scholarly journals Durable Progression-Free Survival With the Use of BRAF and MEK Inhibitors in Four Cases With BRAF V600E-Mutated Gliomas

2021 ◽  
Vol 28 ◽  
pp. 107327482110400
Author(s):  
Michael J. Fusco ◽  
Yolanda Piña ◽  
Robert J. Macaulay ◽  
Solmaz Sahebjam ◽  
Peter A. Forsyth ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Mapk Pathway ◽  
Case Series ◽  
Progression Free Survival ◽  
Mitogen Activated Protein Kinase ◽  
Braf V600e ◽  
Who Grade ◽  
Free Survival ◽  
Mek Inhibitors ◽  
Primary Brain Tumors

Introduction BRAF V600 E mutations have been identified in a subset of patients with primary brain tumors. Combination therapy with BRAF and Mitogen-activated protein kinase (MEK) inhibitors (BRAF/MEKi) targeting sequential steps in the MAPK pathway has replaced BRAFi monotherapy as the standard of care in multiple tumors with BRAF V600 E mutations, and clinical evidence for this strategy continues to grow in primary brain tumors. Case series We describe four patients with BRAF V600 E mutated gliomas, including a 21-year-old woman with a ganglioglioma WHO grade I, a 19-year-old man with a pleomorphic xanthoastrocytoma WHO grade III, and 21-year-old and 33-year-old women with epithelioid GBM WHO grade IV, who achieved durable progression-free survival with combination BRAF/MEKi. Conclusion Combination of BRAF/MEK inhibition can be a novel, promising approach as targeted therapy in gliomas with BRAF V600 E mutations, especially those that are resistant to standard therapy. Our cases, along with other early reports utilizing dabrafenib/trametinib, highlight the importance of somatic next-generation sequencing, particularly in younger patients. Interim results from clinical trials utilizing dabrafenib/trametinib have been promising thus far, and our case series suggests that durable clinical benefit is possible, even in the setting of glioblastoma, WHO grade IV.

Dual BRAF/MEK therapy in BRAF V600E-mutated primary brain tumors: a case series showing dramatic clinical and radiographic responses and a reduction in cutaneous toxicity

2020 ◽  
Vol 133 (6) ◽  
pp. 1704-1709 ◽  
Author(s):  
Aaron Bernstein ◽  
Oliver D. Mrowczynski ◽  
Amrit Greene ◽  
Sandra Ryan ◽  
Catherine Chung ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Pilocytic Astrocytoma ◽  
Case Series ◽  
Mek Inhibitor ◽  
Pleomorphic Xanthoastrocytoma ◽  
Inhibitor Therapy ◽  
Braf V600e ◽  
Dual Inhibitor ◽  
Cutaneous Toxicity ◽  
Primary Brain Tumors

OBJECTIVEBRAF V600E is a common oncogenic driver in a variety of primary brain tumors. Dual inhibitor therapy using dabrafenib (a selective oral inhibitor of several mutated forms of BRAF kinase) and trametinib (a reversible inhibitor of MEK1 and MEK2) has been used successfully for treatment of metastatic melanoma, anaplastic thyroid cancer, and other tumor types, but has been reported in only a few patients with primary brain tumors and none with pleomorphic xanthoastrocytoma. Here, the authors report on the substantial clinical response and reduction in cutaneous toxicity in a case series of BRAF V600E primary brain cancers treated with dual BRAF/MEK inhibitor therapy.METHODSThe authors treated 4 BRAF V600E patients, each with a different type of primary brain tumor (pilocytic astrocytoma, papillary craniopharyngioma, ganglioglioma, and pleomorphic xanthoastrocytoma) with the combination of dabrafenib and trametinib.RESULTSThe patients with pilocytic astrocytoma, pleomorphic xanthoastrocytoma, and papillary craniopharyngioma experienced near-complete radiographic and complete clinical responses after 8 weeks of therapy. A substantial partial response (by RANO [Response Assessment in Neuro-Oncology] criteria) was observed in the patient with ganglioglioma. The patient with craniopharyngioma developed dramatic, diffuse verrucal keratosis within 2 weeks of starting dabrafenib. This completely resolved within 2 weeks of adding trametinib.CONCLUSIONSDual BRAF/MEK inhibitor therapy represents an exciting treatment option for patients with BRAF V600E primary brain tumors. In addition to greater efficacy than single-agent dabrafenib, this combination has the potential to mitigate cutaneous toxicity, one of the most common and concerning BRAF inhibitor–related adverse events.

