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Ipilimumab In Patients With Melanoma And Brain Metastases: An Open-label, Phase 2 Trial.

K. Margolin, M. Ernstoff, O. Hamid, D. Lawrence, D. Mcdermott, I. Puzanov, J. Wolchok, J. I. Clark, M. Sznol, T. Logan, J. Richards, T. Michener, Á. Balogh, K. Heller, F. S. Hodi
Published 2012 · Medicine

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BACKGROUND 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. METHODS 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. FINDINGS 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. INTERPRETATION 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. FUNDING Bristol-Myers Squibb.
This paper references
10.1002/cncr.25634
Prognostic factors for survival in melanoma patients with brain metastases
M. Davies (2011)
10.1007/s00262-006-0272-1
Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion: an update on implications for chronic infections and tumor evasion
Christian Blank (2006)
10.1016/J.IJROBP.2007.06.074
A new prognostic index and comparison to three other indices for patients with brain metastases: an analysis of 1,960 patients in the RTOG database.
P. Sperduto (2008)
10.1200/JCO.2008.16.5449
Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens.
M. Dudley (2008)
10.1007/s00432-002-0323-8
Temozolomide and whole brain irradiation in melanoma metastatic to the brain: a phase II trial of the Cytokine Working Group
K. Margolin (2002)
10.1007/s10637-009-9376-8
A phase II multicenter study of ipilimumab with or without dacarbazine in chemotherapy-naïve patients with advanced melanoma
E. Hersh (2009)
10.4049/jimmunol.177.12.8448
NK and CD4 Cells Collaborate to Protect against Melanoma Tumor Formation in the Brain1
R. Prins (2006)
10.1016/S0959-8049(11)72514-X
A phase II study combining ipilimumab and fotemustine in patients with metastatic melanoma: The NIBIT-M1 trial.
A. D. Di Giacomo (2011)
10.1016/J.IJROBP.2006.01.024
Gamma-Knife radiosurgery in the management of melanoma patients with brain metastases: a series of 106 patients without whole-brain radiotherapy.
C. Gaudy-Marqueste (2006)
10.2307/2530286
A Confidence Interval for the Median Survival Time
R. Brookmeyer (1982)
10.1097/CMR.0b013e3283364a37
Complete regression of a previously untreated melanoma brain metastasis with ipilimumab
N. Schartz (2010)
10.1016/0021-9681(61)90060-1
The determinatio of the number of patients required in a preliminary and a follow-up trial of a new chemotherapeutic agent.
E. Gehan (1961)
10.1093/ANNONC/MDI392
Stereotactic radiosurgery for brain oligometastases: good for some, better for all?
T. Gupta (2005)
10.3171/2010.5.JNS1014
Outcome predictors of Gamma Knife surgery for melanoma brain metastases. Clinical article.
D. N. Liew (2011)
10.1002/cncr.24899
Tumor cell expression of programmed cell death‐1 ligand 1 is a prognostic factor for malignant melanoma
R. Hino (2010)
10.1200/JCO.2011.29.15_SUPPL.TPS230
A phase II study combining ipilimumab and fotemustine in patients with metastatic melanoma: The NIBIT-M1 trial.
A. D. Giacomo (2011)
10.1172/JCI41911
Trafficking of immune cells in the central nervous system.
E. Wilson (2010)
10.1097/CMR.0b013e32834d3d88
Safety and clinical activity of ipilimumab in melanoma patients with brain metastases: retrospective analysis of data from a phase 2 trial
J. Weber (2011)
10.1038/ncponc1183
CTLA-4 blockade with ipilimumab induces significant clinical benefit in a female with melanoma metastases to the CNS
F. S. Hodi (2008)
10.1200/JCO.2005.04.5716
Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4.
Kimberly E. Beck (2006)
10.1016/J.CTRV.2004.05.001
The treatment of brain metastases in melanoma patients.
D. Bafaloukos (2004)
10.1056/NEJMoa1104621
Ipilimumab plus dacarbazine for previously untreated metastatic melanoma.
C. Robert (2011)
10.1093/annonc/mdq013
Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study.
S. O’Day (2010)
10.1016/S1470-2045(09)70334-1
Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study.
J. Wolchok (2010)
10.1002/cncr.22605
Multimodality treatment of melanoma brain metastases incorporating stereotactic radiosurgery (SRS)
W. Samlowski (2007)
10.1200/JCO.2004.11.044
Temozolomide for the treatment of brain metastases associated with metastatic melanoma: a phase II study.
S. Agarwala (2004)
10.1056/NEJMoa1003466
Improved survival with ipilimumab in patients with metastatic melanoma.
F. S. Hodi (2010)
10.1200/JCO.2004.08.140
Determinants of outcome in melanoma patients with cerebral metastases.
K. Fife (2004)
10.1093/jnci/92.3.205
New Guidelines to Evaluate the Response to Treatment in Solid Tumors.
P. Therasse (2000)
10.4103/0973-1482.80458
Can current prognostic scores reliably guide treatment decisions in patients with brain metastases from malignant melanoma?
C. Nieder (2011)
10.1158/1078-0432.CCR-09-1624
Guidelines for the Evaluation of Immune Therapy Activity in Solid Tumors: Immune-Related Response Criteria
J. Wolchok (2009)
10.3171/2008.4.17537
Early brain tumor metastasis reduction following Gamma Knife surgery.
Arnaldo Neves Da Silva (2009)
10.1016/S0959-8049(02)00731-1
Brain metastases following interleukin-2 plus interferon-alpha-2a therapy: a follow-up study in 94 stage IV melanoma patients.
A. Schmittel (2003)
10.1093/BIOMET/26.4.404
THE USE OF CONFIDENCE OR FIDUCIAL LIMITS ILLUSTRATED IN THE CASE OF THE BINOMIAL
C. J. Clopper (1934)
10.1002/cncr.22367
Prognostic factors for survival after stereotactic radiosurgery vary with the number of cerebral metastases
M. Diluna (2007)



