Response of metastatic glioma to vemurafenib

Leaver, Katie Emily; Zhang, Niushen; Ziskin, Jennifer; Vogel, Hannes; Recht, Lawrence D.; Thomas, Reena

doi:10.1093/nop/npv054

Cited by 20 publications

(26 citation statements)

References 25 publications

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“…With BRAFi/MEKi therapy we encountered an earlier than expected remarkable treatment response that was similar with other reports ( Table 2). Five glioblastoma patients, all of them 40 years old or younger, have been described in the literature where BRAFi monotherapy was given as second line salvage treatment and only one as primary treatment [21,22,[25][26][27][28].…”

Section: Discussionmentioning

confidence: 99%

Regression of BRAFV600E mutant adult glioblastoma after primary combined BRAF-MEK inhibitor targeted therapy: a report of two cases

Woo

Lam

et al. 2019

Oncotarget

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Background: Up to 15% of young adults with glioblastoma have the activating oncogenic BRAF V600E mutation, an actionable target of the MAPK signal transduction pathway governing tumor cell proliferation. Small molecule inhibitors of BRAF and MEK, a downstream protein immediately following BRAF, have been shown to confer a survival advantage for patients with BRAF V600E mutant advanced melanoma. We describe our experience using this combined target therapy for two patients with BRAF V600E mutant glioblastoma (GBM) as primary treatment due to extenuating clinical circumstances that prohibited the prescription of standard treatment.Case Presentation: The two patients were both 22 years old on presentation. After the initial tumor resection, they both developed rapid deterioration in performance status within a few weeks due to leptomeningeal metastases. In view of the critical condition, BRAF and MEK inhibitors were prescribed as first line treatment. The two patients both achieved dramatic clinical response, which was parallel to the impressive radiological regression of the disease. Unfortunately, the duration of disease control was short as drug resistance developed rapidly. The two patients died 7 and 7.5 month after initial diagnosis of GBM.Conclusions: Primary treatment with inhibitors of BRAF and MEK can lead to tumor regression for patients with BRAF V600E mutant glioblastoma. We therefore recommend that all young GBM patients should undergo BRAF V600E mutation testing, especially for those with unusual aggressive clinical course.

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Section: Discussionmentioning

confidence: 99%

Regression of BRAFV600E mutant adult glioblastoma after primary combined BRAF-MEK inhibitor targeted therapy: a report of two cases

Woo

Lam

et al. 2019

Oncotarget

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“…10,[18][19][20][21][22][23][24] In total, adult HGG or GBM cases were composed of 4 GBM/eGBM, 9 aPXA, and 1 anaplastic ganglioglioma, with 10 patients treated with single-agent BRAFi (5 with vemurafenib, 5 with dabrafenib) and 4 treated with combination BRAFi/MEKi (all with dabrafenib + trametinib). With the exception of 2 patients treated in the first-line setting, all others were treated at recurrence.…”

Section: Efficacymentioning

confidence: 99%

“…Second, many of the reports describe rapid clinical improvement after initiating BRAF-targeted therapy. 10,19,21,23 This point is key given that several of the patients described had a poor performance status that precluded more aggressive treatments, such as standard cytotoxic chemotherapy or radiation. Similarly, BRAF inhibitors are generally well tolerated, with manageable side effects.…”

Section: Efficacymentioning

confidence: 99%

BRAF-Targeted Therapy in the Treatment of BRAF -Mutant High-Grade Gliomas in Adults

