The First Line Treatment of Advanced or Metastatic BRAF Mutant Melanoma: A Network Meta-analysis

Purpose: The treatments for advanced or metastatic BRAF mutant melanoma are ourish, but the most effective treatment is unclear. Here, we conducted a network meta-analysis (NMA) in unresectable stage III or advanced (or metastatic) stage IV BRAF mutant melanoma patients to estimate the ecacy of various rst line treatments. Methods: A comprehensive search for RCTs in PubMed and EMBASE was conducted to January 2021. Randomized control trials of unresectable stage III or advanced stage IV BRAF mutant melanoma were eligible if not receive previously treatment. By a Bayesian network meta-analysis, the effectiveness of each treatment was estimated and ranked based on the odds ratio (OR) for Object response rate (ORR) and hazard ratio (HR) for Overall survival (OS). Results: Eight trials enrolling 3272 patients were included. Combination dabrafenib and trametinib with pembrolizumab (HR: 0.37; 95% condence interval [CI]: 0.21-0.66; compared with dacarbazine) ranked as the best effective treatment for OS. Conclusion: Combination pembrolizumab with trametinib and dabrafenib and combination atezolizumab with trametinib and dabrafenib appear more effective as rst line treatments for unresectable stage III or advanced (or metastatic) stage IV BRAF mutant melanoma patients. Whereas, further RCTs are needed to complete the network.


Introduction
Approximate 40% to 60% of cutaneous melanoma patients carry BRAF mutation, which could constitutively activate the downstream signaling through the MAP kinase pathway and increase melanoma cells proliferation and survival. [1,2] A latest randomized control trial (RCT) indicates a landmark OS rate of 34% after 5years by targeting this signaling pathway. [3] Combination BRAF and MEK inhibitors could increase melanoma antigens and involve in transporting CD8+ and CD4+ cells to melanoma. [4][5][6][7] Although this combination therapy leads to a considerable cancer response of 75% in BRAF mutant melanoma patients,[8] most responses are short-lived. [9] Furthermore, patients quickly acquired resistance to it and resulted in relapse within months. [10][11][12] A three-year pooled analysis indicated that at least 70% of patients experienced relapse or metastasis within the rst 3 years of therapy. [13] Interestingly, we found an increased expression of PD-1 and PD-L1 in advanced or metastatic BRAF mutant melanoma patients who accept the treatment of BRAF inhibitors. [4] And anti-PD-1 immune checkpoint The Risk of bias The assessment of the risk of bias was conducted by Mr. Yang and Mrs. Zhong with the Cochrane Risk of bias tool. [30] All RCTs were assessed by three grades: high risk, unclear risk, or low risk. The extraction of data was carried out by Mr. Yang and Mrs. Zhong and independently veri ed by Mrs. Wu.

Statistical analysis
we conducted this NMA with R (R Project for Statistical Computing; version 3.6.2; gemtc package). [31] The OR and 95% CIs were used to estimate ORR. The HR and 95% CIs were used to estimate OS. For any comparison, an OR for ORR bigger than 1 or an HR for OS smaller than 1 means that the treatment was more effective. The heterogeneity between the comparisons was estimated by the I-squared statistic.
DIC was used for model selection. The chain of model was three. The adaptation was 10000 and model iteration was 100000. Edge-splitting was used for the evaluation of inconsistency. Additionally, we ranked all outcomes by the probability.

Ranking
Ranking analysis for ORR performed with SUCRA suggested that combination atezolizumab with cobimetinib and vemurafenib had the highest probability to rank at the rst place for ORR (0.59), combination vemurafenib and cobimetinib ranked at the second place for ORR (0.57), combination dabrafenib and trametinib ranked at the third place for ORR (0.72), combination pembrolizumab with trametinib and dabrafenib ranked at the fourth place for ORR (0.39) ( gure 2). Ranking analysis for OS performed with SUCRA suggested that combination pembrolizumab with trametinib and dabrafenib had the highest probability to rank at the rst place for OS (0.78), combination atezolizumab with cobimetinib and vemurafenib ranked at the second place for OS (0.54), combination vemurafenib and cobimetinib ranked at the third place for OS (0.45), combination dabrafenib and trametinib ranked at the fourth place for OS (0.47) ( gure 3).

