ReviewSurvival of patients with advanced metastatic melanoma: The impact of novel therapies
Introduction
Systemic treatment of advanced metastatic melanoma has been an unmet medical need for decades. Chemotherapy with dacarbazine or other cytotoxic drugs resulted in median survival times of 7–9 months and no therapeutic regimen, either other chemotherapeutic agents, biochemotherapy, or immunotherapy proved to be superior to dacarbazine in terms of survival [1]. In these times, long-term survival of 5 years and more was only achieved in 5–10% of patients regardless of the specific therapy strategy used.
Recently, during the last few years, the treatment of metastatic melanoma has been rapidly evolving. Approximately 40–50% of metastatic cutaneous melanomas harbour a BRAF V600 mutation, constitutively activating the mitogen-activated protein kinase (MAPK) pathway [2]. The BRAF inhibitors vemurafenib and dabrafenib were developed to specifically target this driver mutation and further similar compounds like encorafenib are still under study [3], [4]. Another target is the signalling molecule MEK downstream of BRAF, and its blockade can likewise inactivate the MAPK pathway [5]. Both, BRAF and MEK inhibitors showed superior activity in BRAF V600-mutated melanoma in comparison to dacarbazine, and led to a significantly increased progression-free (PFS) and overall survival (OS) in the respective patients. Even more efficacious is the combined inhibition of both targets, BRAF and MEK, and thus a simultaneous application of vemurafenib plus cobimetinib or dabrafenib plus trametinib led to a further prolongation of PFS and OS [6], [7], [8], [9].
New immunotherapeutic approaches for metastatic melanoma are another promising approach, which developed simultaneously and in parallel to MAPK pathway inhibitors, resulting in two separate novel treatment strategies. Presently, targeting immune checkpoints, which normally terminate immune responses after antigen activation, is a main focus in the treatment of advanced melanoma. Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is an immunomodulatory molecule that down-regulates T-cell-activation. Ipilimumab, a fully human monoclonal antibody that blocks CTLA-4 was the first successfully developed drug of a new class of therapeutics named immune checkpoint inhibitors. Long-term survival of up to 20% of treated patients has been reported with ipilimumab [10], [11], [12]. Programmed-death-1 (PD1) is another immune checkpoint target expressed on activated T-cells mediating immunosuppression. Its ligands PD-L1 (B7-H8) and PD-L2 (B7-DC) are expressed on many tumour cells, stroma cells and other cell types including leucocytes. The immunosuppressive action of the PD1 receptor is activated in the effector phase of the interaction between T lymphocytes and tumour cells, and the blockade of this receptor seems to be more effective towards T-cell-activation than CTLA-4 blockade. Nivolumab (BMS-936558) is a fully human IgG4 monoclonal antibody directed against PD1. Pembrolizumab (MK-3475) is a selective, humanised monoclonal IgG4-kappa anti-PD1 antibody. The efficacy of both agents was studied in advanced melanoma and other solid tumours [13], [14], [15]. Other PD-1 and PD-L1 inhibitors are also under evaluation.
With regard to these new developments in the treatment of advanced melanoma, only few of these therapies have yet been compared to one another, and trials have not yet been conducted to evaluate the optimal sequence of therapies with rigorous, randomised designs. For BRAF-mutant patients, multiple therapy strategies with documented survival improvement exist from which to choose. However, there are no clear data as to which regimen should be administered in the first, second, or even third line, or whether there are patient characteristics or biomarkers helpful for treatment selection.
This work analyses selected clinical trials representative for the new treatment strategies in advanced melanoma and compares their survival outcome by digitisation of published Kaplan–Meier survival curves. Only prospective trials with similar inclusion and exclusion criteria were included. Compassionate use programmes were excluded. Data analysis is exploratory, does not include statistical testing, and comparisons are descriptive only. We intended to support current clinical decision-making in the individualised treatment of advanced metastatic melanoma while awaiting the conduct of definitive trials aimed at comparing individual and sequential treatment strategies.
Section snippets
Search strategy and selection criteria
We searched PubMed from 1st January 2002 to 1st June 2015, with the algorithm “melanoma [Title] AND (vemurafenib OR PLX4032 OR dabrafenib OR GSK-2118436 OR LGX818 OR trametinib OR GSK-1120212 OR cobimetinib OR GDC-0973 OR ipilimumab OR MDX-010 OR tremelimumab OR CP-675,206 OR nivolumab OR MDX-1106 OR pembrolizumab OR MK-3475) AND clinical trial NOT review”, and with the algorithm “(BRAF [ti] OR NRAS [ti]) AND melanoma [ti] AND survival”, respectively. We also sourced relevant articles
Explorative analysis of survival outcomes
Thirty-five Kaplan–Meier curves for either PFS or OS or both were available from the publications of 17 clinical trials selected by the above mentioned criteria (Table 1 and Supplementary Table 1) [3], [4], [6], [7], [8], [9], [11], [12], [14], [15], [18], [19], [20], [21], [22], [23], [24], [25], [26]. After digitisation, the survival curves were newly grouped and displayed by treatment line (first-line versus second or later lines) and therapy strategy (chemotherapy, single-agent BRAF
Discussion
A tremendous improvement in the survival of advanced metastatic melanoma patients has been achieved by the recently developed therapy strategies of kinase inhibitors as well as immune checkpoint blockers. In this regard, combination regimens of BRAF and MEK inhibitors proved to be superior to single-agent regimens with BRAF inhibitors. Within the group of immune checkpoint blockers, the first head-to-head comparative trials (KEYNOTE-006; CheckMate-067) demonstrated the PD-1 inhibitors to
Authors' contributions
Selma Ugurel: literature search, figures, data analysis, data interpretation, writing.
Joachim Röhmel: figures, data analysis, data interpretation, writing.
Paolo A. Ascierto: data interpretation, writing.
Keith T. Flaherty: data interpretation, writing.
Jean Jacques Grob: data interpretation, writing.
Axel Hauschild: data interpretation, writing.
James Larkin: data interpretation, writing.
Georgina V. Long: data interpretation, writing.
Paul Lorigan: data interpretation, writing.
Grant A. McArthur:
Conflict of interest statement
Selma Ugurel: relevant financial activities (Medac, BMS, Merck, Roche).
Joachim Röhmel: none.
Paolo A. Ascierto: relevant financial activities (BMS, Roche, Merck, Ventana, Amgen, Novartis).
Keith T. Flaherty: relevant financial activities (BMS, Merck, Novartis, Roche).
Jean Jacques Grob: relevant financial activities (BMS, Merck, Novartis, Roche).
Axel Hauschild: relevant financial activities (Amgen, BMS, Celgene, Eisai, GSK, MedImmune, Mela Sciences, Merck, Novartis, OncoSec, Roche).
James Larkin:
Role of the funding source
No funding source to declare.
Ethics committee approval
Not applicable.
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