scholarly journals Overall survival and progression-free survival in patients with primary brain tumors after treatment: is the outcome of [18F] FDOPA PET a prognostic factor in these patients?

2019 ◽  
Vol 33 (7) ◽  
pp. 471-480 ◽  
Author(s):  
Agostino Chiaravalloti ◽  
Vincenzo Esposito ◽  
Francesco Ursini ◽  
Eugenio Di Giorgio ◽  
Maddalena Zinzi ◽  
...  
Keyword(s):  
Overall Survival ◽  
Prognostic Factor ◽  
Brain Tumors ◽  
Progression Free Survival ◽  
Free Survival ◽  
Primary Brain Tumors

scholarly journals BRAF, MEK, and EGFR Triplet Inhibitors as Salvage Therapy in BRAF-Mutated Metastatic Colorectal Cancer—A Case Series Study Target Therapy of BRAF-Mutated mCRC

Medicina ◽  
2021 ◽  
Vol 57 (12) ◽  
pp. 1339
Author(s):  
Jen-Hao Yeh ◽  
Hsiang-Lin Tsai ◽  
Yen-Cheng Chen ◽  
Ching-Chun Li ◽  
Ching-Wen Huang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Metastatic Colorectal Cancer ◽  
Case Series ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Mitogen Activated Protein Kinase ◽  
Free Survival ◽  
Mitogen Activated Protein ◽  
Epidermal Growth

Backgroundand objectives: Patients with BRAF-mutated metastatic colorectal cancer have considerably poorer responses to conventional systemic treatment. The real-world effects of triplet therapy with BRAF, mitogen-activated protein kinase kinase, and epidermal growth factor receptor inhibitors in Asia have not been well-reported. Materials and Methods: This single-center case series included patients with BRAF-mutated metastatic colorectal cancer undergoing triplet therapy after failure of prior systemic treatment from 2016 to 2020. The primary outcome was progression-free survival, and secondary outcomes were overall survival, response rate, disease control rate, and adverse events. Results: Nine eligible patients with BRAF-mutated metastatic colorectal cancer receiving triplet therapy were enrolled, with a median follow-up time of 14.5 months (range, 1–26). Most patients (88.8%) had two or more prior systemic treatments, and the triplet regimen was mainly dabrafenib, trametinib, and panitumumab. The overall response rate and disease control rate were 11.1% and 33.3%, respectively. Median progression-free survival and overall survival were 2.9 and 7.4 months, respectively, and a trend toward better overall survival was found with left-sided metastatic colorectal cancer compared with right-sided disease (9.2 vs. 6.9 months, p = 0.093). Adverse events were mostly Grade 1–2, including nausea, hypertension, gastrointestinal symptoms, and skin disorders. Conclusions: In this single-center case series, triplet therapy with BRAF, mitogen-activated protein kinase kinase, and epidermal growth factor receptor inhibitors in BRAF-mutated metastatic colorectal cancer had an acceptable safety profile and reasonable efficacy.

scholarly journals Rapid Response in a Patient with Relapsed/Refractory Multiple Myeloma Treated with BRAF/MEK Inhibitors

2020 ◽  
Vol 2020 ◽  
pp. 1-4
Author(s):  
Steve Biko Otieno ◽  
Syed Nasir ◽  
Alva Weir ◽  
Robert Johnson
Keyword(s):  
Multiple Myeloma ◽  
Mapk Pathway ◽  
Progression Free Survival ◽  
Mitogen Activated Protein Kinase ◽  
Hairy Cell ◽  
Free Survival ◽  
Refractory Multiple Myeloma ◽  
Mitogen Activated Protein ◽  
Inhibitor Resistance ◽  
Cancer Côlon