Discussion
In the constant upgrading process of the treatment regimens for unresected stage III or metastatic stage IV BRAF mutant melanoma patients, monotherapy, due to high drug resistance, gradually replaced by double combination therapy. [41] And the combination MEK inhibitors and BRAF inhibitors appears to be the best treatment for BRAF V600 mutant melanoma patients. [42] Then, a previous network meta-analysis including an update to November 2018 of treatments for these special melanoma patients compared various double combination therapy and monotherapy. [43] That NMA showed that combination dabrafenib with trametinib seemed to be the best treatment for PFS while combination nivolumab with ipilimumab seemed to be the best treatment for OS. That NMA also showed that dacarbazine monotherapy seemed to be the worst treatment of these treatments, which was the same as ours.
Interestingly, we found an increased expression of PD-1 and PD-L1 in advanced or metastatic BRAF mutant melanoma patients who accept the treatment of BRAF inhibitors. [4] Pembrolizumab, as an anti-PD-1 immune checkpoint inhibitor, rstly estimated in KEYNOTE-001. [44] Until 2019, these data con rmed its durable antitumor activity in advanced melanoma. [45] In the second course of the phase III KEYNOTE-006,[46] the estimated 5-year survival outcome showed that pembrolizumab was more effective than ipilimumab in advanced and ipilimumab-naive melanoma patients. Atezolizumab, as an anti-PD-L1 immune checkpoint inhibitor, was originally used to cure lung and breast cancer patients alone or combined with other treatments. Then, atezolizumab monotherapy showed an ORR of 30% in advanced melanoma. [47] Immune checkpoint inhibitors provide more durable responses but their response rates are relatively lower. [24] Therefore, a triple combination therapy of MEK inhibitors, BRAF inhibitors and anti-PD-1 or anti-PD-L1 immune checkpoint inhibitors need to be conducted. [25,26] The rst triple combination therapy was conducted in KEYNOTE-022 trials (combination pembrolizumab with dabrafenib and trametinib), which showed that the triple combination therapy was more effective than combination MEK inhibitors and BRAF inhibitors, though it has a higher rate of adverse events.
[28] IMspire150 trials found that triple combination therapy (combination atezolizumab with cobimetinib and vemurafenib) was tolerable and safe, and vitally induced a better result of progression-free survival (PFS) in BRAF mutant melanoma patients. [27] Despite the overall survival in IMspire150 trials was not reached, the curves of overall survival began to separate indicated that the triple combination therapy was more effective which was the same as the delayed separation in KEYNOTE-022 trials.
Unlike previous NMA, our NMA included triple combination therapies like combination atezolizumab with cobimetinib and vemurafenib and combination pembrolizumab with trametinib and dabrafenib. [27,28,32] The two trials evaluated combination immune checkpoint therapy with MEK inhibitors and BRAF inhibitors in advanced or metastatic BRAF mutant melanomas. This NMA contained 8 phase 2 or 3 RCTs, with 3272 patients, and estimated the effectiveness of various rst-line treatments for unresected stage III or metastatic stage IV melanoma patients (table 1). Additionally, our NMA carried out a complete search on PubMed and EMBASE updated to January 2021 with a low risk of bias. The results showed that combination atezolizumab with cobimetinib and vemurafenib was associated with the best ORR. Though not the best, combination pembrolizumab with trametinib and dabrafenib still showed considerable effectiveness for ORR. Combination pembrolizumab with trametinib and dabrafenib was associated with the best OS, and combination atezolizumab with cobimetinib and vemurafenib was the second for OS. According to the result of ORR and OS, these two combination treatments were likely to rank as the most appropriate treatments for unresected stage III or metastatic stage IV BRAF mutant melanoma patients.

Limitations
Although this NMA had no heterogeneity and absent inconsistency, it stills had limitations. First, the same as previous NMA, [43] ICIs may be used in indolent melanoma patients, which limited the universality of our outcomes in all BRAF mutant patients. Second, our NMA for OS was based on HR and its CI, without consideration of survival curves, which need further research to perfect the results.

Declarations
Funding: This work was supported by grants from the National Natural Science Foundation of Liaoning Province (NO. 20180530081 to Chunli Wu) and Young and middle-aged scienti c and technological talents support program of Shenyang City (NO. RC200554 to Chunli Wu).

Con ict of Interest Disclosures:
The authors declare that they have no con ict of interest.
Availability of data and material: Mr. Yang had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Yang.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Yang.
Critical revision of the manuscript for important intellectual content: Yang, Zhong, Wen.
References Figure 1 Network of evidence for objective response rate and overall survival Ranking analysis for objective response rate Ranking analysis for overall survival

Supplementary Files
This is a list of supplementary les associated with this preprint. Click to download. PRISMA2009ChecklistMSWord.doc PRISMA2009FlowDiagramMSWord.doc