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      The impact of current treatment modalities on the outcomes of patients with melanoma brain metastases: A systematic review

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          Abstract

          Patients with melanoma brain metastases (MBM) still have a very poor prognosis. Several treatment modalities have been investigated in an attempt to improve the management of MBM. This review aimed to evaluate the impact of current treatments for MBM on patient‐ and tumor‐related outcomes, and to provide treatment recommendations for this patient population. A literature search in the databases PubMed, Embase, Web of Science and Cochrane was conducted up to January 8, 2019. Original articles published since 2010 describing patient‐ and tumor‐related outcomes of adult MBM patients treated with clearly defined systemic therapy were included. Information on basic trial demographics, treatment under investigation and outcomes (overall and progression‐free survival, local and distant control and toxicity) were extracted. We identified 96 eligible articles, comprising 95 studies. A large variety of treatment options for MBM were investigated, either used alone or as combined modality therapy. Combined modality therapy was investigated in 71% of the studies and resulted in increased survival and better distant/local control than monotherapy, especially with targeted therapy or immunotherapy. However, neurotoxic side‐effects also occurred more frequently. Timing appeared to be an important determinant, with the best results when radiotherapy was given before or during systemic therapy. Improved tumor control and prolonged survival can be achieved by combining radiotherapy with immunotherapy or targeted therapy. However, more randomized controlled trials or prospective studies are warranted to generate proper evidence that can be used to change the standard of care for patients with MBM.

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          Combined vemurafenib and cobimetinib in BRAF-mutated melanoma.

          The combined inhibition of BRAF and MEK is hypothesized to improve clinical outcomes in patients with melanoma by preventing or delaying the onset of resistance observed with BRAF inhibitors alone. This randomized phase 3 study evaluated the combination of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib. We randomly assigned 495 patients with previously untreated unresectable locally advanced or metastatic BRAF V600 mutation-positive melanoma to receive vemurafenib and cobimetinib (combination group) or vemurafenib and placebo (control group). The primary end point was investigator-assessed progression-free survival. The median progression-free survival was 9.9 months in the combination group and 6.2 months in the control group (hazard ratio for death or disease progression, 0.51; 95% confidence interval [CI], 0.39 to 0.68; P<0.001). The rate of complete or partial response in the combination group was 68%, as compared with 45% in the control group (P<0.001), including rates of complete response of 10% in the combination group and 4% in the control group. Progression-free survival as assessed by independent review was similar to investigator-assessed progression-free survival. Interim analyses of overall survival showed 9-month survival rates of 81% (95% CI, 75 to 87) in the combination group and 73% (95% CI, 65 to 80) in the control group. Vemurafenib and cobimetinib was associated with a nonsignificantly higher incidence of adverse events of grade 3 or higher, as compared with vemurafenib and placebo (65% vs. 59%), and there was no significant difference in the rate of study-drug discontinuation. The number of secondary cutaneous cancers decreased with the combination therapy. The addition of cobimetinib to vemurafenib was associated with a significant improvement in progression-free survival among patients with BRAF V600-mutated metastatic melanoma, at the cost of some increase in toxicity. (Funded by F. Hoffmann-La Roche/Genentech; coBRIM ClinicalTrials.gov number, NCT01689519.).
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            Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study

            Nivolumab monotherapy and combination nivolumab plus ipilimumab increase proportions of patients achieving a response and survival versus ipilimumab in patients with metastatic melanoma; however, efficacy in active brain metastases is unknown. We aimed to establish the efficacy and safety of nivolumab alone or in combination with ipilimumab in patients with active melanoma brain metastases.
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              Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial.

