Melanoma Brain Metastases in the Era of Targeted Therapy and Checkpoint Inhibitor Therapy.
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ABSTRACT:
SUBMITTER: Rieth JM
PROVIDER: S-EPMC8037963 | biostudies-literature |
REPOSITORIES: biostudies-literature
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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.
| S-EPMC7771556 | biostudies-literature
Project description:In the current era of molecularly targeted therapies and precision medicine, choice of cancer treatment has been increasingly tailored according to the molecular or genomic characterization of the cancer the individual has. Previously, the clinical observation of inadequate control of brain metastases was widely attributed to a lack of central nervous system (CNS) penetration of the anticancer drugs. However, more recent data have suggested that there are genetic explanations for such observations. Genomic analyses of brain metastases and matching primary tumor and other extracranial metastases have revealed that brain metastases can harbor potentially actionable driver mutations that are unique to them. Identification of genomic alterations specific to brain metastases and targeted therapies against these mutations represent an important research area to potentially improve survival outcomes for patients who develop brain metastases. Novel approaches in genomic testing such as that using cell-free circulating tumor DNA (ctDNA) in the cerebrospinal fluid (CSF) facilitate advancing our understanding of the genomics of brain metastases, which is critical for precision medicine. CSF-derived ctDNA sequencing may be particularly useful in patients who are unfit for surgical resection or have multiple brain metastases, which can harbor mutations that are distinct from their primary tumors. Compared to the traditional chemotherapeutics, novel targeted agents appear to be more effective in controlling the CNS disease with better safety profiles. Several brain metastases-dedicated trials of various targeted therapies are currently underway to address the role of these agents in the treatment of CNS disease. This review focuses on recent advances in genomic profiling of brain metastases and current knowledge of targeted therapies in the management of brain metastases from cancers of the breast, lung, colorectum, kidneys, and ovaries as well as melanoma.
| S-EPMC5622141 | 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:Targeted therapies (TT) and immune checkpoint inhibitors (ICI) have become increasingly important in the treatment of metastatic malignant melanoma in recent years. We examined implementation and effectiveness of these new therapies over time in Germany with a focus on regional differences. We analyzed data from 12 clinical cancer registries in 8 federal states in Germany over the period 2000-2016. A total of 3871 patients with malignant melanoma in Union internationale contre le cancer (UICC) stage IV at primary diagnosis (synchronous metastases) or with metachronous metastases were included. We investigated differences in survival of patients treated with new and conventional therapies by log-rank tests for Kaplan-Meier curves. Cox regression models were estimated to adjust therapy effects for demographic, regional, and prognostic factors. New systemic therapies were increasingly applied throughout Germany. TT were most frequently documented in Eastern Germany (East: 11.2%; West: 6.3%), whereas ICI therapies were more frequently used in Western Germany (East: 1.7%; West: 3.9%). TT had a relevant influence on patient survival (hazard ratio (HR) = 0.831; 95%-CI = (0.729; 0.948)). Survival was worse in Eastern Germany (HR = 1.470; 95%-CI = (1.347; 1.604)) relative to Western Germany. Treatment and survival prospects of patients with melanoma differed considerably between Western and Eastern Germany. The differences in regional medication behavior and survival require further exploration.
| S-EPMC7565277 | 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:Malignant melanoma is the third most common type of tumor that causes brain metastases. Patients with cerebral involvement have a dismal prognosis and their treatment is an unmet medical need. Brain involvement is a multistep process involving several signaling pathways such as Janus kinase/signal Transducer and Activator of Transcription (JAK/STAT), Phosphoinositide 3-kinase/Protein Kinase B (PI3K/AKT), Vascular Endothelial Growth Factor and Phosphatase and Tensin Homolog (PTEN). Recently therapy that targets the MAPK signaling (BRAF/MEK inhibitors) and immunotherapy (anti-CTLA4 and anti-PD1 agents) have changed the therapeutic approaches to stage IV melanoma. In contrast, there are no solid data about patients with brain metastases, who are usually excluded from clinical trials. Retrospective data showed that BRAF-inhibitors, alone or in combination with MEK-inhibitors have interesting clinical activity in this setting. Prospective data about the combinations of BRAF/MEK inhibitors have been recently published, showing an improved overall response rate. Short intracranial disease control is still a challenge. Several attempts have been made in order to improve it with combinations between local and systemic therapies. Immunotherapy approaches seem to retain promising activity in the treatment of melanoma brain metastasis as showed by the results of clinical trials investigating the combination of anti-CTL4 (Ipilimumab) and anti-PD1(Nivolumab). Studies about the combination or the sequential approach of target therapy and immunotherapy are ongoing, with immature results. Several clinical trials are ongoing trying to explore new approaches in order to overcome tumor resistance. At this moment the correct therapeutic choices for melanoma with intracranial involvement is still a challenge and new strategies are needed.
