Resúmenes Epistemonikos
← vista completaPublicado el 27 de febrero de 2023 | http://doi.org/10.5867/medwave.2023.01.2666
Dabrafenib plus trametinib versus nivolumab for advanced melanoma
Dabrafenib más trametinib versus nivolumab para el tratamiento del melanoma avanzado
Abstract
Introduction The incidence of cutaneous melanoma has increased worldwide over the years, and an incidence of 3 cases per 100,000 men and women is estimated in Chile. Though most of the patients are diagnosed at an early stage of the disease and have a good prognosis, advanced melanoma has poor survival results. For the treatment of melanoma, the combination of dabrafenib plus trametinib has been demonstrated to improve the outcome versus dabrafenib alone, but only indirect evidence is available for its efficacy and safety compared with immunotherapy, like nivolumab. The aim of this study is to review the available evidence to report results of efficacy and safety of dabrafenib plus trametinib in comparison with nivolumab in metastatic melanoma.
Methods We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews selected, reanalyzed data of primary studies, and generated a summary of the findings table using the GRADE approach.
Results and conclusions We identified five systematic reviews, including seven studies overall that included one intervention of our interest, of which all were randomized trials. We only found indirect evidence comparing dabrafenib plus trametinib versus nivolumab that came from Network Meta-Analyses. We concluded that it is not possible to decide if dabrafenib plus trametinib is a better strategy for advanced melanoma treatment than nivolumab because the certainty of the evidence is very low for efficacy and safety outcomes.
Main messages
- It is not possible to conclude if dabrafenib plus trametinib versus nivolumab increases the overall survival because the certainty of the evidence is very low.
- It is not possible to conclude if dabrafenib plus trametinib versus nivolumab increase the progression-free survival because the certainty of the evidence is very low.
- It is not possible to conclude if nivolumab increases the response to the treatment and has less toxicity compared to dabrafenib plus trametinib because the certainty of the evidence is very low.
Problem
Melanoma is a type of cancer that develops in skin or mucosal cells as a result of a series of abnormalities in the genetic melanocyte pathway. The most common mutation in melanoma is on the BRAF gene promoting growth deregulation of melanocytes [1].
The incidence of cutaneous melanoma has increased worldwide over the years. In Chile, an incidence of 3 cases per 100,000 men and women has been estimated, which is lower than the worldwide incidence of 3.4 per 100,000 men and women [2]. The melanoma mortality in Chile is greater than mortality worldwide (0.96 in 100,000 versus 0.56 in 100,000) [2]. Whilst most patients are diagnosed at an early stage of the disease and with a good prognosis, patients with advanced melanoma (unresectable stage III and metastatic stage IV) have poor survival results [3].
Multiple innovative therapies are available for the treatment of advanced melanoma, like target therapies and checkpoint inhibitors. Target therapies are focused in BRAF mutation, which is the most common oncogene mutation in melanoma, occurring in 10-30% of these primary tumors [1]. Among the former, dabrafenib plus trametinib, a BRAF inhibitor combined with a MEK inhibitor, has been shown to improve survival and delay the disease progression when compared with dabrafenib alone [4,5]. Within checkpoint inhibitor, Nivolumab is an anti-PD-1, which has been shown to be an effective treatment for melanoma in monotherapy or combined with ipilimumab, a CTLA-4 inhibitor [6,7,8]. In Chile, Nivolumab is available in public health system, but the other therapies are not funded and are only available for out-of-pocket expenses.
There is no consensus about the best treatment for advanced melanoma. There are no published studies directly comparing the efficacy and safety of treatments with the combination of BRAF/MEK inhibitors versus PD-1 inhibitors. In this review, we show the results of different published network meta-analyses that included the combination of dabrafenib plus trametinib versus nivolumab to determine which treatment has better results in terms of efficacy and safety for patients with advanced melanoma.
Methods
We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others, to identify systematic reviews and their included primary studies. We extracted data from the identified reviews and reanalyzed data from primary studies included in those reviews. With this information, we generated a structured summary denominated FRISBEE (Friendly Summary of Body of Evidence using Epistemonikos), using a pre-established format, which includes key messages, a summary of the body of evidence (presented as an evidence matrix in Epistemonikos), a summary of findings table following the GRADE approach, and a table of other considerations for decision-making.
