Indirect treatment comparison of dabrafenib plus trametinib versus vemurafenib plus cobimetinib in previously untreated metastatic melanoma patients

Abstract

BackgroundMetastatic melanoma is an aggressive form of skin cancer with a high mortality rate and the fastest growing global incidence rate of all malignancies. The introduction of BRAF/MEK inhibitor combinations has yielded significant increases in PFS and OS for melanoma. However, at present, no direct comparisons between different BRAF/MEK combinations have been conducted. In light of this, an indirect treatment comparison was performed between two BRAF/MEK inhibitor combination therapies for metastatic melanoma, dabrafenib plus trametinib and vemurafenib plus cobimetinib, in order to understand the relative efficacy and toxicity profiles of these therapies.MethodsA systematic literature search identified two randomized trials as suitable for indirect comparison: the coBRIM trial of vemurafenib plus cobimetinib versus vemurafenib and the COMBI-v trial of dabrafenib plus trametinib versus vemurafenib. The comparison followed the method of Bucher et al. and analyzed both efficacy (overall survival [OS], progression-free survival [PFS], and overall response rate [ORR]) and safety outcomes (adverse events [AEs]).ResultsThe indirect comparison revealed similar efficacy outcomes between both therapies, with no statistically significant difference between therapies for OS (hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.68 − 1.30), PFS (HR 1.05, 95% CI 0.79 − 1.40), or ORR (risk ratio [RR] 0.90, 95% CI 0.74 − 1.10). Dabrafenib plus trametinib differed significantly from vemurafenib plus cobimetinib with regard to the incidence of treatment-related AE (RR 0.92, 95% CI 0.87 − 0.97), any AE grade ≥3 (RR 0.71, 95% CI 0.60 − 0.85) or dose interruption/modification (RR 0.77, 95% CI 0.60 − 0.99). Several categories of AEs occurred significantly more frequently with vemurafenib plus cobimetinib, while some occurred significantly more frequently with dabrafenib plus trametinib. For severe AEs (grade 3 or above), four occurred significantly more frequently with vemurafenib plus cobimetinib and no severe AE occurred significantly more frequently with dabrafenib plus trametinib.ConclusionsThis indirect treatment comparison suggested that dabrafenib plus trametinib had comparable efficacy to vemurafenib plus cobimetinib but was associated with reduced adverse events.

Computational Study on the Effect of Inactivating/Activating Mutations on the Inhibition of MEK1 by Trametinib

“…Enhanced MEK activity can cause abnormal activation in the RAS-RAF-MEK-ERK pathway, which has been reported to be responsible for the pathogenesis of inflammation and approximately 30% of all human malignancies [4,5]. Thus, MEK has been the target of various drug discoveries [6][7][8][9][10][11][12][13][14], and inhibition of MEK activity may be used to treat MEK pathway activation-driven cancers.…”

BRAF and MEK Inhibitors Influence the Function of Reprogrammed T Cells: Consequences for Adoptive T-Cell Therapy

“…The strategy of combining BRAFi and MEKi with immunotherapy requires a better understanding of the effects of kinase inhibition on normal immune cell function. Although the two currently approved combinations of BRAFi and MEKi appear similarly effective against melanoma [ 28 ], their effects on healthy cells, not bearing BRAF mutations, but employing the respective signaling pathway, may significantly differ. BRAFi have for example a paradoxical effect on wild-type BRAF [ 29 ], which is more pronounced for Vem than for Dabra [ 30 ].…”

Quality‐of‐life outcomes in patients with advanced melanoma: A review of the literature

“…The opportunity for cross‐trial comparison is very interesting, but interpretation of results from an HRQoL perspective is challenging and should be done cautiously. For example, Daud, Gill, Kamra, Chen, and Ahuja () performed a comparison of efficacy and safety results between the COMBI‐v and coBRIM trials that showed a better safety profile for dabrafenib plus trametinib compared with vemurafenib plus cobimetinib, an observation that does not necessarily translate into a difference in HRQoL outcomes. The blinded or unblinded nature of a trial's design can also greatly impact the perception of benefit and thus comparisons between trials with open‐label and double‐blind designs should be interpreted cautiously.…”