This paper is referenced by
10.1186/s13014-020-1485-8
Stereotactic radiosurgery combined with targeted/ immunotherapy in patients with melanoma brain metastasis
I. Hadi (2020)
10.3978/j.issn.2304-3865.2014.05.13
Checkpoint inhibitors in the treatment of cutaneous malignant melanoma.
J. Lutzky (2014)
10.1016/j.radonc.2018.06.017
Stereotactic radiosurgery and immunotherapy in melanoma brain metastases: Patterns of care and treatment outcomes.
P. Gabani (2018)
10.1016/j.wneu.2018.12.222
Immunotherapy for High Grade Gliomas: A Clinical Update and Practical Considerations for Neurosurgeons.
J. Young (2019)
10.1002/cncr.30946
Improved survival of patients with melanoma brain metastases in the era of targeted BRAF and immune checkpoint therapies
S. Sloot (2018)
10.1002/cam4.50
Targeting hyperactivation of the AKT survival pathway to overcome therapy resistance of melanoma brain metastases
H. Niessner (2013)
10.1007/s00117-017-0281-4
Malignes Melanom
Julia K Winkler (2017)
brAIN metAStASeS IN mALIgNANt meLANomA-treAtmeNt optIoNS ANd recommeNdAtIoNS
C. Enăchescu (2014)
10.1093/neuonc/nou107
DNA methylation and gene deletion analysis of brain metastases in melanoma patients identifies mutually exclusive molecular alterations.
D. Marzese (2014)
10.1016/j.cytogfr.2017.07.002
Immunotherapy targeting immune check-point(s) in brain metastases.
Anna Maria Di Giacomo (2017)
10.1002/cam4.1223
High frequency of brain metastases after adjuvant therapy for high‐risk melanoma
W. Samlowski (2017)
PI 3 K pathway inhibition achieves potent antitumor activity in melanoma brain metastases in vitro and in vivo
H. Niessner (2017)
10.1186/s12885-020-6624-y
A phase II open label, randomised study of ipilimumab with temozolomide versus temozolomide alone after surgery and chemoradiotherapy in patients with recently diagnosed glioblastoma: the Ipi-Glio trial protocol
N. Brown (2020)
10.1111/ajco.12998
The changing paradigm of management in melanoma brain metastases
R. Ladwa (2018)
10.7573/dic.212242
Metastatic melanoma – a review of current and future drugs
T. Velho (2012)
10.5114/wo.2012.29283
Recent advances in melanoma treatment – American Society of Clinical Oncology (ASCO) 2012 perspective
J. Mackiewicz (2012)
10.1200/JCO.2015.60.9503
Treatment of Brain Metastases.
X. Lin (2015)
10.1155/2013/946392
A Patient with HIV Treated with Ipilimumab and Stereotactic Radiosurgery for Melanoma Metastases to the Brain
J. Ruzevick (2013)
10.1007/s11060-020-03657-8
Type and timing of systemic therapy use predict overall survival for patients with brain metastases treated with radiation therapy
Kevin Yijun Fan (2020)
10.1016/j.adro.2020.10.019
Usefulness of Simple Original Interstitial Lung Abnormality Scores for Predicting Radiation Pneumonitis Requiring Steroidal Treatment After Definitive Radiation Therapy for Patients With Locally Advanced Non-Small Cell Lung Cancer
T. Kashihara (2020)
Combination of BRAF Inhibitors and Brain Radiotherapy in Patients With Metastatic Melanoma Shows Minimal Acute Toxicity
N. Jamieson (2013)
10.15496/PUBLIKATION-14506
Hirnmetastasen des malignen Melanoms. Therapiebesonderheiten
R. Rauschenberg (2016)
10.5772/INTECHOPEN.75447
Management of Brain Metastases from Solid Tumors
R. Liubota (2018)
10.1016/j.ejca.2018.05.012
Patterns of disease control and survival in patients with melanoma brain metastases undergoing immune-checkpoint blockade.
Laura Milsch (2018)
10.1016/j.ejca.2016.12.017
The majority of patients with metastatic melanoma are not represented in pivotal phase III immunotherapy trials.
M. Donia (2017)
10.1016/j.ijrobp.2016.06.005
Brain Metastases From Melanoma: Therapy at the Crossroads.
J. Kirkpatrick (2016)
10.21037/apm.2018.07.10
Immunotherapy and radiotherapy for metastatic cancers.
A. Bang (2018)
10.1097/CCO.0b013e32835dae4f
Update on the role of ipilimumab in melanoma and first data on new combination therapies
M. Maio (2013)
10.1200/JCO.2013.51.8936
Reply to N. Rompoti et al.
I. Satzger (2013)
10.1016/j.cdtm.2017.12.001
Management of gastrointestinal adverse events induced by immune-checkpoint inhibitors
Zheng-hang Wang (2018)
10.1016/j.wneu.2013.02.025
Predictors of survival, neurologic death, local failure, and distant failure after gamma knife radiosurgery for melanoma brain metastases.
Matthew Neal (2014)
10.1186/s12916-015-0536-8
Advances in the treatment of newly diagnosed glioblastoma
Brett J. Theeler (2015)
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