| S-EPMC7352598 | biostudies-literature
Project description:The successes of checkpoint blockade immunotherapy (CBI) and BRAFV600-targeted therapy trials have generated substantial promise for revolutionizing the management of patients with advanced melanoma. However, because early clinical trials of CBIs and BRAFV600-targeted therapy either excluded or included disproportionately fewer cases of melanoma brain metastases (MBMs), the survival benefit of these novel therapies for MBM remains unknown. We, therefore, evaluated the characteristics, management, and overall survival (OS) of patients who presented with cutaneous MBMs during 2010 to 2015 using the National Cancer Database, which comprises 70% of all newly diagnosed U.S. cancers. OS was analyzed with risk-adjusted proportional hazards and compared by Kaplan-Meier techniques. We found that 2,753 (36%) of patients presenting with stage 4 melanoma had MBMs. Following the 2011 FDA approvals for CBI and BRAFV600-targeted therapy, MBM patients demonstrated a 91% relative increase in 4-year OS to 14.1% from 7.4% preapproval (P < 0.001). Postapproval, the proportion of MBM patients who received CBI rose from 10.5% in 2011 to 34.0% in 2015 (P < 0.001). Initial CBI in MBM patients displayed an improved median and 4-year OS of 12.4 months (compared with 5.2 months; P < 0.001) and 28.1% (compared with 11.1%), respectively. These benefits were pronounced in MBM patients without extracranial metastases, in which CBI demonstrated improved median and 4-year OS of 56.4 months (compared with 7.7 months; P < 0.001) and 51.5% (compared with 16.9%), respectively. Using a large national cohort composed of a "real-life" MBM treatment population, we demonstrated the dramatic OS improvements associated with novel checkpoint blockade immunotherapies. Cancer Immunol Res; 6(9); 1039-45. ©2018 AACR.
| S-EPMC6230261 | biostudies-literature
Project description:PurposeMelanoma brain metastases (MBM) occur in ?50% of melanoma patients. Although both radiation therapy (RT) and immune checkpoint inhibitor (ICI) are used alone or in combination for MBM treatment, the role of this combination and how these treatments could best be sequenced remains unclear.Methods and materialsWe conducted a retrospective analysis of patients with resected MBM who underwent treatment with RT, ICI, or a combination of RT and ICI. Among the latter, we specifically investigated the differential gene expression via RNA-sequencing between patients who received RT first then ICI (RT ? ICI) versus ICI first then RT (ICI ? RT). We used a glycoprotein-transduced syngeneic melanoma mouse model for validation experiments.ResultsWe found that for patients with resected MBM, a combination of RT and ICI confers superior survival compared with RT alone. Specifically, we found that RT ? ICI was superior compared with ICI ? RT. Transcriptome analysis of resected MBM revealed that the RT ? ICI cohort demonstrated deregulation of genes involved in apoptotic signaling and key modulators of inflammation that are most implicated in nuclear factor kappa-light-chain-enhancer of activated B cells signaling. In a preclinical model, we showed that RT followed by anti-programmed death-ligand 1 therapy was superior to the reverse sequence of therapy, supporting the observations we made in patients with MBM.ConclusionsOur study provides initial insights into the optimal sequence of RT and ICI in the treatment of MBM after surgical resection. Prospective studies examining the best sequence of RT and ICI are necessary, and our study contributes to the rationale to pursue these.
