Ipilimumab in patients with melanoma and brain metastases: An open-label, phase 2 trial

ArticleinThe Lancet Oncology 13(5):459-65 · March 2012with38 Reads
DOI: 10.1016/S1470-2045(12)70090-6 · Source: PubMed
Brain metastases commonly develop in patients with melanoma and are a frequent cause of death of patients with this disease. Ipilimumab improves survival in patients with advanced melanoma. We aimed to investigate the safety and activity of this drug specifically in patients with brain metastases. Between July 31, 2008, and June 3, 2009, we enrolled patients with melanoma and brain metastases from ten US centres who were older than 16 years into two parallel cohorts. Patients in cohort A were neurologically asymptomatic and were not receiving corticosteroid treatment at study entry; those in cohort B were symptomatic and on a stable dose of corticosteroids. Patients were to receive four doses of 10 mg/kg intravenous ipilimumab, one every 3 weeks. Individuals who were clinically stable at week 24 were eligible to receive 10 mg/kg intravenous ipilimumab every 12 weeks. The primary endpoint was the proportion of patients with disease control, defined as complete response, partial response, or stable disease after 12 weeks, assessed with modified WHO criteria. Analyses of safety and efficacy included all treated patients. This trial is registered with ClinicalTrials.gov, number NCT00623766. We enrolled 72 patients: 51 into cohort A and 21 into cohort B. After 12 weeks, nine patients in cohort A exhibited disease control (18%, 95% CI 8-31), as did one patient in cohort B (5%, 0·1-24). When the brain alone was assessed, 12 patients in cohort A (24%, 13-38) and two in cohort B (10%, 1-30) achieved disease control. We noted disease control outside of the brain in 14 patients (27%, 16-42) in cohort A and in one individual (5%, 0·1-24) in cohort B. The most common grade 3 adverse events in cohort A were diarrhoea (six patients [12%]) and fatigue (six [12%]); in cohort B, they were dehydration (two individuals [10%]), hyperglycaemia (two [10%]), and increased concentrations of serum aspartate aminotransferase (two [10%]). One patient in each cohort had grade 4 confusion. The most common grade 3 immune-related adverse events were diarrhoea (six patients [12%]) and rash (one [2%]) in cohort A, and rash (one individual [5%]) and increased concentrations of serum aspartate aminotransferase (two [10%]) in cohort B. One patient in cohort A died of drug-related complications of immune-related colitis. Ipilimumab has activity in some patients with advanced melanoma and brain metastases, particularly when metastases are small and asymptomatic. The drug has no unexpected toxic effects in this population. Bristol-Myers Squibb.
    • "A phase II trial of ipilimumab, which included patients with symptomatic and asymptomatic brain metastases, found that 10% and 24% achieved partial response or stable disease, respectively. Median OS was 3.7 and 7 months, and 2-year OS was 10% and 24%, respectively [177]. Another phase II study was designed to evaluate ipilimumab combined with fotemustine, a chloroethyl-nitrosourea alkylating agent, for the treatment of patients with asymptomatic brain metastases. "
    [Show abstract] [Hide abstract] ABSTRACT: The development of brain metastases in patients with advanced stage melanoma is common, but the molecular mechanisms responsible for their development are poorly understood. Melanoma brain metastases cause significant morbidity and mortality and confer a poor prognosis; traditional therapies including whole brain radiation, stereotactic radiotherapy, or chemotherapy yield only modest increases in overall survival (OS) for these patients. While recently approved therapies have significantly improved OS in melanoma patients, only a small number of studies have investigated their efficacy in patients with brain metastases. Preliminary data suggest that some responses have been observed in intracranial lesions, which has sparked new clinical trials designed to evaluate the efficacy in melanoma patients with brain metastases. Simultaneously, recent advances in our understanding of the mechanisms of melanoma cell dissemination to the brain have revealed novel and potentially therapeutic targets. In this review, we provide an overview of newly discovered mechanisms of melanoma spread to the brain, discuss preclinical models that are being used to further our understanding of this deadly disease and provide an update of the current clinical trials for melanoma patients with brain metastases.
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    • "All rights reserved. comparison of data from trials testing the same drug regimen in extracranial-only versus active brain metastases-specific disease setting support that agents that demonstrate efficacy in extracranial disease generally also show activity in MBMs, lessening concerns about issues related to penetration of the BBB (Azer et al., 2014; Goldberg et al., 2016; Margolin et al., 2012). Indeed, existing data support that brain metastases significantly compromise the BBB to a greater degree than primary brain tumors (Gerstner and Fine, 2007). "
    [Show abstract] [Hide abstract] ABSTRACT: Melanoma central nervous system (CNS) metastases are increasing and the challenges presented by this patient population remain complex. In December 2015, the Melanoma Research Foundation and the Wistar Institute hosted the First Summit on Melanoma Central Nervous System (CNS) Metastases in Philadelphia, Pennsylvania. Here, we provide a review of the current status of the field of melanoma brain metastasis research; identify key challenges and opportunities for improving outcomes in patients with melanoma brain metastases; and set a framework to optimize future research in this critical area. This article is protected by copyright. All rights reserved.
    Full-text · Article · Sep 2016
    • "Ipililumab is a humanized monoclonal antibody against cytotoxic T lymphocyte antigen-4 (CTLA-4); it shows activity in melanoma brain metastasis, particularly if asymptomatic, by improving overall survival. [8,102,103] A phase 2 study of ipilimumab and fotemustine showed an overall immune disease control rate of 50% and median progression-free survival of 4.3 months, with increased incidence in hematological and nonhematological toxicity. Clinical trials for the assessment of immune checkpoint inhibition strategies in CNS metastases are ongoing. "
    [Show abstract] [Hide abstract] ABSTRACT: The incidence of metastatic disease in the central nervous system (CNS) is rising. According to current estimates, up to a third of adult cancer patients will suffer from CNS metastasis. Clinical evidence-based data from prospective randomized trials are rare, however, because CNS metastasis patients were often excluded from clinical trial participation. The management of CNS metastasis patients is therefore rather ill-defined and an interdisciplinary challenge. Recent basic and translational science data have begun contributing to a more profound understanding of the molecular mechanisms leading to invasion of tumor cells into the CNS. This report reviews advances, challenges, and perspectives in this field.
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