Patients with relapsed and refractory multiple myeloma have a poor prognosis. The mitogen-activated protein kinase (MAPK) pathway has been implicated in the pathogenesis of multiple myeloma. Several mutations in this pathway can lead to its constitutive activation leading to oncogenesis. One such mutation is BRAFV600E which is a therapeutic target in the treatment of melanoma, lung cancer, colon cancer, thyroid cancer, and hairy cell leukemia. BRAFV600E-directed therapy currently does not have approval in multiple myeloma. It has been proposed that this mutation leads to proteasome inhibitor resistance. About 4–10% of multiple myeloma cases harbor the BRAFV600E mutation. Herein, we report a case of a patient with relapsed and refractory multiple myeloma who had a progression-free survival (PFS) of 8.5 months on BRAF-targeted therapy.

Eleven Month Progression–Free Survival on Vemurafenib Monotherapy in a Patient With Recurrent and Metastatic BRAF V600E–Mutated Glioblastoma WHO Grade 4

2017 ◽  
pp. 1-5 ◽  
Author(s):  
Kanita Beba Abadal ◽  
Meggen A. Walsh ◽  
Anthony T. Yachnis ◽  
David D. Tran ◽  
Ashley P. Ghiaseddin
Keyword(s):  
Progression Free Survival ◽  
Braf V600e ◽  
Who Grade ◽  
Free Survival

scholarly journals RTID-05. INDIGO: A GLOBAL, RANDOMIZED, DOUBLE-BLIND, PHASE 3 STUDY OF VORASIDENIB (AG-881) VS PLACEBO IN PATIENTS WITH RESIDUAL/RECURRENT GRADE II GLIOMA WITH AN ISOCITRATE DEHYDROGENASE 1/2 (IDH1/2) MUTATION

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii194-ii194
Author(s):  
Ingo Mellinghoff ◽  
Martin van den Bent ◽  
Jennifer Clarke ◽  
Elizabeth Maher ◽  
Katherine Peters ◽  
...  
Keyword(s):  
High Risk ◽  
Dose Escalation ◽  
Objective Response ◽  
Data Monitoring Committee ◽  
Progression Free Survival ◽  
High Risk Population ◽  
Low Grade ◽  
Who Grade ◽  
Free Survival ◽  
Grade Ii

Abstract BACKGROUND Low-grade gliomas (LGGs; WHO grade II) are incurable and ultimately progress to high-grade gliomas. The current treatment options are surgery followed by observation (“watch and wait”) for patients with lower risk for disease progression or postoperative chemoradiotherapy (high-risk population). There are no approved targeted therapies. IDH1 and IDH2 mutations (mIDH1/2) occur in approximately 80% and 4% of LGGs, respectively, and promote tumorigenesis via neomorphic production of D-2-hydroxyglutarate. Vorasidenib, an oral, potent, reversible, brain-penetrant pan-inhibitor of mIDH1/2, was evaluated in 76 patients with glioma in two phase 1 studies (dose escalation and perioperative) and was associated with a favorable safety profile at daily doses below 100 mg. Preliminary clinical activity was observed in non-enhancing glioma patients in both studies, with an objective response rate (ORR) of 18.2% and median progression-free survival of 31.4 months in the dose escalation study. METHODS Approximately 366 patients will be randomized 1:1 to vorasidenib (50 mg QD) or matched placebo and stratified by 1p19q status (intact vs co-deleted). Key eligibility criteria: age ≥ 12 years; grade II oligodendroglioma or astrocytoma (per WHO 2016 criteria) not in need of immediate treatment and without high-risk features; centrally confirmed mIDH1/2 status; ≥ 1 surgery for glioma with most recent ≥ 1 year but ≤ 5 years before randomization, and no other anticancer therapy; Karnofsky performance status ≥ 80%; and centrally confirmed measurable, non-enhancing disease evaluable by magnetic resonance imaging. Crossover from placebo to the vorasidenib arm is permitted upon centrally confirmed radiographic progression per RANO-LGG criteria. Primary endpoint: progression-free survival assessed by independent review. Secondary endpoints: safety and tolerability, tumor growth rate assessed by volume, ORR, overall survival, and quality of life. Clinical data will be reviewed regularly by an independent data monitoring committee. The study is currently enrolling patients in the US, with additional countries planned (NCT04164901).

