Triple combinations of immunotherapy and targeted therapy in patients with melanoma with brain metastases
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PROVIDER: S-EPMC10113078 | biostudies-literature | 2023 Jan
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:Melanoma patients frequently develop brain metastases. The most widely used score to predict survival is the molGPA based on a mixed treatment of stereotactic radiotherapy (SRT) and whole brain radiotherapy (WBRT). In addition, systemic therapy was not considered. We therefore aimed to evaluate the performance of the molGPA score in patients homogeneously treated with SRT and concurrent targeted therapy or immunotherapy (TT/IT). METHODS:This retrospective analysis is based on an international multicenter database (TOaSTT) of melanoma patients treated with TT/IT and concurrent (?30?days) SRT for brain metastases between May 2011 and May 2018. Overall survival (OS) was studied using Kaplan-Meier survival curves and log-rank testing. Uni- and multivariate analysis was performed to analyze prognostic factors for OS. RESULTS:One hundred ten patients were analyzed. 61, 31 and 8% were treated with IT, TT and with a simultaneous combination, respectively. A median of two brain metastases were treated per patient. After a median follow-up of 8?months, median OS was 8.4?months (0-40?months). The molGPA score was not associated with OS. Instead, cumulative brain metastases volume, timing of metastases (syn- vs. metachronous) and systemic therapy with concurrent IT vs. TT influenced OS significantly. Based on these parameters, the VTS score (volume-timing-systemic therapy) was established that stratified patients into three groups with a median OS of 5.1, 18.9 and 34.5?months, respectively (p?=?0.001 and 0.03). CONCLUSION:The molGPA score was not useful for this cohort of melanoma patients undergoing local therapy for brain metastases taking into account systemic TT/IT. For these patients, we propose a prognostic VTS score, which needs to be validated prospectively.
| S-EPMC7268472 | biostudies-literature
Project description:Brain metastases (BM) continue to represent an unmet clinical need in oncology. Immunotherapy and targeted therapy hold great promise in the treatment of BM. Emerging data are confirming the activity of these agents in patients with BM. Genomic studies have confirmed that clinically actionable mutations are present in BM and they can be used in clinical studies to link targeted therapies with their genetic targets. Furthermore, as molecular signatures associated with sensitivity and resistance to immunotherapies are developed, we will better be able to select BM patients who will most benefit from these therapies. Understanding the genetic and immune evolution within BM should drive the next generation of immunotherapy and target therapy, as well as increase the accuracy of the selection process for these therapies.
| S-EPMC6020878 | biostudies-other
Project description:Brain metastases commonly develop in melanoma and are associated with poor overall survival of about five to nine months. Fortunately, new therapies, including immune checkpoint inhibitors and BRAF/MEK inhibitors, have been developed. The aim of this study was to identify outcomes of different treatment strategies in patients with melanoma brain metastases in the era of checkpoint inhibitors. Patients with brain metastases secondary to melanoma were identified at a single institution. Univariate and multivariable analyses were performed to identify baseline and treatment factors, which correlated with progression-free and overall survival. A total of 209 patients with melanoma brain metastases were identified. The median overall survival of the cohort was 5.3 months. On multivariable analysis, the presence of non-cranial metastatic disease, poor performance status (ECOG 2-4), whole-brain radiation therapy, and older age at diagnosis of brain metastasis were associated with poorer overall survival. Craniotomy (HR 0.66, 95% CI 0.45-0.97) and treatment with a CTLA-4 checkpoint inhibitor (HR 0.55, 95% CI 0.32-0.94) were the only interventions associated with improved overall survival. Further studies with novel agents are needed to extend lifespan in patients with brain metastases in melanoma.
| S-EPMC8037963 | biostudies-literature
Project description:Opinion statementBrain metastases are a major clinical challenge occurring in up to 60% of patients suffering from metastatic melanoma. They cause significant clinical symptoms and impair the overall survival prognosis. The introduction of targeted therapies including BRAF and MEK inhibitors as well as CTLA-4 and PD-1 axis targeting immune checkpoint inhibitors have dramatically improved the treatment and prognosis of patients with extracranial metastatic melanoma. Although, similar response rates for extra- and intracranial metastases have been reported, only few data from brain metastasis specific trails are available so far. The following review will provide an overview on the currently available data on targeted therapies, remaining questions and the most important side effects in the special clinical situation of melanoma brain metastases.
| S-EPMC5378732 | biostudies-literature
Project description: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.
