Elsevier

European Journal of Cancer

Volume 130, May 2020, Pages 126-138
European Journal of Cancer

Original Research
Survival of patients with advanced metastatic melanoma: The impact of MAP kinase pathway inhibition and immune checkpoint inhibition - Update 2019

https://doi.org/10.1016/j.ejca.2020.02.021Get rights and content

Highlights

  • An exploratory analysis was performed on 84 survival curves from 26 clinical trials in advanced metastatic melanoma.

  • In first-line, BRAF plus MEK inhibition was superior to PD-1 plus/minus CTLA-4 blockade within the first 12 months.

  • After 12 months, checkpoint blockers revealed superiority in the long-term survival.

  • In second-line or higher, BRAF plus MEK inhibition was superior to anti-PD-1 monotherapy throughout the first three years.

Abstract

Background

Recent therapeutic strategies, particularly MAP kinase pathway inhibitors (BRAF, MEK) and immune checkpoint blockers (CTLA-4, PD-1), have been put on the test for their differential impact on long-term survival of metastatic melanoma patients. Various agents, dose regimens and combinations have been tested against each other vigorously within these two therapy groups. However, results from prospective head-to-head comparative trials comparing both strategies against each other are still lacking.

Methods

We performed an exploratory analysis of survival data from selected clinical trials representative for these two treatment strategies in advanced metastatic melanoma. 84 Kaplan–Meier survival curves from 26 trials were digitised and grouped by therapy strategy and treatment line. For each of these groups, mean survival curves were generated for progression-free (PFS) and overall survival (OS) by weighted averaging.

Results

Survival curves grouped together by therapy strategy revealed a high concordance, with a larger extent in the first-line setting compared to higher treatment lines. In first-line therapy, the averaged 3-year OS proportions were 41.3% for BRAF plus MEK inhibition, 49.9% for PD-1 inhibition, and 58.4% for CTLA-4 plus PD-1 inhibition. Comparison of the mean PFS and OS curves of kinase inhibition and checkpoint blockade revealed a superiority of combined BRAF plus MEK inhibition within the first 12 months, later changing to a superiority of PD-1 blockers alone or in combination with CTLA-4 blockade. In second-line or higher, BRAF plus MEK inhibition was superior to anti-PD-1 monotherapy throughout the first three years; averaged 3-year OS proportions were 42.4% for BRAF plus MEK inhibition, and 40.1% for PD-1 inhibition.

Conclusions

and relevance: These results need confirmation by head-to-head comparative randomised clinical trials.

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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