Sustained Tumor Control With MAPK Inhibition in BRAF V600-Mutant Adult Glial and Glioneuronal Tumors.

OBJECTIVE: To assess whether RAF and MEK inhibitors (RAFi/MEKi) can provide long-term clinical benefit in adult patients with BRAF V600-mutant glial and glioneuronal tumors (GGNTs), we analyzed tumor response and long-term outcome in a retrospective cohort. METHODS: We performed a retrospective search in the institutional databases of 6 neuro-oncology departments for adult patients with recurrent or disseminated BRAF V600-mutant GGNTs treated with RAFi/MEKi. RESULTS: Twenty-eight adults with recurrent or disseminated BRAF V600-mutant gangliogliomas (n = 9), pleomorphic xanthoastrocytomas (n = 9), and diffuse gliomas (n = 10) were included in the study. At the time that treatment with RAFi/MEKi was started, all tumors displayed radiologic features of high-grade neoplasms. Thirteen patients received RAFi as single agents (vemurafenib [n = 11], dabrafenib [n = 2]), and 15 received combinations of RAFi/MEKi (vemurafenib + cobimetinib [n = 5], dabrafenib + trametinib [n = 10]). Eleven patients achieved a partial or complete response (11 of 28, 39%), with a median reduction of -78% in their tumor burden. Responders experienced a median increase of 10 points in their Karnofsky Performance Status (KPS) score and a median progression-free survival of 18 months, which was longer than achieved with first-line treatment (i.e., 7 months, p = 0.047). Responders had better KPS score (p = 0.018) and tended to be younger (p = 0.061) and to be treated earlier (p = 0.099) compared to nonresponders. Five patients were rechallenged with RAFi/MEKi at progression, with novel tumor responses in 2. On univariate and multivariate analyses, response to RAFi/MEKi was an independent predictor of overall survival. CONCLUSIONS: Our study highlights the long-term clinical benefits of RAFi/MEKi in adult patients with BRAF V600-mutant GGNTs and encourages rechallenge in responders. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that, for adult patients with BRAF V600-mutant GGNT, RAFi/MEKi can reduce tumor burden and provide clinical benefit.

Clinical response to dabrafenib plus trametinib in a pediatric ganglioglioma with BRAF p.T599dup mutation.

In this follow-up report, we present updated information regarding a previously reported pediatric patient with a World Health Organization grade I ganglioglioma harboring a BRAF p.T599dup mutation (Cold Spring Harb Mol Case Stud 4: a002618). This patient, based on our initial finding, is receiving combination targeted therapy with a selective BRAF inhibitor (dabrafenib) plus MEK inhibitor (trametinib). The combination therapy was started after the patient experienced progressive tumor growth and worsening neurological symptoms, including visual changes, headaches, and peripheral neuropathy, despite 9 months of treatment with adjuvant chemotherapy (vinblastine). The patient has been receiving dabrafenib plus trametinib for 15 months and continues to have stable disease as well as improved neurological symptoms. Although combinatorial therapy targeting BRAF and MEK using dabrafenib and trametinib, respectively, is indicated for tumors harboring a BRAF p.V600E/K mutation, our report demonstrates efficacy of this combination in a non-V600E BRAF-mutated tumor. The identification of BRAF alterations may assist clinicians in determining alternative targeted treatment strategies, especially considering the paucity of effective treatments for primary brain tumors and the poor prognosis associated with many central nervous system (CNS) diagnoses. Additional case studies or larger cohort reports will continue to clarify the efficacy of BRAF and/or MEK inhibitors in patients whose tumors harbor a BRAF alteration.

Pediatric low-grade glioma in the era of molecular diagnostics.

Low grade gliomas are the most frequent brain tumors in children and encompass a spectrum of histologic entities which are currently assigned World Health Organisation grades I and II. They differ substantially from their adult counterparts in both their underlying genetic alterations and in the infrequency with which they transform to higher grade tumors. Nonetheless, children with low grade glioma are a therapeutic challenge due to the heterogeneity in their clinical behavior - in particular, those with incomplete surgical resection often suffer repeat progressions with resultant morbidity and, in some cases, mortality. The identification of up-regulation of the RAS-mitogen-activated protein kinase (RAS/MAPK) pathway as a near universal feature of these tumors has led to the development of targeted therapeutics aimed at improving responses while mitigating patient morbidity. Here, we review how molecular information can help to further define the entities which fall under the umbrella of pediatric-type low-grade glioma. In doing so we discuss the specific molecular drivers of pediatric low grade glioma and how to effectively test for them, review the newest therapeutic agents and their utility in treating this disease, and propose a risk-based stratification system that considers both clinical and molecular parameters to aid clinicians in making treatment decisions.

Combination of BRAF and MEK inhibition in BRAF V600E mutant low-grade ganglioglioma.

