Survival Advantage With Radiation Combined With a Selective BRAFV600E Inhibitor in an Orthotopic, Intracranial Model of BRAFV600E-mutated High-grade Gliomas

Dasgupta, Tina; Yang, X.; Hashizume, Rintaro; Olow, Aleksandra; Kolkowitz, Ilan; Weiß, W.; Mueller, S.; Nicolaides, Theo; James, Claire D.; Haas‐Kogan, Daphne A.

doi:10.1016/j.ijrobp.2012.07.125

Cited by 8 publications

(6 citation statements)

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“…In murine orthotopic xenografts of high-grade glioma, treatment with BRAFi and RT resulted in a survival advantage compared with either modality alone (77). BRAFi alone is being investigated in other histologies; a prospective SWOG study is investigating BRAFi for patients with mutated stage IV colorectal cancer (ClinicalTrials.gov identifier: NCT02164916).…”

Section: Recommendationsmentioning

confidence: 99%

Avoiding Severe Toxicity From Combined BRAF Inhibitor and Radiation Treatment: Consensus Guidelines from the Eastern Cooperative Oncology Group (ECOG)

Anker

Grossmann

Atkins

et al. 2016

International Journal of Radiation Oncology*Biology*Physics

141

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BRAF kinase gene V600 point mutations drive approximately 40% to 50% of all melanomas, and BRAF inhibitors (BRAFi) have been found to significantly improve survival outcomes. Although radiation therapy (RT) provides effective symptom palliation, there is a lack of toxicity and efficacy data when RT is combined with BRAFi, including vemurafenib and dabrafenib. This literature review provides a detailed analysis of potential increased dermatologic, pulmonary, neurologic, hepatic, esophageal, and bowel toxicity from the combination of BRAFi and RT for melanoma patients described in 27 publications. Despite 7 publications noting potential intracranial neurotoxicity, the rates of radionecrosis and hemorrhage from whole brain RT (WBRT), stereotactic radiosurgery (SRS), or both do not appear increased with concurrent or sequential administration of BRAFis. Almost all grade 3 dermatitis reactions occurred when RT and BRAFi were administered concurrently. Painful, disfiguring nondermatitis cutaneous reactions have been described from concurrent or sequential RT and BRAFi administration, which improved with topical steroids and time. Visceral toxicity has been reported with RT and BRAFi, with deaths possibly related to bowel perforation and liver hemorrhage. Increased severity of radiation pneumonitis with BRAFi is rare, but more concerning was a potentially related fatal pulmonary hemorrhage. Conversely, encouraging reports have described patients with leptomeningeal spread and unresectable lymphadenopathy rendered disease free from combined RT and BRAFi. Based on our review, the authors recommend holding BRAFi and/or MEK inhibitors ≥3 days before and after fractionated RT and ≥1 day before and after SRS. No fatal reactions have been described with a dose <4 Gy per fraction, and time off systemic treatment should be minimized. Future prospective data will serve to refine these recommendations.

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Section: Recommendationsmentioning

confidence: 99%

Avoiding Severe Toxicity From Combined BRAF Inhibitor and Radiation Treatment: Consensus Guidelines from the Eastern Cooperative Oncology Group (ECOG)

Anker

Grossmann

Atkins

et al. 2016

International Journal of Radiation Oncology*Biology*Physics

141

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“…However, the median elimination half-life is only 50 h for vemurafenib, and even shorter for dabrafenib (5 h) ( 26 , 27 ). It is therefore difficult to account for the improved LC observed using a traditional radiosensitization model in which the drug is expected to be present at the time of radiation, as shown in vitro for melanoma cell lines ( 28 , 29 ). We also analyzed the timing of BRAF inhibitor exposure on LC with SRS, and we did not observe any correlation.…”

Section: Discussionmentioning

confidence: 99%

BRAF Mutation Is Associated with Improved Local Control of Melanoma Brain Metastases Treated with Gamma Knife Radiosurgery

et al. 2016

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ObjectivesEvidence has implicated a possible role of tumor mutation status on local control (LC) with radiotherapy. BRAF is a proto-oncogene that is mutated in approximately 50% of patients with melanoma. We sought to analyze the influence of BRAF status on LC of melanoma brain metastases (MBM) following Gamma Knife radiosurgery (GK).MethodsAmong 125 patients treated with GK for MBM at our institution between 2006 and 2015, we identified 19 patients with 69 evaluable metastases whose BRAF mutation status was known and follow-up imaging was available. LC of individual metastases was compared based on BRAF mutation status using statistical techniques to control for measurements of multiple metastases within each patient. CNS progression was defined as either local failure or development of new lesions.ResultsOf the 69 metastases, BRAF was mutated in 30 and wild-type in 39. With a median follow-up of 30 months for all patients and a median follow-up of 5.5 months for treated lesions, 1-year LC was significantly better among metastases with mutated vs. wild-type BRAF (69 vs. 34%, RR = 0.3, 95% CI = 0.1–0.7, p = 0.01). BRAF mutation was found to be a significant predictor of LC after stereotactic radiosurgery (SRS) in both univariate [RR = 0.3 (95% CI 0.1–0.7, p = 0.01)] and multivariate [RR = 0.2 (95% CI 0.1–0.7, p = 0.01)] analyses. There was also a trend toward improved CNS progression free survival (PFS) at 1 year (26 vs. 0%, p = 0.06), favoring BRAF-mutated patients.ConclusionIn this retrospective study, MBM treated with GK had significantly improved LC for patients with BRAF mutation vs. wild-type. Our data suggest that BRAF mutation may sensitize tumors to radiosurgery, and that BRAF wild-type tumors may be more radioresistant.

