A systematic review and network meta‐analysis of immunotherapy and targeted therapy for advanced melanoma

Lima, João Paulo da Silveira Nogueira; Georgieva, Mina; Haaland, Benjamin; Lopes, Gilberto

doi:10.1002/cam4.1001

Cited by 48 publications

(46 citation statements)

References 49 publications

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“…These T cells can mount an antigen-specific response (3), but during progression, they become ineffective due to a local immunosuppressive milieu (4). Immune-escape mechanisms in melanoma include activation of the PD-1/PD-L1 pathway, which can be bypassed by checkpoint inhibitors such as nivolumab and pembrolizumab (5). Target therapy with BRAF inhibitors (BRAFi) can also enhance melanoma immunogenicity.…”

Section: Introductionmentioning

confidence: 99%

Collapse of the Plasmacytoid Dendritic Cell Compartment in Advanced Cutaneous Melanomas by Components of the Tumor Cell Secretome

Vescovi

Monti

Moratto³

et al. 2019

Cancer Immunology Research

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Melanoma is an immunogenic neoplasm infiltrated by T cells, although these adaptive T cells usually fail to eradicate the tumor. Plasmacytoid dendritic cells (PDCs) are potent regulators of the adaptive immune response and can eliminate melanoma cells via TLR-mediated effector functions. The PDC compartment is maintained by progressively restricted bone marrow progenitors. Terminally differentiated PDCs exit the bone marrow into the circulation, then home to lymph nodes and inflamed peripheral tissues. Infiltration by PDCs is documented in various cancers. However, their role within the melanoma immune contexture is not completely known. We found that in locoregional primary cutaneous melanoma (PCM), PDC infiltration was heterogeneous, occurred early, and was recurrently localized at the invasive margin, the site where PDCs interact with CD8 þ T cells. A reduced PDC density was coupled with an increased Breslow thickness and somatic mutations at the NRAS p.Q61 codon. Compared with what was seen in PCM, high numbers of PDCs were found in regional lymph nodes, as also identified by in silico analysis. In contrast, in metastatic melanoma patients, PDCs were mostly absent in the tumor tissues and were significantly reduced in the circulation, particularly in the advanced M1c group. Exposure of circulating PDCs to melanoma cell supernatant (SN-mel) depleted of extracellular vesicles resulted in significant PDC death. SN-mel exposure also resulted in a defect of PDC differentiation from CD34 þ progenitors. These findings indicate that soluble components released by melanoma cells support the collapse of the PDC compartment, with clinical implications for refining TLR agonist-based trials.

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Section: Introductionmentioning

confidence: 99%

Collapse of the Plasmacytoid Dendritic Cell Compartment in Advanced Cutaneous Melanomas by Components of the Tumor Cell Secretome

Vescovi

Monti

Moratto³

et al. 2019

Cancer Immunology Research

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“…In the absence of head-to-head comparisons of dabrafenib-trametinib and most of the comparators, some authors have indirectly compared these drugs according to pharmacological class, and others have evaluated them individually. However, these comparisons do not independently and comprehensively cover all immunotherapies, such as nivolumab and pembrolizumab (Amdahl, Chen, & Delea, 2016;da Silveira et al, 2017;Devji et al, 2017;Zoratti, Devji, Levine, Thabane, & Xie, 2019). In relation to this, two approaches were used in this study because clinical guidelines consider nivolumab, nivolumab-ipilimumab, and pembrolizumab as therapeutic alternatives in the treatment of unresectable advanced/metastatic melanoma with and without BRAF-V600 mutation: one with a specific population with BRAF-V600 mutation and another with a population either with or without the mutation (National Comprehensive Cancer Network, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…Considering the use of immunotherapies (ipilimumab, nivolumab, nivolumab-ipilimumab, and pembrolizumab) for advanced/metastatic melanoma with or without BRAF-V600 mutation and targeted therapies (vemurafenib, dabrafenib, dabrafenib-trametinib, and vemurafenib -cobimetinib) for advanced/metastatic melanoma with BRAF-V600 mutation and since head-to-head studies of immunotherapies and targeted therapies have not been conducted (da Silveira, Georgieva, Haaland, & de Lima Lopes, 2017;Devji, Levine, Neupane, Beyene, & Xie, 2017), the present study aimed to evaluate and compare the clinical efficacy and safety of dabrafenib-trametinib with those of the currently available therapies in the treatment of patients with unresectable advanced/metastatic melanoma and BRAF-V600 mutation.…”

mentioning

confidence: 99%

Efficacy and safety of dabrafenib–trametinib in the treatment of unresectable advanced/metastatic melanoma with BRAF‐V600 mutation: A systematic review and network meta‐analysis

