Targeted drug therapy for meningiomas

Norden, Andrew D.; Drappatz, Jan; Wen, Patrick Y.

doi:10.3171/foc-07/10/e12

Cited by 46 publications

(13 citation statements)

References 135 publications

(213 reference statements)

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“…Patients with recurrent meningioma who have exhausted surgical and radiotherapy options have limited therapeutic choices. Despite interest in treating such patients with cytotoxic chemotherapy and targeted molecular agents, no effective drug therapy has emerged [5, 7]. …”

Section: Introductionmentioning

confidence: 99%

Phase II trials of erlotinib or gefitinib in patients with recurrent meningioma

Raizer²,

et al. 2009

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There are no established treatments for recurrent meningioma when surgical and radiation options are exhausted. The epidermal growth factor receptor (EGFR) is often over-expressed in meningiomas and may promote tumor growth. In open label, single arm phase II studies of the EGFR inhibitors gefitinib (NABTC 00-01) and erlotinib (NABTC 01-03) for recurrent malignant gliomas, we included exploratory subsets of recurrent meningioma patients. We have pooled the data and report the results here. Patients with recurrent histologically confirmed meningiomas with no more than 2 previous chemotherapy regimens were treated with gefitinib 500 mg/day or erlotinib 150 mg/day until tumor progression or unacceptable toxicity. Twenty-five eligible patients were enrolled with median age 57 years (range 29–81) and median Karnofsky performance status (KPS) score 90 (range 60–100). Sixteen patients (64%) received gefitinib and 9 (36%) erlotinib. Eight patients (32%) had benign tumors, 9 (36%) atypical, and 8 (32%) malignant. For benign tumors, the 6-month progression-free survival (PFS6) was 25%, 12-month PFS (PFS12) 13%, 6-month overall survival (OS6) 63%, and 12-month OS (OS12) 50%. For atypical and malignant tumors, PFS6 was 29%, PFS12 18%, OS6 71%, and OS12 65%. The PFS and OS were not significantly different by histology. There were no objective imaging responses, but 8 patients (32%) maintained stable disease. Although treatment was well-tolerated, neither gefitinib nor erlotinib appear to have significant activity against recurrent meningioma. The role of EGFR inhibitors in meningiomas is unclear. Evaluation of multi-targeted inhibitors and EGFR inhibitors in combination with other targeted molecular agents may be warranted.

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Section: Introductionmentioning

confidence: 99%

Phase II trials of erlotinib or gefitinib in patients with recurrent meningioma

Raizer²,

et al. 2009

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“…However, systemic therapy options are severely limited. For many years, chemotherapeutics have been tried and systematically failed at changing the clinical management of meningiomas (Jenkinson et al, 2015; Norden, Drappatz, & Wen, 2007). There has been a steady increase in the understanding of molecular pathobiology of meningiomas, but identifying molecular determinants of aggressiveness/prognosis have been elusive.…”

Section: Discussionmentioning

confidence: 99%

Kinomic Alterations in Atypical Meningioma

Anderson

Taylor

Fiveash

et al. 2015

MRAJ

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Background We sought to profile Atypical Meningioma in a high-throughput manner to better understand the altered signaling within these tumors and specifically the kinases altered in recurrent atypical meningioma. Kinomic Profiles could be used to identify prognostic biomarkers for responders/non-responders to classify future patients that are unlikely to benefit from current therapies. Directly these results could be used to identify drug-actionable kinase targets as well. Methods Peptide-substrate microarray kinase activity analysis was conducted with a PamStation®12 analyzing the tyrosine kinome in each tumor kinetically against ~144 target peptides. These data were then analyzed relative to clinical outcome (e.g., tumor recurrence). Results 3 major clusters of atypical meningiomas were identified with highly variant peptides primarily being targets of EGFR family, ABL, BRK and BMX kinases. Kinomic analysis of recurrent atypical meningiomas indicated patterns of increased phosphorylation of BMX, TYRO3 and FAK substrates as compared to non-recurrent tumors. Conclusion The atypical meningiomas profiled here exhibited molecular sub-clustering that may have phenotypic corollaries predictive of outcome. Recurrent tumors had increases in kinase activity that may predict resistance to current therapies, and may guide selection of directed therapies. Taken together these data further the understanding of kinomic alteration in atypical meningioma, and the processes that may not only mediate recurrence, but additionally may identify kinase targets for intervention.

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“…Precision medicine potentially has tremendous applicability in neuro-oncology and will allow patients to receive individualized therapies that target the genetic mutations underlying their diseases [ 4 ]. Indeed, early phase n-of-1 and small cohort investigational trials studies have already begun to demonstrate the potential of precision medicine in neuro-oncology [ 5 – 7 ].…”

Section: Introductionmentioning

confidence: 99%

Ethical considerations of neuro-oncology trial design in the era of precision medicine

2017

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The field of oncology is currently undergoing a paradigm shift. Advances in the understanding of tumor biology and in tumor sequencing technology have contributed to the shift towards precision medicine, the therapeutic framework of targeting the individual oncogenic changes each tumor harbors. The success of precision medicine therapies, such as targeted kinase inhibitors and immunotherapies, in other cancers have motivated studies in brain cancers. The high specificity and cost of these therapies also encourage a shift in clinical trial design away from randomized control trials towards smaller, more exclusive early phase clinical trials. While these new trials advance the clinical application of increasingly precise and individualized therapies, their design brings ethical challenges . We review the pertinent ethical considerations for clinical trials of precision medicine in neuro-oncology and discuss methods to protect patients in this new era of trial design.

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Targeted drug therapy for meningiomas

Cited by 46 publications

References 135 publications

Phase II trials of erlotinib or gefitinib in patients with recurrent meningioma

Phase II trials of erlotinib or gefitinib in patients with recurrent meningioma

Kinomic Alterations in Atypical Meningioma

Ethical considerations of neuro-oncology trial design in the era of precision medicine

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