OBJECTIVES:

There is a lack of comparative evidence of novel treatments for advanced melanoma. We synthesised effectiveness and safety evidence using a network meta-analysis (NMA).

METHODS:

A systematic literature review was performed in Embase, Medline, and Cochrane to retrieve effectiveness and safety evidence of randomised controlled phase-III trials (RCTs; time frame January 1, 2010 to March 1, 2017). Evidence on effectiveness (hazard ratio [HR] for progression-free survival [PFS]) and safety (relative risk [RR] for a grade ≥III adverse event [AE]) was synthesised by means of a Bayesian fixed-effect NMA. Reference treatment was dacarbazine. In accordance with RCTs, dacarbarzine was pooled with temozolomide, paclitaxel, and paclitaxel in combination with carboplatin.

RESULTS:

Out of 1,100 citations, 25 phase-III RCTs were identified. Twenty-one (seventeen) treatments could be included in the effectiveness (safety) NMA. Dabrafenib plus trametinib was identified as most effective treatment, both in terms of HR for PFS (0.21 [95%CrI: 0.17-0.27]) and probability of being the best treatment (PBB: 61% of the simulations). Vemurafenib plus cobimetinib followed as second-best (PBB: 39%; HR PFS: 0.22 [95%CrI: 0.17-0.29]) and dabrafenib as third option (HR PFS: 0.32 [95%CrI: 0.23-0.42]). In case of no BRAF-mutation, nivolumab plus ipilimumab ranked best (PBB: 97%; HR PFS: 0.37 [95%CrI: 0.27-0.49]), followed by nivolumab (HR PFS: 0.50 [95%CrI:0.40-0.62]) and pembrolizumab (HR PFS 3-weekly: 0.51 [95%CrI:0.36-0.71]). Prembolizumab was most favourable regarding safety (RR for AE 2-weekly [3-weekly]: 0.45 [0.59]; 95%CrI:0.25-0.72 [0.35-0.92]; PBB: 87% [11%]). Six treatments ranked better than dacarbazine, ten ranked lower. The four most effective treatments (HR for PFS) ranked lower than dacarbazine regarding safety.

CONCLUSIONS:

Until new evidence from RCTs becomes available, our study provides valuable insights into each novel treatment’s comparative effectiveness and safety. Dabrafenib plus trametinib seems the most effective treatment for advanced melanoma, closely followed by vemurafenib plus cobimetinib. Both treatments have, however, less favourable safety outcomes.