| S-EPMC6061393 | biostudies-literature
Project description:Advances in systemic treatment and in brain imaging have led to a higher incidence of diagnosed brain metastases. In the treatment of brain metastases, stereotactic radiotherapy and radiosurgery, systemic immunotherapy, and targeted drug therapy are important evidence-based options. In this review, we summarize the available evidence on the treatment of brain metastases of the three main types of cancer that give rise to them: non-small-cell lung cancer, breast cancer, and malignant melanoma. This narrative review is based on pertinent original articles, meta-analyses, and systematic reviews that were retrieved by a selective search in PubMed. These publications were evaluated and discussed by an expert panel including radiation oncologists, neurosurgeons, and oncologists. There have not yet been any prospective randomized trials concerning the optimal combination of local stereotactic radiotherapy/radiosurgery and systemic immunotherapy or targeted therapy. Retrospective studies have consistently shown a benefit from early combined treatment with systemic therapy and (in particular) focal radiotherapy, compared to sequential treatment. Two metaanalyses of retrospective data from cohorts consisting mainly of patients with non-small-cell lung cancer and melanoma revealed longer overall survival after combined treatment with focal radiotherapy and checkpoint inhibitor therapy (rate of 12-month overall survival for combined versus non-combined treatment: 64.6% vs. 51.6%, p <0.001). In selected patients with small, asymptomatic brain metastases in non-critical locations, systemic therapy without focal radiotherapy can be considered, as long as follow-up with cranial magnetic resonance imaging can be performed at close intervals. Brain metastases should be treated by a multidisciplinary team, so that the optimal sequence of local and systemic therapies can be determined for each individual patient.
| S-EPMC8841640 | biostudies-literature
Project description:We investigated the value of O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET) PET for treatment monitoring of immune checkpoint inhibition (ICI) or targeted therapy (TT) alone or in combination with radiotherapy in patients with brain metastasis (BM) since contrast-enhanced MRI often remains inconclusive. Methods: We retrospectively identified 40 patients with 107 BMs secondary to melanoma (n = 29 with 75 BMs) or non-small cell lung cancer (n = 11 with 32 BMs) treated with ICI or TT who had 18F-FET PET (n = 60 scans) for treatment monitoring from 2015 to 2019. Most patients (n = 37; 92.5%) had radiotherapy during the course of the disease. In 27 patients, 18F-FET PET was used to differentiate treatment-related changes from BM relapse after ICI or TT. In 13 patients, 18F-FET PET was performed for response assessment to ICI or TT using baseline and follow-up scans (median time between scans, 4.2 mo). In all lesions, static and dynamic 18F-FET PET parameters were obtained (i.e., mean tumor-to-brain ratios [TBR], time-to-peak values). Diagnostic accuracies of PET parameters were evaluated by receiver-operating-characteristic analyses using the clinical follow-up or neuropathologic findings as a reference. Results: A TBR threshold of 1.95 differentiated BM relapse from treatment-related changes with an accuracy of 85% (P = 0.003). Metabolic responders to ICI or TT on 18F-FET PET had a significantly longer stable follow-up (threshold of TBR reduction relative to baseline, ≥10%; accuracy, 82%; P = 0.004). Furthermore, at follow-up, time to peak in metabolic responders increased significantly (P = 0.019). Conclusion: 18F-FET PET may add valuable information for treatment monitoring in BM patients treated with ICI or TT.
| S-EPMC8049362 | biostudies-literature
Project description:Melanoma is an aggressive malignancy with a deplorable penchant for spreading to the brain. While focal therapies such as surgery and stereotactic radiosurgery can help provide local control, the majority of patients still develop intracranial progression. Novel therapeutic combinations to improve outcomes for melanoma brain metastases (MBM) are clearly needed. Ipilimumab, the anticytotoxic T-lymphocyte-associated antigen 4 monoclonal antibody, has been shown to improve survival in patients with metastatic melanoma, but many of these trials either excluded or had very few patients with MBM. This article will review the efficacy and limitations of ipilimumab therapy for MBM, describe the current evidence for combining ipilimumab with radiation therapy, illustrate potential mechanisms for synergy, and discuss emerging clinical trials specifically investigating this combination in MBM.
| S-EPMC4578585 | biostudies-literature
Project description:Aim: Immune checkpoint inhibitor (ICI) efficacy is undefined for melanoma brain metastases (MBM) with concurrent corticosteroid exposure. Materials & methods: We retrospectively evaluated patients with untreated MBM who received corticosteroids (≥1.5 mg dexamethasone equivalent) within 30 days of ICI. mRECIST criteria and Kaplan-Meier methods defined intracranial progression-free survival (iPFS). The lesion size-response association was evaluated with repeated measures modeling. Results: A total of 109 MBM were evaluated. The patient level intracranial response rate was 41%. Median iPFS was 2.3 months and overall survival was 13.4 months. Larger lesions were more likely to progress, with diameter >2.05 cm most predictive of progression (OR: 18.9; 95% CI: 2.6-139.5; p = 0.004). There was no difference in iPFS with steroid exposure pre- versus post-ICI initiation. Conclusion: In the largest reported ICI+corticosteroid cohort, we identify size dependent MBM response.
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Project description: Not available
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