Johanns¹,

Ansstas²,

Dahiya³

2018

J Natl Compr Canc Netw

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Use of small molecule inhibitors specific to activating BRAF V600 mutations first demonstrated efficacy in metastatic melanoma.1 Recently, similar results were observed in patients with BRAF-mutated non-small cell lung cancer, leading to FDA approval in June 2017. 2,3 Furthermore, the observation that combining BRAF inhibition (BRAFi) with MEK inhibition (MEKi) leads to improved efficacy and reduced resistance without increased toxicity has set the bar for any future multidrug combination. 4,5 These observations, along with encouraging early-phase data in other histologies, such as papillary thyroid cancer 6 and hairy cell leukemia, 7 which both have high frequencies of BRAF V600E mutations, have led to increasing interest in exploring the role of BRAFi and MEKi in all BRAF-mutated cancers, regardless of histology.8 However, the lack of efficacy in BRAF-mutated colorectal cancer cautions against the agnostic generalization of results with these agents.For primary central nervous system (CNS) tumors, increasing evidence has suggested that BRAFi therapy may be effective. Preliminary results from a phase I/II study of dabrafenib in relapsed or progressive pediatric BRAF V600E-mutated low-grade gliomas reported an 82% clinical benefit rate (stable disease or better at 6 months) among 32 evaluable subjects.9 A subsequent phase II study is underway evaluating the efficacy of combined BRAFi/MEKi in a similar patient population (ClinicalTrials.gov identifier: NCT02684058). Conversely, the efficacy of these agents in adult patients, particularly those with high-grade gliomas (HGGs; WHO grade III) or glioblastoma (GBM; WHO grade IV), which are more common in adults, remains undefined. Two recent publications in JNCCN-an earlier work by Johanns et al 10 and an article by Schreck et al found elsewhere in this issue describing the successful use of combined BRAFi/MEKi therapy in adults with HGG or GBM-contribute to this growing body of literature, suggesting a therapeutic role for these agents in primary CNS disease, and raise several important clinical considerations. IncidenceSeveral large retrospective studies have attempted to estimate the frequency of BRAF mutations in pediatric and adult primary CNS tumors [11][12][13][14][15] ; for adult GBM, the frequency of these mutations is approximately 1% to 3%. Interestingly, the only missense mutation found to date in adult or pediatric primary CNS tumors is the V600E variant. Despite the relatively low frequency of BRAF mutations, it is increased among several subsets of adult patients with GBM: approximately 15% of GBM cases in patients aged 17 to 35 years will harbor a BRAF V600E mutation. 15 Remarkably, BRAF mutations in this cohort were found in similar frequency and were mutually exclusive to other common mutations in IDH1 (17%) and H3F3A (19%), suggesting that BRAF-mutated GBM represents a distinct subgroup. Likewise, the incidence of BRAF V600E is approximately 50% in epithelioid GBM (eGBM), a rare variant of IDH wild-type GBM recognized in the revised 2016 WHO classif...

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“…11 There have been a few cas-es in which targeted treatment with BRAF inhibitors has been successfully attempted, but resistance emerges in a few months, similar to what has been seen in melanoma and other tumor types. [12][13][14] The emergence of resistance over time has been reproduced in preclinical glioma models, 15,16 although these models have also shown that dual inhibition with BRAF and MEK inhibitors can prevent resistance.…”

mentioning

confidence: 99%

“…16 However, to date, case reports in adults with primary brain tumors have only examined BRAF inhibition, resulting in a mix of response and progression (Table 1). 12,14,[22][23][24][25] Whether adding an MEK inhibitor would change the clinical course is unknown. To answer this question, 2 clinical trials evaluating the activity of dabrafenib and trametinib in pediatric patients with recurrent BRAF V600-mutated low-or high-grade gliomas (ClinicalTrials.gov identifiers: NCT02124772 and NCT02684058, respectively) are open or planned to open shortly.…”

mentioning

confidence: 99%

Concurrent BRAF/MEK Inhibitors in BRAF V600–Mutant High-Grade Primary Brain Tumors

Schreck¹,

Guajardo

Lin³

et al. 2018

J Natl Compr Canc Netw

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V600 mutations are being identified in patients with primary brain tumors more often as molecular testing becomes widely available. Targeted treatment with BRAF inhibitors has been attempted in individual cases with some responses, whereas others showed no response or developed resistance. Preclinical work suggests that gliomas could be more responsive to the concurrent use of BRAF and MEK inhibition for MAP kinase pathway suppression. This report presents 2 cases of malignant brain tumors with V600E mutations that were resistant to radiation and temozolomide, and reports on their response to targeted treatment with the BRAF and MEK inhibitors dabrafenib and trametinib. One patient with an anaplastic pleomorphic xanthoastrocytoma experienced a partial response for 14 months, demonstrated by progressive tumor shrinkage and clinical improvement; however, this was followed by clinical and radiographic progression. The patient with glioblastoma continued to have stable disease after 16 months of treatment. These cases are encouraging in a disease that urgently needs new treatments. Further work is necessary to understand response rates, duration, and survival in primary brain tumors.

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Response of metastatic glioma to vemurafenib

Cited by 20 publications

References 25 publications

Regression of BRAFV600E mutant adult glioblastoma after primary combined BRAF-MEK inhibitor targeted therapy: a report of two cases

Regression of BRAFV600E mutant adult glioblastoma after primary combined BRAF-MEK inhibitor targeted therapy: a report of two cases

BRAF-Targeted Therapy in the Treatment of BRAF -Mutant High-Grade Gliomas in Adults

Concurrent BRAF/MEK Inhibitors in BRAF V600–Mutant High-Grade Primary Brain Tumors

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