WHAT IS KNOWN AND OBJECTIVE: Post-surgical management of low grade gangliogliomas is controversial with paucity of data for the use of chemotherapy. BRAF mutations are present in a number of glioma subtypes and offer an opportunity for treatment with targeted therapy. CASE SUMMARY: A 32-year-old man with an unresectable, BRAF V600E mutant, WHO grade 1 ganglioglioma is commenced on combination BRAF and MEK inhibition (vemurafenib and cobimetinib). Partial radiological and clinical response was noted after 13 weeks of treatment. Treatment complication with grade 2 skin and liver toxicity was resolved with dose interruption and reduction. WHAT IS NEW AND CONCLUSION: Combination BRAF and MEK inhibition present a safe and feasible treatment strategy in unresectable BRAF V600E mutant low grade ganglioglioma.

Efficacy of Dabrafenib for three children with brainstem BRAFV600E positive ganglioglioma.

PURPOSE: Children with unresectable brainstem-infiltrated ganglioglioma have poor progression-free survival when treated with conventional chemotherapy and radiation regimens. The BRAFV600E mutation occurs in a large number of gangliogliomas, making them amenable for targeted therapy using mutation-specific kinase inhibitors. However, limited data exists on the effectiveness and best treatment duration of these inhibitors in this tumor setting. METHOD: Retrospective description of three cases of childhood brainstem ganglioglioma with BRAFV600E mutation treated in the long-term with Dabrafenib, a specific BRAFV600E kinase inhibitor. RESULTS: Dabrafenib resulted in rapid tumoral regression and significant and durable clinical and radiological improvement. However, all patients had rapid clinical and radiological relapse within days to weeks following treatment discontinuation but showed similar rapid and sustained therapeutic response when Dabrafenib was re-introduced. This targeted therapy has been well tolerated despite its long-term use of 4.8 to 5.5 years in the three patients. CONCLUSION: Dabrafenib is effective and seemingly safe and well tolerated in our three patients. We observed sustained chemosensitivity even when re-introducing this kinase inhibitor after its discontinuation after 2 years of therapy. These cases indicate the need to re-evaluate the timing and means of Dabrafenib discontinuation in pediatric patients with BRAFV600E mutated gangliogliomas and better assess the future implications of its long-term use.

Bevacizumab in treating the cystic components of pediatric low-grade gliomas: A report of four patients.

Low-grade gliomas (LGG) are among the most common types of brain tumors in children and young adults. These tumors often consist of solid and cystic components. Bevacizumab is a documented treatment for progressive LGG, yet the impact of therapy on the cystic component of these tumors is unknown. We present four patients with prominently cystic LGG treated with bevacizumab at the time of progression. In each case, the cystic component responded to treatment. This is the first known study to investigate bevacizumab's impact on the cystic component of low-grade gliomas.

Response to the BRAF/MEK inhibitors dabrafenib/trametinib in an adolescent with a BRAF V600E mutated anaplastic ganglioglioma intolerant to vemurafenib.

Efficacy of BRAF V600E targeted therapies in brain tumors harboring the mutation has been shown in several case reports and is currently being studied in larger clinical trials. Monotherapy with vemurafenib has been associated with significant side effects, including rashes, papillomas, and squamous cell carcinomas. Here we describe an adolescent female with anaplastic ganglioglioma and significant skin reaction to vemurafenib with subsequent tumor response and tolerance to the BRAF/MEK inhibitor combination of dabrafenib and trametinib without recurrence of previous reaction.

Successful Retreatment of a Child with a Refractory Brainstem Ganglioglioma with Vemurafenib.

A child with brainstem ganglioglioma underwent subtotal resection and focal radiation. Magnetic resonance imaging confirmed tumor progression 6 months later. Another partial resection revealed viable BRAF V600E-positive residual tumor. Vemurafenib (660 mg/m(2) /dose) was administered twice daily, resulting in >70% tumor reduction with sustained clinical improvement for 1 year. Vemurafenib was then terminated, but significant tumor progression occurred 3 months later. Vemurafenib was restarted, resulting in partial response. Toxicities included Grade I pruritus and Grade II rash. Vemurafenib was effectively crushed and administered in solution via nasogastric tube. We demonstrate benefit from restarting vemurafenib therapy.

Recurrent ganglioglioma in adults treated with BRAF inhibitors.

Thirteen adult patients with temozolomide, surgery and radiation refractory ganglioglioma were screened for the BRAF V600E mutation. Three (23%) were found positive for the presence of the BRAF mutation and were treated with the BRAF inhibitor dabrafenib. Dabrafenib was well tolerated with no grade 3 or higher toxicity. The median number of cycles was 7 (a cycle was defined as 1 month of daily dabrafenib) and best response was stable disease in two patients and a partial response in one patient. Median progression-free survival was 7 months with a range of 4-10 months.

