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

Margolin, Kim; Ernstoff, Marc S.; Hamid, Omid; Lawrence, Donald P.; McDermott, David F.; Puzanov, Igor; Wolchok, Jedd D.; Clark, Joseph I.; Sznol, Mario; Logan, Theodore F.; Richards, Jon M.; Michener, Tracy; Balogh, Agnès; Heller, Kevin N.; Hodi, F. Stephen

doi:10.1016/s1470-2045(12)70090-6

Cited by 975 publications

(718 citation statements)

References 29 publications

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“…The interaction between the immune system, tumor and the tumor microenvironment has been the focus of intense investigation—specifically the role of the PD‐1/PDL‐1 signaling axis,38 The efficacy of PD‐1 inhibition (i.e., nivolumab and pembrolizumab) as a monotherapy or in combination therapy has shown favorable survival in clinical trials for patients with advanced melanoma and NSCLC 39, 40, 41, 42, 43. However, the role of immune checkpoint inhibitors in the treatment of CNS cancers, including metastasis, is currently being defined,44, 45 and our current results provide further support for these agents in this context.…”

Section: Discussionmentioning

confidence: 99%

Profiles of brain metastases: Prioritization of therapeutic targets

Ferguson

Zheng

Xiu

et al. 2018

Intl Journal of Cancer

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We sought to compare the tumor profiles of brain metastases from common cancers with those of primary tumors and extracranial metastases in order to identify potential targets and prioritize rational treatment strategies. Tumor samples were collected from both the primary and metastatic sites of nonsmall cell lung cancer, breast cancer and melanoma from patients in locations worldwide, and these were submitted to Caris Life Sciences for tumor multiplatform analysis, including gene sequencing (Sanger and next‐generation sequencing with a targeted 47‐gene panel), protein expression (assayed by immunohistochemistry) and gene amplification (assayed by in situ hybridization). The data analysis considered differential protein expression, gene amplification and mutations among brain metastases, extracranial metastases and primary tumors. The analyzed population included: 16,999 unmatched primary tumor and/or metastasis samples: 8,178 nonsmall cell lung cancers (5,098 primaries; 2,787 systemic metastases; 293 brain metastases), 7,064 breast cancers (3,496 primaries; 3,469 systemic metastases; 99 brain metastases) and 1,757 melanomas (660 primaries; 996 systemic metastases; 101 brain metastases). TOP2A expression was increased in brain metastases from all 3 cancers, and brain metastases overexpressed multiple proteins clustering around functions critical to DNA synthesis and repair and implicated in chemotherapy resistance, including RRM1, TS, ERCC1 and TOPO1. cMET was overexpressed in melanoma brain metastases relative to primary skin specimens. Brain metastasis patients may particularly benefit from therapeutic targeting of enzymes associated with DNA synthesis, replication and/or repair.

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Section: Discussionmentioning

confidence: 99%

Profiles of brain metastases: Prioritization of therapeutic targets

Ferguson

Zheng

Xiu

et al. 2018

Intl Journal of Cancer

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“…A clinical point of interest surrounding ipilimumab and other checkpoint-inhibitor immunotherapies relates to the use of concomitant steroid administration. This question has not be thoroughly investigated, although findings from a phase II study of ipilimumab in patients with brain metastases suggested a detrimental effect on the response rate in a cohort receiving concurrent steroids 83 . More broadly, however, data from multiple patient series have demonstrated that administration of steroids at the time of immune-related toxicity does not affect the potential long-term benefit from immune-checkpoint blockade 84 .…”

Section: Immunotherapy With Immune-checkpoint Inhibitorsmentioning

confidence: 99%

Targeted agents and immunotherapies: optimizing outcomes in melanoma

et al. 2017

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“…Ipilimumab, an immunomodulating monoclonal antibody, alone also has shown activity in patient with both asymptomatic and symptomatic melanoma brain metastases. Activity was improved in patients with smaller asymptomatic lesions compared with those with symptomatic lesions and using steroids.This study established that ipilimumab alone has CNS activity without significant unexpected adverse effects [60]. SRS combined with an anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA4) agent ipilimumab was shown in one series to improve median survival duration from 4.9 to 21.3 months; the result was largely confirmed by another study [34,61].…”

Section: Melanoma and Immunotherapymentioning

confidence: 66%

The Rationale for Targeted Therapies and Stereotactic Radiosurgery in the Treatment of Brain Metastases

et al. 2016

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Brain metastases are the most common intracranial malignancy. Many approaches, including radiation therapy, surgery, and cytotoxic chemotherapy, have been used to treat patients with brain metastases depending on the patient's disease burden and symptoms. However, stereotactic surgery (SRS) has revolutionized local treatment of brain metastases. Likewise, targeted therapies, including small-molecule inhibitors and monoclonal antibodies that target cancer cell metabolism or angiogenesis, have transformed managing systemic disease. Prospective data on combining these treatments for synergistic effect are limited, but early data show favorable safety and efficacy profiles.The combination of SRS and targeted therapy will further individualize treatment, potentially obviating the need for cytotoxic chemotherapy or whole-brain radiation.There is a great need to pursue research into these exciting modalities and novel combinations to further improve the treatment of patients with brain metastases.This article discusses reported and ongoing clinical trials assessing the safety and efficacy of targeted therapy during SRS. The Oncologist 2016;21:244-251 Implications for Practice: Treatment of patients with brain metastases requires a multidisciplinary approach. Stereotactic radiosurgery is increasingly used in the upfront setting to treat new brain metastasis. Targeted therapies have revolutionized systemic treatment of many malignancies and may sometimes be used as initial treatment in metastatic patients. There is sparse literature regarding safety and efficacy of combining these two treatment modalities. This article summarizes the supporting literature and highlights ongoing clinical trials in combining radiosurgery with targeted therapy.

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

Cited by 975 publications

References 29 publications

Profiles of brain metastases: Prioritization of therapeutic targets

Profiles of brain metastases: Prioritization of therapeutic targets

Targeted agents and immunotherapies: optimizing outcomes in melanoma

The Rationale for Targeted Therapies and Stereotactic Radiosurgery in the Treatment of Brain Metastases

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