              Dabrafenib is an inhibitor of BRAF kinase that is selective for mutant BRAF. We aimed to assess its safety and tolerability and to establish a recommended phase 2 dose in patients with incurable solid tumours, especially those with melanoma and untreated, asymptomatic brain metastases. We undertook a phase 1 trial between May 27, 2009, and March 20, 2012, at eight study centres in Australia and the USA. Eligible patients had incurable solid tumours, were 18 years or older, and had adequate organ function. BRAF mutations were mandatory for inclusion later in the study because of an absence of activity in patients with wild-type BRAF. We used an accelerated dose titration method, with the first dose cohort receiving 12 mg dabrafenib daily in a 21-day cycle. Once doses had been established, we expanded the cohorts to include up to 20 patients. On the basis of initial data, we chose a recommended phase 2 dose. Efficacy at the recommended phase 2 dose was studied in patients with BRAF-mutant tumours, including those with non-Val600Glu mutations, in three cohorts: metastatic melanoma, melanoma with untreated brain metastases, and non-melanoma solid tumours. This study is registered with ClinicalTrials.gov, number NCT00880321. We enrolled 184 patients, of whom 156 had metastatic melanoma. The most common treatment-related adverse events of grade 2 or worse were cutaneous squamous-cell carcinoma (20 patients, 11%), fatigue (14, 8%), and pyrexia (11, 6%). Dose reductions were necessary in 13 (7%) patients. No deaths or discontinuations resulted from adverse events, and 140 (76%) patients had no treatment-related adverse events worse than grade 2. Doses were increased to 300 mg twice daily, with no maximum tolerated dose recorded. On the basis of safety, pharmacokinetic, and response data, we selected a recommended phase 2 dose of 150 mg twice daily. At the recommended phase 2 dose in 36 patients with Val600 BRAF-mutant melanoma, responses were reported in 25 (69%, 95% CI 51·9-83·7) and confirmed responses in 18 (50%, 32·9-67·1). 21 (78%, 57·7-91·4) of 27 patients with Val600Glu BRAF-mutant melanoma responded and 15 (56%, 35·3-74·5) had a confirmed response. In Val600 BRAF-mutant melanoma, responses were durable, with 17 patients (47%) on treatment for more than 6 months. Responses were recorded in patients with non-Val600Glu BRAF mutations. In patients with melanoma and untreated brain metastases, nine of ten patients had reductions in size of brain lesions. In 28 patients with BRAF-mutant non-melanoma solid tumours, apparent antitumour activity was noted in a gastrointestinal stromal tumour, papillary thyroid cancers, non-small-cell lung cancer, ovarian cancer, and colorectal cancer. Dabrafenib is safe in patients with solid tumours, and an active inhibitor of Val600-mutant BRAF with responses noted in patients with melanoma, brain metastases, and other solid tumours. GlaxoSmithKline. Copyright © 2012 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                h.w.kapiteijn@lumc.nl
                Journal
                Int J Cancer
                Int. J. Cancer
                10.1002/(ISSN)1097-0215
                IJC
                International Journal of Cancer
                John Wiley & Sons, Inc. (Hoboken, USA )
                0020-7136
                1097-0215
                23 November 2019
                15 March 2020
                : 146
                : 6 ( doiID: 10.1002/ijc.v146.6 )
                : 1479-1489
                Affiliations
                [ 1 ] Department of Medical Oncology Leiden University Medical Center Leiden The Netherlands
                [ 2 ] Department of Neurology Leiden University Medical Center Leiden The Netherlands
                [ 3 ] Department of Neurology Haaglanden Medical Center The Hague The Netherlands
                [ 4 ] Department of Radiation Oncology Leiden University Medical Center The Netherlands
                [ 5 ] Leiden University Medical Center, Department of Clinical Oncology Leiden The Netherlands
                Author notes
                [*] [* ] Correspondence to: Ellen H.W. Kapiteijn, Leiden University Medical Center, Department of Clinical Oncology, PO BOX 9600, 2300 RC Leiden, the Netherlands, Tel.: +31‐71‐526‐6760, Fax: +31‐71‐526‐3486, E‐mail: h.w.kapiteijn@ 123456lumc.nl
                Author information
                https://orcid.org/0000-0002-2400-4626
                Article
                IJC32696
                10.1002/ijc.32696
                7004107
                31583684
                5bd89a44-0182-41b7-b69e-843bfb341f4a
                © 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 16 July 2019
                : 30 August 2019
                : 11 September 2019
                Page count
                Figures: 4, Tables: 0, Pages: 11, Words: 8139
                Categories
                Mini Review
                Mini Review
                Custom metadata
                2.0
                15 March 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.5 mode:remove_FC converted:06.02.2020

                Oncology & Radiotherapy
                brain metastases,melanoma,treatment,outcome
                Oncology & Radiotherapy
                brain metastases, melanoma, treatment, outcome

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