scholarly journals EXTH-16. TREATMENT OF THREE DIFFERENT BRAF-V600E POSITIVE BRAIN TUMORS WITH VEMURAFENIB AND DABRAFENIB/TRAMETINIB: A CASE SERIES

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii90-ii90
Author(s):  
Nikita Dhir ◽  
Sheila Chandrahas ◽  
Chibuzo O’Suoji ◽  
Mohamad Al-Rahawan
Keyword(s):  
Targeted Therapy ◽  
Brain Tumors ◽  
Tumor Regression ◽  
Case Series ◽  
Pediatric Brain Tumors ◽  
Braf V600e ◽  
Cns Tumors ◽  
Braf Inhibitors ◽  
Pediatric Brain ◽  
Pediatric Cns Tumors

Abstract BACKGROUND The BRAF-V600E gene is a protein kinase involved in regulation of the mitogen activated protein kinase pathway (MAPK/MEK) and downstream extracellular receptor kinase (ERK). The BRAF-V600E mutation has a significant role in the progression of pediatric brain tumors. 85% of pediatric CNS tumors express the BRAF mutation. Thus, BRAF targeted therapy in pediatric CNS malignancies has potential to become the standard of care for tumors expressing this mutation. OBJECTIVE Current pediatric CNS brain tumor treatment focuses on chemotherapy and radiation, causing significant toxic side effects for patients. The significance of this case series lies in relaying our experience using targeted therapy in BRAF-V600E positive CNS pediatric brain tumors. METHODS We followed the disease course, progression, and treatment of three pediatric patients with three different CNS tumors. Each of these individuals was treated with surgical resection, chemotherapy, and/or radiation as per standard protocol. When that modality failed to reduce tumor progression, we found that each of their different tumors was BRAF-V600E positive and they were all started on targeted therapy. DISCUSSION Vemurafenib, Dabrafenib, and Trametinib are BRAF-V600E/MEK inhibitors that were initially used to treat melanomas. However, more research has shown that various pediatric CNS tumors are BRAF-V600 positive. Therapy with these BRAF inhibitors has been shown to slow tumor progression, but toxicity can be severe. This case series shows one patient with successful tumor regression, one patient with prolonged disease stabilization, and one patient with initial response but subsequent progression and ultimate death. It has been shown that using BRAF inhibitors in lower grade CNS tumors are more effective than higher grade CNS tumors. CONCLUSION The success of Vemurafenib and Dabrafenib/Trametinib in causing pediatric CNS tumor regression is promising, but further studies are needed to solidify their role in pediatric CNS cancers.

scholarly journals PATH-18. A MULTI-CENTER CASE SERIES OF ADULT K27M MUTATED DIFFUSE MIDLINE GLIOMAS REVEALING A POPULATION UNIQUE FROM PAEDIATRIC CASES

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii167-ii168
Author(s):  
Alexander Yuile ◽  
Madhawa De Silva ◽  
Marina Kastelan ◽  
Veronica Cheung ◽  
Joanne Sy ◽  
...  
Keyword(s):  
Older Patients ◽  
Selection Criteria ◽  
Case Series ◽  
Progression Free Survival ◽  
Paediatric Population ◽  
Asia Pacific ◽  
Royal North Shore Hospital ◽  
Free Survival ◽  
Delay In Diagnosis ◽  
Presenting Symptoms