Summary of findings
The assessment of efficacy and safety of treatment with dabrafenib plus trametinib compared with nivolumab in patients with advanced melanoma is based on seven randomized trials [4,5,6,7,8,13,14]. Regarding these trials, five systematic reviews [3,9,10,11,12] performed an indirect comparison using network meta-analysis methods. Three [3,10,11] were bayesian analyses and two [9,12] were frequentist analyses.
Two studies (531 patients) [4,5] evaluated the combination of dabrafenib with trametinib against dabrafenib, one study (704 patients) [13] versus vemurafenib, and one study (120 patients) [14] against a triple combination: pembrolizumab plus dabrafenib plus trametinib.
One study (418 patients) [7] compared nivolumab versus dacarbazine. One study (405 patients) [8] evaluated nivolumab against chemotherapy (dacarbazine/carboplatin and paclitaxel/carboplatin). One study (901 patients) [6] compared the combination of nivolumab and ipilimumab versus nivolumab or ipilimumab alone.
Only three randomized trials [7],[18],[22] included patients from Chile, but is not possible to know their contribution to the intention-to-treat population of the studies.
Because of the structure of a network meta-analysis, no systematic review allowed for the data extraction to be used in a new meta-analysis, therefore, the outcomes were presented as a narrative synthesis. The summary of the results is as follows:
-
It is not possible to establish with clarity if the combination of dabrafenib and trametinib increases the overall survival in patients with advanced melanoma compared to nivolumab because the certainty of evidence has been evaluated as very low.
-
It is not possible to establish with clarity if the combination of dabrafenib and trametinib increases progression-free survival in patients with advanced melanoma compared to nivolumab because the certainty of evidence has been evaluated as very low.
-
It is not possible to establish with clarity if nivolumab increases the response to treatment in patients with advanced melanoma compared with dabrafenib plus trametinib because the certainty of evidence has been evaluated as very low.
-
It is not possible to establish with clarity if nivolumab is associated with fewer severe or grade III/IV adverse events in patients with advanced melanoma compared to dabrafenib plus trametinib because the certainty of evidence has been evaluated as very low.
-
We did not find studies that evaluated the quality of life in patients with advanced melanoma.
Other considerations for decision-making
To whom this evidence does and does not apply
The evidence in this summary applies to adults with advanced melanoma (non-resectable stage III and metastatic stage IV).
About the outcomes included in this summary
The outcomes included in this review are the most clinically relevant and most reported by the included systematic reviews.
The overall survival represents the risk of dying from any given cause and it is the most clinically relevant outcome in patients with advanced melanoma.
Both progression-free survival and the proportion of patients that respond to the treatment, are efficacy outcomes and drivers of clinical treatment decisions.
The adverse events to treatments are relevant because they impact directly the quality of life and treatment adherence.
Balance between benefits and risks, and certainty of the evidence
The combination of dabrafenib and trametinib has been demonstrated to be effective against vemurafenib or dabrafenib alone, and it has been demonstrated to be effective against chemotherapy. Nivolumab has also been demonstrated to be effective against chemotherapy. However, when comparing the two interventions, it is not possible to determine which treatment is better for advanced melanoma in terms of overall survival, disease-progression, response to treatment, and toxicity, because the certainty of the evidence is very low.
An increase in the certainty of the evidence for this recommendation could occur by the development of a study that evaluates the two interventions directly, because currently there is only indirect evidence published through network meta-analyses.
Resource considerations
One of the systematic reviews had results of cost-effectiveness. Pike et al [11] made a network meta-analysis and carried out a cost-effectiveness study of seven new drugs for the treatment of advanced melanoma, from the Norwegian health system perspective. The results of the aforementioned study showed that nivolumab could be the most cost-effective strategy among the available treatments for advanced melanoma in Norway, but exceeding the willingness-to-pay for this health system.
For this study, the main source of uncertainty was the limited information available for each treatment, and it could be improved if it would exist direct evidence for the evaluated comparators.
What would patients and their doctors think about this intervention
Currently, for the treatment of patients with advanced melanoma, most clinicians use immunotherapy with checkpoint inhibitors as a first option, due to its overall survival advantage and safety profile. For patients with BRAF mutation and a high burden of disease, or a rapidly progressing disease, most doctors prefer dabrafenib plus trametinib, due to its benefits in response rate, progression-free survival and overall survival.
