on the application within 3 months. If both applications were approved, the combination would have a full approval in the United States and across 28 European Union states plus Iceland, Norway, and Liechtenstein.
"The CHMP positive opinion and FDA priority review of Tafinlar and Mekinist validate the importance of this targeted therapy combination for patients with the most serious form of skin cancer," Bruno Strigini, president, Novartis Oncology, said in a statement. "We look forward to working with the US and EU regulatory authorities to help bring this targeted therapy combination to more patients who may benefit."
In the phase III COMBI-d trial, 423 patients with BRAFV600E/K
-mutant melanoma were randomized to receive dabrafenib with 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. The primary endpoint of the study was investigator-assessed progression-free survival (PFS) and secondary endpoints included OS, overall response rate (ORR), duration of response, and safety.
In a final analysis of the study presented at the 2015 ASCO Annual Meeting,1
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.
“Subgroup analysis for the overall survival showed that every subgroup benefited from the combination compared with dabrafenib monotherapy, including subgroups analyzed by age, BRAF
mutation genotype, tumor stage, LDH, and number of disease sites,” lead author Georgina V. Long, BSc, PhD, MBBS, clinical researcher at the Melanoma Institute Australia and Westmead Hospital in Sydney, said when the data were presented.
The median PFS was 11.0 months with the combination compared with 8.8 months for dabrafenib plus placebo (HR = 0.67; 95% CI, 0.53-0.84; P
<.001). The 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 arms; 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 (52% vs 25%). The incidence of cutaneous squamous cell carcinoma and keratoacanthoma was 9% with single-agent dabrafenib and 3% with the combination. Additionally, other skin-related AEs were lower with the combination.
“Grade 3 AEs occurred in 30% of patients in each arm,” said Long. “There was no predominant adverse event of grade 3 except pyrexia, which occurred in 7% of patients in the combination arm.”
In the second phase III trial used for the application, COMBI-v, 704 patients were randomized 1:1 to receive the combination of trametinib and dabrafenib (n = 352) or vemurafenib alone (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. Findings from the final analysis of the study were presented at the 2014 ESMO Annual Meeting.2
The median PFS with the combination was 11.4 versus 7.3 months with vemurafenib (HR = 0.56; P
<.001). The 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.