Abstract BACKGROUND Histone mutations in the K27M gene were first described in 2014, and incorporated into the WHO CNS tumour classification system in 2016. They are typically associated with diffuse midline gliomas (DMG). Presenting symptoms vary greatly, with some experiencing significant delay in diagnosis. Median survival is only 9-12 months for these patients. Biopsy samples are small, and in some due to location, not performed. Although data is predominately based on the paediatric population, DMGs are seen in both adolescence and adults. In this multi-site retrospective study, we describe 11 adult patients with K27M DMG gliomas across two tertiary Neuro-Oncology services in Sydney, Australia. To the authors’ knowledge we present the largest known collection of adult K27M cases in the Asia-Pacific region with correlation of treatment, clinicopathologic and radiologic features with outcomes. METHODS The glioma databases of Royal North Shore Hospital (RNSH) and Royal Prince Alfred Hospital (RPAH) between January 2009 and March 2020 were interrogated to identify patients. Selection criteria included patients aged ≥ 18 years who presented with a DMG, had undergone biopsy, and had confirmed K27M via next generation sequencing. Clinicopathologic, radiologic and treatment outcomes were extracted for correlation. RESULTS Eleven patients fitting the selection criteria were identified and reported. The median age at diagnosis was 30 years and 4 were female. Five presented with hydrocephalus, the most common presenting symptoms were headaches and nausea and/or vomiting (n= 4 and n= 2 respectively). The median progression-free survival was 13 months (4-31 months) and the median overall survival was 23 months (4-59 months). CONCLUSION This case series reports the outcomes of older patients with K27M. The clinical course demonstrated suggests a divergence from paediatric biology. Ongoing studies are required to further characterise the histopathological and clinical differences of these tumours in older patients.

scholarly journals PCV chemotherapy alone for WHO grade 2 oligodendroglioma: prolonged disease control with low risk of malignant progression

2021 ◽  
Author(s):  
Jonathan Weller ◽  
Sophie Katzendobler ◽  
Philipp Karschnia ◽  
Stefanie Lietke ◽  
Rupert Egensperger ◽  
...  
Keyword(s):  
Stereotactic Biopsy ◽  
Tumor Volume ◽  
Progression Free Survival ◽  
Who Grade ◽  
Free Survival ◽  
First Relapse ◽  
Pcv Chemotherapy ◽  
Grade 3 ◽  
Histological Progression

Abstract Introduction The role of chemotherapy alone in newly diagnosed WHO grade 2 oligodendroglioma after biopsy, incomplete or gross total resection remains controversial. We here analyze the clinical outcome of four patient cohorts being treated with either procarbazine, CCNU and vincristine (PCV) or temozolomide (TMZ) after biopsy, resection only, or wait-and-scan after biopsy. Methods Patients (n = 142) with molecularly defined oligodendroglioma (WHO 2016) were assigned to four cohorts: W&S, wait-and-scan after stereotactic biopsy (n = 59); RES, surgical resection only (n = 27); TMZ, temozolomide after biopsy (n = 26) or PCV (n = 30) after biopsy. Presurgical MRI T2 tumor volumes were obtained by manual segmentation. Progression-free survival (PFS), post-recurrence PFS (PR-PFS) and rate of histological progression to grade 3 were analyzed. Results PFS was longest after PCV (9.1 years), compared to 5.1 years after W&S, 4.4 years after RES and 3.6 years after TMZ. The rate of histological progression from grade 2 to 3 within 10 years was 9% for the PCV, 29% for the W&S, 67% for the RES and 75% for the TMZ group (p = 0.01). In the W&S group, patients treated with PCV at first relapse had a longer PFS from intervention than those treated with TMZ (7.2 vs 4.0 years, p = 0.04). Multivariate analysis identified smaller tumor volume prior to any intervention (p = 0.02) to be prognostic for PFS. Conclusions PCV chemotherapy alone is an effective treatment for WHO grade 2 oligodendroglioma, with long PFS and low rate of histological progression.

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