Given the very low certainty of the evidence, it is unlikely that clinicians change their common practice with the results of this review, but it could shed some light on the effects and benefits of target therapies.
Differences between this summary and other sources
One systematic review [3] concluded that anti-PD-1/PD-L1 plus anti-CTLA-4 treatment is the best strategy to treat advanced melanoma regardless of its BRAF mutation status. Two systematic reviews [3],[9] concluded that dabrafenib plus trametinib could be the most effective alternative against advanced melanoma in patients with BRAF mutation. One systematic review [10] concluded that dabrafenib plus trametinib could have the most short-term efficacy among the combined alternatives. One systematic review [11] concluded that combined therapies have similar effectiveness to immunotherapy with PD-1 checkpoint inhibitors, and the last systematic review [12] concluded that immunotherapy, like nivolumab, has better acceptability than most target therapies in severe adverse events.
The results of the systematic reviews agree with the recommendation of international medical societies. The European Society for Medical Oncology (ESMO) [25] recommends PD-1 inhibitors, such as nivolumab, as a “standard of care” in first-line treatment against advanced melanoma, except in patients with BRAF mutations. For those patients, the ESMO recommends the treatment with BRAF/MEK inhibitors such as dabrafenib plus trametinib. This recommendation coincides with that of the National Comprehensive Cancer Network (NCCN) [26], asserting with their highest recommendation grade the use of checkpoint inhibitors as a first-line of treatment in advanced melanoma, and the use of target therapies (like BRAF/MEK) when patients have a BRAF V600 mutation.
All systematic reviews [3],[9],[10],[11],[12] included in this review declare the necessity of more evidence to make direct and indirect analyses, and to be able to increase the certainty of the evidence. This agrees with our results indicating that it is not possible to draw a conclusion because the certainty of the evidence is very low.
Could this evidence change in the future?
Owing to the uncertainty in the evidence, it is likely that the results of this review could change in the future due to the follow-up of current studies or because new studies may be available at some point.
Actually, five studies included in our review [4],[5],[6],[8],[13] have recently published updated results in clinical outcomes [27],[28],[29],[30],[31]. These updates were not included in the systematic reviews. Two of them [28],[29] were about nivolumab and the other three [29],[30],[31] were about dabrafenib plus trametinib.
Three studies [6],[7],[8] included in this review are currently active, and, thus, might contribute with new evidence in future.
We searched in PROSPERO for new systematics reviews. The search resulted in five new network meta-analysis [32],[33],[34],[35],[36] in development including our comparison of interest. The search in clinicaltrials.gov showed three studies of interest: one study in the stage of recruitment [37] including dabrafenib plus trametinib, and two studies in active stage but with no publications yet, one using nivolumab [38] and the other using a new treatment combination of nivolumab plus dabrafenib plus trametinib [39].
How we conducted this summary
Using automated and collaborative means, we compiled all the relevant evidence for the question of interest and presented it as a matrix of evidence.
Follow the link to access the interactive version (Figure 1):
The upper portion of the matrix of evidence will display a warning of “new evidence” if new systematic reviews are published after the publication of this summary. Even though the project considers the periodical update of these summaries, users are invited to comment in Medwave or to contact the authors through email if they find new evidence to update the summary, and the summary should be updated earlier.
After creating an account in Epistemonikos, users will be able to save matrices and receive automated notifications any time potentially relevant new evidence appears.
This article is part of the Epistemonikos Evidence Synthesis project. It was elaborated with a pre-established methodology, following rigorous methodological standards and an internal peer review process. Each of these articles corresponds to a summary, denominated FRISBEE (Friendly Summary of Body of Evidence using Epistemonikos), whose main objective is to synthesize the body of evidence for a specific question with a friendly format to clinical professionals. Its main resources are based on the evidence matrix of Epistemonikos and the analysis of results using GRADE methodology. Further details of the methods for developing this FRISBEE are described here (
Epistemonikos foundation is a non-profit organization aiming to bring information closer to health decision-makers with technology. Its main development is Epistemonikos database (
