Impact of New Systemic Treatment and Radiotherapy in Melanoma Patients with Leptomeningeal Metastases

Abstract

Importance: Few data are available on patients with leptomeningeal disease (LM) from melanoma treated with new systemic therapies. Objective: To gain a better understanding of patients, disease characteristics, and therapeutic interventions in melanoma patients with LM in the era of new systemic treatment. Design: Clinical characteristics, treatments, and survival of melanoma patients diagnosed with LM, isolated or associated with brain metastases, were collected. The Cox regression model assessed the influence of patient and melanoma characteristics on survival. Setting: Monocentric, retrospective, real-life cohort of patients with LM from melanoma. Participants: All patients followed up at Saint-Louis University Hospital and diagnosed with LM between December 2013 and February 2020 were included. For each patient identified, a central review by dermato-oncologist and neuro-oncologist experts was performed to confirm the diagnosis of LM. Exposure: Impact of new systemic therapies and radiotherapy. Results: Among the 452 advanced melanoma patients followed at St Louis Hospital between 2013 and 2020, 41 patients with LM from melanoma were identified. Among them, 29 patients with a diagnosis of LM “confirmed” or “probable” after central neuro-oncologists reviewing were included. Nineteen patients had known melanoma brain metastases at LM diagnosis. Among the 27 patients treated with systemic therapy, 17 patients were treated with immunotherapy, 5 patients received targeted therapy, 1 was treated with chemotherapy, and 4 patients were treated with anti-PD-1 in combination with BRAF inhibitor. The median overall survival (OS) from LM diagnosis was 5.1 months. Median OS was 7.1 months for the 9 patients receiving systemic therapy combined with radiotherapy, and 3.2 months for the 20 patients not receiving combined radiotherapy. Elevated serum lactate dehydrogenase (LDH) (HR 1.44, 95% CI 1.09–1.90, p < 0.01) and presence of neurological symptoms at LM diagnosis (HR 2.96, 95% CI 1.25–6.99, p = 0.01) were associated with poor survival. At the time of data analysis, five patients were still alive with a median follow-up of 47.4 months and had persistent complete response. Conclusion: Targeted therapy and immunotherapy are promising new treatment options in LM from melanoma that can increase overall survival, and may induce long lasting remission in some patients.

Leptomeningeal Disease (LMD) in Patients with Melanoma Metastases

“…However, this method only relies on the morphology of the tumor cells, and lacks specific information about the molecular diagnosis. LMD can be diagnosed prior to the appearance of any clinical signs in 10–40% of cases [ 12 , 59 ].…”

“…Promising results from utilizing immunotherapy in metastatic melanoma treatment have encouraged researchers to explore the efficiency of immunotherapy for LMM patients [ 8 , 12 , 131 , 132 ]. Few retrospective studies have been conducted to evaluate immunotherapy’s efficacy on LMM patient outcomes due to the novelty of FDA approval for metastatic melanoma immunotherapy [ 8 , 12 , 131 , 132 ].…”

“…In particular, LMD from melanoma (LMM) portends an abysmal prognosis, with a mean overall survival (OS) of 3.5 months, even with aggressive treatment [ 8 ]. Retrospective studies have reported concomitant brain metastasis in 60–85% of LMM cases [ 9 , 10 , 11 , 12 ].…”

Leptomeningeal Metastases from Solid Tumors: Recent Advances in Diagnosis and Molecular Approaches

“…It is not clear whether the association of BRAF inhibitors and MEK inhibitors may improve the efficacy in LM as reported in BM and extracranial sites [198]; however, initial reports regarding the combination of targeted therapy and immunotherapy with RT are emerging. In this regard, 28 patients with LM were treated with targeted therapy (n = 5), traditional chemotherapy (n = 1), anti-PD-1 alone (n = 17) or in combination with a BRAF inhibitor (n = 4), achieving a median OS of 7.1 months for the patients receiving systemic therapy combined with RT and 3.2 months for those not receiving RT [199].…”

CD11c+CD163+ Cells and Signal Transducer and Activator of Transcription 3 (STAT3) Expression Are Common in Melanoma Leptomeningeal Disease

“…Patients with parenchymal brain metastases have multiple treatment options including surgery, stereotactic radiosurgery, systemic therapies including the BRAF and MEK inhibitors, monotherapy with the immune checkpoint inhibitors ipilimumab or pembrolizumab, and/or the combination ipilimumab and nivolumab, which have demonstrated efficacy in clinical trials for metastatic melanoma patients with parenchymal brain metastases (3)(4)(5)(6)(7)(8). In contrast, there are very few treatment options for LMD patients (9,10), especially once patients develop LMD while on these agents. Notably, LMD often causes severe neurological deficits that can critically impact quality of life.…”