| S-EPMC7839060 | biostudies-literature
Project description:Purpose:Stereotactic radiosurgery (SRS) in combination with immunotherapy (IMT) or targeted therapy is increasingly being used in the setting of melanoma brain metastases (MBMs). The synergistic properties of combination therapy are not well understood. We compared the distant intracranial failure rates of intact MBMs treated with SRS, SRS?+?IMT, and SRS?+?targeted therapy. Methods and materials:Combination therapy was defined as delivery of SRS within 3 months of IMT (anti-CTLA-4 /anti-PD-1 therapy) or targeted therapy (BRAF/MEK inhibitors). The primary endpoint was distant intracranial failure after SRS, which was defined as any new MBM identified on brain magnetic resonance imaging. Outcomes were evaluated using the Kaplan Meier method and Cox proportional hazards. Results:A total of 72 patients with melanoma with 233 MBMs were treated between April 2006 and April 2016. The number of MBMs within each treatment group was as follows: SRS: 121; SRS?+?IMT: 48; and SRS?+?targeted therapy: 64. The median follow-up was 8.9 months. One-year distant intracranial control rates for SRS, SRS?+?IMT, and SRS?+?targeted therapy were 11.5%, 60%, and 10%, respectively (P?<?.001). On multivariate analysis, after adjusting for steroid use and number of MBMs, SRS?+?IMT remained associated with a significant reduction in distant intracranial failure compared with SRS (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.29-0.80; P?=?.003) and compared with SRS?+?targeted therapy (HR, 0.41; 95% CI, 0.25-0.68; P?=?.001).One-year local control for SRS, SRS?+?IMT, and SRS?+?targeted therapy was 66%, 85%, and 72%, respectively (P?=?.044). On multivariate analysis, after adjusting for dose, SRS?+?IMT remained associated with a significant reduction in local failure compared with SRS alone (HR, 0.37; 95% CI, 0.14-0.95; P?=?.04). Conclusions:SRS with immunotherapy is associated with decreased distant and local intracranial failure compared with SRS alone. Prospective studies are warranted to validate this result.
| S-EPMC5707419 | biostudies-literature
Project description:INTRODUCTION:Brain metastases are common in metastatic melanoma and radiosurgery is often utilized for local control. Immune checkpoint inhibitors (CPIs) play a central role in contemporary melanoma management; however, there is limited data exploring outcomes and potential toxicities for patients treated with CPIs and radiosurgery. METHODS:We retrospectively identified all consecutive cases of newly diagnosed melanoma brain metastases (MBM) treated with Gamma Knife radiosurgery at a single institution between 2012 and 2017, and included only patients that initiated CPIs within 8 weeks before or after radiosurgery. RESULTS:Thirty-eight patients were included with a median follow-up of 31.6 months. Two-year local control was 92%. Median time to out-of-field CNS and extra-CNS progression were 8.4 and 7.9 months, respectively. Median progression-free survival (PFS) was 3.4 months and median overall survival (OS) was not reached (NR). Twenty-five patients (66%) received anti-CTLA4 and 13 patients (34%) received anti-PD-1+/-anti-CTLA4. Compared with anti-CTLA4, patients that received anti-PD-1+/-anti-CTLA4 had significant improvements in time to out-of-field CNS progression (p = 0.049), extra-CNS progression (p = 0.015), and PFS (p = 0.043), with median time to out-of-field CNS progression of NR vs. 3.1 months, median time to extra-CNS progression of NR vs. 4.4 months, and median PFS of 20.3 vs. 2.4 months. Six patients (16%) developed grade ≥ 2 CNS toxicities (grade 2: 3, grade 3: 3, grade 4/5: 0). CONCLUSIONS:Excellent outcomes were observed in patients that initiated CPIs within 8 weeks of undergoing radiosurgery for newly diagnosed MBM. There appears to be an advantage to anti-PD-1 or combination therapy compared to anti-CTLA4.
| S-EPMC6931903 | biostudies-literature