BRAF inhibitors in BRAF-V600 mutated primary neuroepithelial brain tumors.

INTRODUCTION: Primary neuroepithelial brain tumors encompass a wide variety of glial and glioneuronal neoplasms. Malignant tumors, tumors located in surgically inaccessible locations (e.g., eloquent brain areas, deep structures, brain stem) and recurrent or progressive tumors pose considerable treatment challenges and are candidates for novel therapeutics based on molecular insights. Small kinase inhibitors of v-RAF murine sarcoma viral oncogene homologue B1 (BRAF) have shown considerable antineoplastic activity in some tumor types harboring activating BRAF-V600 mutations (e.g., melanoma) and promising data are emerging on BRAF inhibitor therapy of mutation-bearing primary brain tumors. AREAS COVERED: This review summarizes the available data on BRAF-V600 point mutations and the antineoplastic activity and toxicity profiles of BRAF inhibitors in neuroepithelial brain tumors including diffuse gliomas (glioblastomas, astrocytomas, oligodendrogliomas), pilocytic astrocytomas, pleomorphic xanthoastrocytomas and gangliogliomas. EXPERT OPINION: Activating BRAF-V600 mutations are recurrently found in several glial and glioneuronal brain tumors and the available data indicate that BRAF inhibitors are active and well-tolerated in such tumors. Thus, BRAF inhibitors represent a novel and promising therapeutic opportunity that may alter the disease course of molecularly selected CNS neoplasms in a clinically meaningful way. However, so far the evidence is anecdotal and prospective clinical studies should be conducted.

Response of recurrent BRAFV600E mutated ganglioglioma to Vemurafenib as single agent.

BACKGROUND: Ganglioglioma (GG) and pilocytic astrocytoma (PA) represent the most frequent low-grade gliomas (LGG) occurring in paediatric age. LGGs not amenable of complete resection (CR) represent a challenging subgroup where traditional treatments often fail. Activation of the MAP Kinase (MAPK) pathway caused by the BRAFV600E mutation or the KIAA1549-BRAF fusion has been reported in pediatric GG and PA, respectively. CASE PRESENTATION: We report on a case of BRAFV600E mutated cervicomedullary GG treated with standard chemotherapy and surgery. After multiple relapse, BRAF status was analyzed by immunohistochemistry and sequencing showing a BRAFV600E mutation. Treatment with Vemurafenib as single agent was started. For the first time, a radiological and clinical response was obtained after 3 months of treatment and sustained after 6 months. CONCLUSION: Our experience underline the importance of understanding the driver molecular alterations of LGG and suggests a role for Vemurafenib in the treatment of pediatric GG not amenable of complete surgical resection.

Vemurafenib in pediatric patients with BRAFV600E mutated high-grade gliomas.

We present three pediatric patients with BRAFV600E mutant high-grade gliomas treated by vemurafenib on a nominative authorization level at our institution. One patient with anaplastic ganglioglioma experienced confirmed partial tumor response and significant clinical improvement and she is alive 20 months after start of treatment. A second patient with ganglioglioma responded transiently to re-introduction of vemurafenib after immunotherapy. Pharmacokinetic studies suggest that maximum concentration and exposure of vemurafenib at steady-state is dose-dependent and similar in children to that reported in adults. These cases suggest that BRAFV600 is an oncogenic driver in pediatric gliomas. Further exploration in clinical studies is ongoing.

Feasibility of metronomic maintenance chemotherapy following high-dose chemotherapy for malignant central nervous system tumors.

BACKGROUND: Children less than 5 years of age with malignant central nervous system (CNS) tumors, continue to have a high rate of morbidity and mortality following administration of conventional therapy. In an attempt to avoid the neurologic sequelae associated with craniospinal radiation, strategies such as high-dose chemotherapy (HDCT) followed by peripheral stem cell rescue have been used successfully. Metronomic chemotherapy has also been reported as a potential new treatment strategy in solid tumors, particularly in adults. PROCEDURE: A retrospective chart analysis was performed on 10 patients less than 5 years of age with CNS tumors treated with metronomic chemotherapy shortly after HDCT as part of their clinical care. RESULTS: Metronomic chemotherapy was associated with minimal toxicity and all patients maintained a good quality of life. At the time of this report, all 10 patients are alive. Two patients have relapsed, and the remaining eight, including six patients with metastatic disease, continue to have stable clinical and radiographic disease at a mean of 20 months from the time of diagnosis. CONCLUSIONS: Metronomic chemotherapy in this patient population is feasible and shows encouraging preliminary results, especially in patients with metastatic disease who have not received craniospinal radiation. Further investigation of this strategy in newly diagnosed patients with CNS tumors is warranted.