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“…Treatment with PLX4720 + everolimus also led to significantly smaller tumors when compared to treatment with vehicle alone ( p < 0.0001), PLX4720 alone ( p < 0.0001), or everolimus alone ( p = 0.0082). This is the first in vivo demonstration of combinatorial activity of an mTOR inhibitor with a BRAF inhibitor in gliomas, and will inform future clinical trials in pediatric brain tumor patients (Dasgupta et al, 2013). …”

Section: Mammalian Target Of Rapamycinmentioning

confidence: 88%

“…Combination treatment with PLX4720 and radiation led to a lower tumor proliferation index (Ki67). There was equivalent survival in the combination arms regardless of how radiation was sequenced with the BRAF inhibitor, either concurrently or sequentially (Dasgupta et al, 2012). …”

Section: Brafmentioning

confidence: 99%

The Combination of Novel Targeted Molecular Agents and Radiation in the Treatment of Pediatric Gliomas

Dasgupta¹,

Haas‐Kogan²

2013

Front. Oncol.

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Brain tumors are the most common solid pediatric malignancy. For high-grade, recurrent, or refractory pediatric brain tumors, radiation therapy (XRT) is an integral treatment modality. In the era of personalized cancer therapy, molecularly targeted agents have been designed to inhibit pathways critical to tumorigenesis. Our evolving knowledge of genetic aberrations in pediatric gliomas is being exploited with the use of specific targeted inhibitors. These agents are additionally being combined with XRT to increase the efficacy and duration of local control. In this review, we discuss novel agents targeting three different pathways in gliomas, and their potential combination with XRT. BRAF is a serine/threonine kinase in the RAS/RAF/MAPK kinase pathway, which is integral to cellular division, survival, and metabolism. Two-thirds of pilocytic astrocytomas, a low-grade pediatric glioma, contain a translocation within the BRAF gene called KIAA1549:BRAF that causes an overactivation of the MEK/MAPK signaling cascade. In vitro and in vivo data support the use of MEK or mammalian target of rapamycin (mTOR) inhibitors in low-grade gliomas expressing this translocation. Additionally, 15–20% of high-grade pediatric gliomas express BRAF V600E, an activating mutation of the BRAF gene. Pre-clinical in vivo and in vitro data in BRAF V600E gliomas demonstrate dramatic cooperation between XRT and small molecule inhibitors of BRAF V600E. Another major signaling cascade that plays a role in pediatric glioma pathogenesis is the PI3-kinase (PI3K)/mTOR pathway, known to be upregulated in the majority of high- and low-grade pediatric gliomas. Dual PI3K/mTOR inhibitors are in clinical trials for adult high-grade gliomas and are poised to enter studies of pediatric tumors. Finally, many brain tumors express potent stimulators of angiogenesis that render them refractory to treatment. An analog of thalidomide, CC-5103 increases the secretion of critical cytokines of the tumor microenvironment, including IL-2, IFN-γ, TNF-α, and IL-10, and is currently being evaluated in clinical trials for the treatment of recurrent or refractory pediatric central nervous system tumors. In summary, several targeted inhibitors with radiation are currently under investigation in both translational bench research and early clinical trials. This review article summarizes the molecular rationale for, and the pre-clinical data supporting the combinations of these targeted agents with other anti-cancer agents and XRT in pediatric gliomas. In many cases, parallels are drawn to molecular mechanisms and targeted inhibitors of adult gliomas. We additionally discuss the potential mechanisms underlying the efficacy of these agents.

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Survival Advantage With Radiation Combined With a Selective BRAFV600E Inhibitor in an Orthotopic, Intracranial Model of BRAFV600E-mutated High-grade Gliomas

Cited by 8 publications

References 0 publications

Avoiding Severe Toxicity From Combined BRAF Inhibitor and Radiation Treatment: Consensus Guidelines from the Eastern Cooperative Oncology Group (ECOG)

Avoiding Severe Toxicity From Combined BRAF Inhibitor and Radiation Treatment: Consensus Guidelines from the Eastern Cooperative Oncology Group (ECOG)

BRAF Mutation Is Associated with Improved Local Control of Melanoma Brain Metastases Treated with Gamma Knife Radiosurgery

The Combination of Novel Targeted Molecular Agents and Radiation in the Treatment of Pediatric Gliomas

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