Original ResearchSurvival of patients with advanced metastatic melanoma: The impact of MAP kinase pathway inhibition and immune checkpoint inhibition - Update 2019
Graphical abstract
Introduction
Two major therapy strategies dominate the current treatment of metastatic melanoma: mitogen-activated protein kinase pathway inhibition (MAPKI) and immune checkpoint inhibition (ICI) [1]. Both treatment strategies have been demonstrated to significantly prolong the survival of patients with metastatic melanoma [2,3]. For MAPKI, selective inhibitors of BRAF and MEK were efficacious in BRAF V600-mutated melanoma as single agents, as well as in combination regimens. For ICI, blockers of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed-death-1 (PD-1) were effective in metastatic melanoma as single agents and in combination, respectively.
About 10 years ago, before the era of these two treatment strategies, melanoma patients with nonresectable metastatic disease had median survival times of 6–10 months with dacarbazine monochemotherapy as the therapeutic standard. Today, if patients have access to one of the two above described therapy strategies, median survival times are 24 months and longer. The 5-year overall survival rate of BRAF V600-mutated metastatic melanoma patients treated with the BRAF plus MEK inhibitor combination dabrafenib plus trametinib was shown to be 34% [4]. In comparison, metastatic melanoma patients treated with the PD-1 blocker nivolumab revealed a higher 5-year overall survival rate of 44%, and combined with the CTLA-4 blocker ipilimumab it reached even 52% [5].
For patients whose tumors harbor a BRAF V600 mutation, there is the choice between MAPKI or ICI therapy. Combined MAPKI of BRAF plus MEK has higher response rates than ICI; however, responses to checkpoint blockers appear to be more durable than those to MAPKI. For patients with BRAF V600-mutated melanoma, who are suitable for both therapy options, there are now evidence-based standard of care recommendations that ICI should be chosen as first-line therapy strategy: Patients for whom ICI therapy can be delivered safely for the first few months, i.e. patients whose tumors are not progressing quickly and are not immediately threatening an important organ function, should be considered for ICI first, preserving MAPKI for the subsequent lines [6].
However, in spite of these promising data resulting from various studies comparing different agents, combinations, and dosing regimens within each of both therapy strategies, we are still in the lack of data from randomised clinical trials comparing the two treatment strategies head-to-head. To overcome this currently unmet need, we analyzed publically available survival data from selected clinical trials representative for the new treatment strategies in advanced melanoma by digitization, weighted averaging, and comparison of the respective Kaplan–Meier survival curves [7,8]. Now we report an updated exploratory analysis with follow-up times of 36 months or longer in the first-line setting, allowing new insights into the effect of different treatment strategies on long-term survival.
Section snippets
Search strategy and selection criteria
We searched PubMed from Jan 1, 2002, to May 1, 2019, with the algorithm “metastatic melanoma [Title] AND (vemurafenib OR dabrafenib OR encorafenib OR trametinib OR cobimetinib OR binimetinib OR ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab) AND clinical trial NOT review.” We also sourced relevant articles referenced by other papers and abstracts from clinical meetings held in this time period. All publications were available as full-text papers or conference presentations. Clinical
Exploratory analysis of survival outcomes
A total of 44 Kaplan–Meier curves for PFS (21 for first-line therapy, 23 for second-line or higher), and 40 for OS (21 for first-line therapy, 19 for second-line or higher) were identified from full-text papers or conference presentations of 26 clinical trials selected by the above-mentioned criteria (Table 1 and Supplementary Table 1) [4,[12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37],
Discussion
In our first explorative comparison, we described and tested the methodology of digitizing and comparing publically available Kaplan–Meier survival curves from selected clinical trials in metastatic melanoma [7]. The finding of highly concordant survival curves within the different groups defined by the therapy strategy and treatment line confirmed the feasibility of this methodology. We then focused in particular on the two newer therapy strategies, MAPKI and ICI, and found that both treatment
Role of the funding source
No funding source to declare.
Ethics committee approval
Not applicable.
Authors’ contributions
Selma Ugurel: study design, literature search, figures, data analysis, data interpretation, writing.
Joachim Röhmel: figures, data analysis, data interpretation, writing.
Paolo A. Ascierto: literature search, data interpretation, writing.
Jürgen C. Becker: literature search, data interpretation, writing.
Keith T. Flaherty: literature search, data interpretation, writing.
Jean Jacques Grob: literature search, data interpretation, writing.
Axel Hauschild: literature search, data interpretation, writing.
Conflict of interest statement
Selma Ugurel: relevant financial activities (research support from Bristol Myers Squibb and Merck Serono; speakers and advisory board honoraria from Bristol Myers Squibb, Merck Sharp, and Dohme, Merck Serono, Novartis and Roche, and travel support from Bristol Myers Squibb, Merck Sharp, and Dohme).
Joachim Röhmel: none.
Paolo A. Ascierto: relevant financial activities (advisory board/consultant for Bristol Myers-Squibb, Roche-Genentech, Merck Sharp & Dohme, Array, Novartis, Merck Serono, Pierre
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