Garzón‐Orjuela

Prieto-Pinto

Lasalvia

et al. 2019

Dermatologic Therapy

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The current systematic review aimed to evaluate and compare the efficacy and safety of dabrafenib–trametinib with those of other therapeutic alternatives in the treatment of patients with unresectable advanced/metastatic melanoma with BRAF‐V600 mutation. The search was carried out on four databases up to July 2018. Two separate network meta‐analyses (NMA) were performed using the frequentist method (random effects): one with an exclusive population with BRAF‐V600 mutation (NMA‐pBRAFV600) and another with mixed population (with or without the mutation: NMA‐pMixed). An evidence profile was included using the GRADE method for NMA. The validity of the final estimator in the NMA‐pMixed was assessed via a sensitivity analysis. Nine clinical trials were included in the NMA‐pBRAFV600. Dabrafenib–trametinib was found to have a favorable effect on overall survival (OS) and progression‐free survival (PFS) compared with dabrafenib, vemurafenib, and dacarbazine and on partial response rate (PRR) and overall response rate compared with dacarbazine and vemurafenib. In the NMA‐pMixed, dabrafenib–trametinib was found to have a positive effect on OS versus ipilimumab 3 mg/kg and on PFS and PRR versus ipilimumab, nivolumab, and pembrolizumab. However, dabrafenib–trametinib and vemurafenib–cobimetinib significantly differed in terms of efficacy. In addition, dabrafenib–trametinib has a favorable effect on Grades 3 and 4 adverse events.

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“…One major mechanism of acquired BRAFi resistance is MAPK pathway activation by the mitogen-activated extracellular signal-regulated kinase (MEK), which may be overcome by selective MEK inhibitors (MEKi) [ 6 ]. Dual targeting of the MAPK signal pathway by a BRAFi/MEKi combination therapy demonstrated significantly improved overall and progression-free survival in patients with advanced BRAF-mutant melanoma compared to BRAFi monotherapy [ 7 ]. BRAFi/MEKi combination therapy is a first-line option in patients with BRAF-mutant metastatic melanoma (National Comprehensive Cancer Network Guidelines Version 1.2017, www.nccn.org ).…”

Section: Introductionmentioning

confidence: 99%

Integrin-targeted quantitative optoacoustic imaging with MRI correlation for monitoring a BRAF/MEK inhibitor combination therapy in a murine model of human melanoma

et al. 2018

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PurposeTo investigate αvβ3-integrin-targeted optoacoustic imaging and MRI for monitoring a BRAF/MEK inhibitor combination therapy in a murine model of human melanoma.Materials and methodsHuman BRAF V600E-positive melanoma xenograft (A375)-bearing Balb/c nude mice (n = 10) were imaged before (day 0) and after (day 7) a BRAF/MEK inhibitor combination therapy (encorafenib, 1.3 mg/kg/d; binimetinib, 0.6 mg/kg/d, n = 5) or placebo (n = 5), respectively. Optoacoustic imaging was performed on a preclinical system unenhanced and 5 h after i. v. injection of an αvβ3-integrin-targeted fluorescent probe. The αvβ3-integrin-specific tumor signal was derived by spectral unmixing. For morphology-based tumor response assessments, T2w MRI data sets were acquired on a clinical 3 Tesla scanner. The imaging results were validated by multiparametric immunohistochemistry (ß3 –integrin expression, CD31 –microvascular density, Ki-67 –proliferation).ResultsThe αvβ3-integrin-specific tumor signal was significantly reduced under therapy, showing a unidirectional decline in all animals (from 7.98±2.22 to 1.67±1.30; p = 0.043). No significant signal change was observed in the control group (from 6.60±6.51 to 3.67±1.93; p = 0.500). Immunohistochemistry revealed a significantly lower integrin expression (ß3: 0.20±0.02 vs. 0.39±0.05; p = 0.008) and microvascular density (CD31: 119±15 vs. 292±49; p = 0.008) in the therapy group. Tumor volumes increased with no significant intergroup difference (therapy: +107±42 mm3; control +112±44mm3, p = 0.841). In vivo blocking studies with αvβ3-integrin antagonist cilengitide confirmed the target specificity of the fluorescent probe.Conclusionsαvβ3-integrin-targeted optoacoustic imaging allowed for the early non-invasive monitoring of a BRAF/MEK inhibitor combination therapy in a murine model of human melanoma, adding molecular information on tumor receptor status to morphology-based tumor response criteria.

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A systematic review and network meta‐analysis of immunotherapy and targeted therapy for advanced melanoma

Cited by 48 publications

References 49 publications

Collapse of the Plasmacytoid Dendritic Cell Compartment in Advanced Cutaneous Melanomas by Components of the Tumor Cell Secretome

Collapse of the Plasmacytoid Dendritic Cell Compartment in Advanced Cutaneous Melanomas by Components of the Tumor Cell Secretome

Efficacy and safety of dabrafenib–trametinib in the treatment of unresectable advanced/metastatic melanoma with BRAF‐V600 mutation: A systematic review and network meta‐analysis

Integrin-targeted quantitative optoacoustic imaging with MRI correlation for monitoring a BRAF/MEK inhibitor combination therapy in a murine model of human melanoma

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