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Kunal Srivastava, Mayur M Amonkar, Amit Ahuja, Ceilidh Stapelkamp, Suzanne Swann, Michelle Casey and Cheena Rana
Objectives: A systematic literature review was undertaken with quantitative analysis, including meta-analysis and Bucher-adjusted indirect treatment comparisons (ITCs), to evaluate efficacy, safety, and tolerability of dabrafenib and trametinib monotherapy versus other first-line metastatic melanoma (MM) treatments.
Methods: Embase®, MEDLINE®, CCTR, and key conferences were searched through October 2012 for relevant randomized controlled trials. Using a random-effects network meta-analysis, dabrafenib and trametinib were compared directly versus dacarbazine (DTIC) and indirectly versus ipilimumab plus DTIC, temozolomide, and vemurafenib. A Rank Preserving Structural Failure Time Method was used to adjust overall survival (OS) estimates in studies that allowed treatment crossover upon progression.
Results: Forty-eight studies (147 publications) met the inclusion criteria; five (2462 patients) contributed to the meta-analysis. Both dabrafenib and trametinib showed a significant reduction in risk of progression directly versus DTIC and indirectly versus ipilimumab plus DTIC and temozolomide; comparable progression-free survival (PFS) indirectly versus vemurafenib; and lower risk of death directly versus DTIC and indirectly versus ipilimumab plus DTIC and vemurafenib (not significant). Dabrafenib demonstrated a significantly reduced risk of treatment discontinuations (due to any cause and to adverse events [AEs]), significantly fewer grade 3/4 AEs versus ipilimumab plus DTIC, and a significantly lower risk of grade 3/4 hematologic AEs (leukopenia, neutropenia, and thrombocytopenia) versus temozolomide. Dabrafenib showed significantly fewer dose interruptions/modifications (risk ratio [RR]=0.18; 95% CI=0.12–0.28; p<0.001) and a significantly lower incidence of photosensitivity (RR=0.05; 95% CI=0.01–0.19; p<0.001) versus vemurafenib.
Conclusions: ITCs of dabrafenib or trametinib in treatment-naïve MM patients showed significantly better PFS directly versus DTIC and indirectly versus ipilimumab plus DTIC and temozolomide, with efficacy comparable with that of vemurafenib. Dabrafenib showed important differences in tolerability and safety versus vemurafenib. Results require cautious interpretation given methodological assumptions and immature OS data for dabrafenib and trametinib. Head-to-head studies remain the gold standard for comparing treatments.