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Melanoma Brain Metastases: Local Therapies, Targeted Therapies, Immune Checkpoint Inhibitors and Their Combinations-Chances and Challenges.

ABSTRACT: Recent phase II trials have shown that BRAF/MEK inhibitors and immune checkpoint inhibitors are active in patients with melanoma brain metastases (MBM), reporting intracranial disease control rates of 50-75%. Furthermore, retrospective analyses suggest that combining stereotactic radiosurgery with immune checkpoint inhibitors or BRAF/MEK inhibitors prolongs overall survival. These data stress the need for inter- and multidisciplinary cooperation that takes into account the individual prognostic factors in order to establish the best treatment for each patient. Although the management of MBM has dramatically improved, a substantial number of patients still progress and die from brain metastases. Therefore, there is an urgent need for prospective studies in patients with MBM that focus on treatment combinations and sequences, new treatment strategies, and biomarkers of treatment response. Moreover, further research is needed to decipher brain-specific mechanisms of therapy resistance.

SUBMITTER: Kuske M

PROVIDER: S-EPMC6061393 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Melanoma Brain Metastases: Local Therapies, Targeted Therapies, Immune Checkpoint Inhibitors and Their Combinations-Chances and Challenges.

Kuske Marvin M Rauschenberg Ricarda R Garzarolli Marlene M Meredyth-Stewart Michelle M Beissert Stefan S Troost Esther G C EGC Glitza Oliva Isabella Claudia OIC Meier Friedegund F

American journal of clinical dermatology 20180801 4

Recent phase II trials have shown that BRAF/MEK inhibitors and immune checkpoint inhibitors are active in patients with melanoma brain metastases (MBM), reporting intracranial disease control rates of 50-75%. Furthermore, retrospective analyses suggest that combining stereotactic radiosurgery with immune checkpoint inhibitors or BRAF/MEK inhibitors prolongs overall survival. These data stress the need for inter- and multidisciplinary cooperation that takes into account the individual prognostic ...[more]

PMID: 29417399

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Project description:BackgroundThe development of brain metastases is common for systemic treatment failure in patients with melanoma and has been associated with a poor prognosis. Recent advances with BRAF and immune checkpoint therapies have led to improved patient survival. Herein, the authors evaluated the risk of de novo brain metastases and survival among patients with melanoma brain metastases (MBM) since the introduction of more effective therapies.MethodsPatients with unresectable AJCC stage III/IV melanoma who received first-line systemic therapy at Moffitt Cancer Center between 2000 and 2012 were identified. Data were collected regarding patient characteristics, stage of disease, systemic therapies, MBM status/management, and overall survival (OS). The risk of de novo MBM was calculated using a generalized estimating equation model and survival comparisons were performed using Kaplan-Meier and Cox proportional analyses.ResultsA total of 610 patients were included, 243 of whom were diagnosed with MBM (40%). Patients with MBM were younger, with a lower frequency of regional metastasis. No significant differences were noted with regard to sex, BRAF status, or therapeutic class. The risk of de novo MBM was found to be similar among patients treated with chemotherapy, biochemotherapy, BRAF-targeted therapy, ipilimumab, and anti-programmed cell death protein 1/programmed death-ligand 1 regimens. The median OS of patients with MBM was significantly shorter when determined from the time of first regional/distant metastasis but not when determined from the time of first systemic therapy. The median OS from the time of MBM diagnosis was 7.5 months, 8.5 months, and 22.7 months, respectively, for patients diagnosed from 2000 to 2008, 2009 to 2010, and 2011 to the time of last follow-up (P = .002).ConclusionsBrain metastases remain a common source of systemic treatment failure. The OS for patients with MBM has improved significantly. Further research into MBM prevention is needed. Cancer 2018;124:297-305. © 2017 American Cancer Society.

Project description:Background: Multiple immune checkpoint inhibitors (ICIs) and targeted therapies have been widely used as adjuvant treatments for high-risk resected melanoma, with unclear comparative efficacy and safety. Methods: PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov were searched from database inception until 6 June 2023. We included RCTs that assess adjuvant ICIs or targeted therapies in high-risk resected melanoma. Frequentist random-effect network meta-analyses (NMA) were performed. The primary outcome was recurrence-free survival (RFS). Results: Eleven trials including 10,712 patients and comparing 10 treatments (nivolumab [Nivo], ipilimumab 3 mg/kg [Ipi3], Ipi10, pembrolizumab [Pemb], vemurafenib [Vemu], bevacizumab [Beva], Nivo + Ipi1, Nivo + Ipi3, dabrafenib plus trametinib [Dab + Tram], and placebo/observation [Pla/Obs]) were included. NMA showed that all treatments showed RFS benefit over placebo/observation except Ipi3 (hazard ratio [HR], 0.78; 95% CI, 0.58-1.05). Combination therapy of Nivo + Ipi3 was the most effective treatment, which significantly improved RFS compared with other treatments. NMA also showed that all treatments were associated with an increased risk of grade 3-5 adverse events over placebo/observation except Nivo (HR, 1.25; 95% CI, 0.87-1.80). NMA suggested that Nivo and Pemb were the two safest treatments except for placebo/observation. Although three combination therapies ranked as the top three in terms of RFS, they did not show significant overall survival benefits compared to monotherapies including Pemb, Nivo, Ipi3, and Ipi10. Conclusion: In this NMA, adjuvant Nivo and Pemb are the preferred options in patients with resected melanoma considering the benefits and harms. Combination therapy of Nivo + Ipi3 may be a promising strategy, but more evidence from phase 3 trials is needed. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=438667, PROSPERO (CRD42023438667).

Dataset Information

Melanoma Brain Metastases: Local Therapies, Targeted Therapies, Immune Checkpoint Inhibitors and Their Combinations-Chances and Challenges.

Publications

Melanoma Brain Metastases: Local Therapies, Targeted Therapies, Immune Checkpoint Inhibitors and Their Combinations-Chances and Challenges.

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