scholarly journals LGG-51. BRAF ALTERATIONS IN PEDIATRIC LOW-GRADE GLIOMAS: RESULTS FROM A BRAZILIAN COHORT

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii376-iii376
Author(s):  
Felipe Restine ◽  
Luis Henrique Sakamoto ◽  
Juliana Monte Real ◽  
Gregorio Pereira ◽  
Jennifer Marx Fernandes ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Braf V600e ◽  
Low Grade ◽  
Diffuse Astrocytoma ◽  
Central Nervous System Neoplasms ◽  
Low Grade Gliomas ◽  
Pilocytic Astrocytomas ◽  
First Results ◽  
Nervous System Neoplasms ◽  
Brazilian Cohort

Abstract BACKGROUND Pediatric low grade gliomas (PLGG) are the most common central nervous system neoplasms in children. These are driven almost exclusively by alterations in the RAS/MAPK pathway. Specifically, alterations in the BRAF gene have emerged as an important target for therapy. This study aimed to identify the frequency of BRAF alterations in a Brazilian cohort of PLGGs. RESULTS Forty-one patients diagnosed between 2001 and 2017 had enough FFPE tissue available for analysis. Real-time PCR test (n=35) was used to assess for BRAFV600E mutations, while BRAF fusions were detected by break-apart fluorescence in situ hybridization (n=30). The histologic distribution was as follows: 73% pilocytic astrocytoma, 12% ganglioglioma, 3% diffuse astrocytoma, 5% pleomorphic xanthoastrocytomas (PXA) and 7% NOS (n = 41). BRAF fusions were present in 21 patients (51%): 17 pilocytic astrocytomas, 2 xanthoastrocytoma, 1 pilomyxoid astrocytoma and 1 diffuse astrocytoma. BRAFV600E was detected in 4 cases (10%): 2 pilocytic astrocytomas, 1 ganglioglioma and 1 PXA. As expected, BRAF translocations were more frequent in pilocytic astrocytomas (p<0.001). From 22 patients treated in our institution, 59% were male with a mean age of 9.7 years, 50% occurred in the posterior fossa and 77% treated by surgery only. One patient relapsed and died from disease (BRAF V600E positive) (follow-up median=44.7 months). These are the first results using a CLIA method showing the frequency of BRAF abnormalities in a Brazilian population. Although preliminary, BRAF alterations are present in 61% of the cases emphasizing the importance of incorporating this analysis in the current work-up guidelines.

Molecular Alterations in Pediatric Low-Grade Gliomas That Led to Death

2021 ◽  
Author(s):  
Jared T Ahrendsen ◽  
Claire Sinai ◽  
David M Meredith ◽  
Seth W Malinowski ◽  
Tabitha M Cooney ◽  
...  
Keyword(s):  
Braf V600e ◽  
Molecular Characteristics ◽  
Low Grade ◽  
Diffuse Astrocytoma ◽  
Term Survival ◽  
Pten Loss ◽  
Low Grade Gliomas ◽  
Molecular Alterations ◽  
Idh1 R132h ◽  
Poor Outcomes

Abstract Pediatric low-grade gliomas (PLGGs) have excellent long-term survival, but death can occasionally occur. We reviewed all PLGG-related deaths between 1975 and 2019 at our institution: 48 patients were identified; clinical data and histology were reviewed; targeted exome sequencing was performed on available material. The median age at diagnosis was 5.2 years (0.4–23.4 years), at death was 13.0 years (1.9–43.2 years), and the overall survival was 7.2 years (0.0–33.3 years). Tumors were located throughout CNS, but predominantly in the diencephalon. Diagnoses included low-grade glioma, not otherwise specified (n = 25), pilocytic astrocytoma (n = 15), diffuse astrocytoma (n = 3), ganglioglioma (n = 3), and pilomyxoid astrocytoma (n = 2). Recurrence occurred in 42/48 cases, whereas progression occurred in 10. The cause of death was direct tumor involvement in 31/48 cases. Recurrent drivers included KIAA1549-BRAF (n = 13), BRAF(V600E) (n = 3), NF1 mutation (n = 3), EGFR mutation (n = 3), and FGFR1-TACC1 fusion (n = 2). Single cases were identified with IDH1(R132H), FGFR1(K656E), FGFR1 ITD, FGFR3 gain, PDGFRA amplification, and mismatch repair alteration. CDKN2A/B, CDKN2C, and PTEN loss was recurrent. Patients who received only chemotherapy had worse survival compared with patients who received radiation and chemotherapy. This study demonstrates that PLGG that led to death have diverse molecular characteristics. Location and co-occurring molecular alterations with malignant potential can predict poor outcomes.

scholarly journals LGG-12. TRAMETINIB FOR PEDIATRIC LOW GRADE GLIOMAS: A SINGLE INSTITUTION EXPERIENCE

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii368-iii368
Author(s):  
Mustafa Barbour ◽  
Michael Angelo Huang
Keyword(s):  
De Novo ◽  
Mapk Pathway ◽  
Neurofibromatosis Type ◽  
Mek Inhibitor ◽  
Pediatric Brain Tumors ◽  
Mitogen Activated Protein Kinase ◽  
Braf V600e ◽  
Low Grade ◽  
Low Grade Gliomas ◽  
Best Response

Abstract INTRODUCTION Low grade gliomas (LGG) are the most common pediatric brain tumors. Tumors not amenable to resection can recur or progress despite treatment with chemotherapy and/or radiation. Recent discovery of the activation of the mitogen-activated-protein-kinase (MAPK) pathway as the primary oncogenic driver for this group of tumors has led to a shift towards the use of BRAF and MEK inhibitors. METHODS Herein we performed a chart review of seven pediatric LGG treated with trametinib, a MEK inhibitor. While most were treated in the relapse setting, one patient was treated for de novo LGG as a result of experiencing multiple severe adverse effects to conventional agents. RESULTS Median age was 14 years old (range: 5 to 17 years). Six of seven patients had tissue for molecular characterization. The 2 patients with Neurofibromatosis Type 1 (NF-1) carried no other molecular aberrations. Two had the BRAF V600e mutation (1 had a concurrent PTPN11 mutation) and 2 were positive for the KIAA1549-BRAF fusion. Average duration on treatment was 8 months (range: 3 to 31 months). Disease control was achieved in 6 of 7 subjects, with one PR as best response. One patient with concurrent BRAF V600e and PTPN11 mutations progressed on trametinib and was switched to dual BRAF and MEK inhibitor therapy. Most common toxicities were acne (57.1%), oral mucositis (42.9%), skin rash, and paronychia (both 28.6%). Three patients required dose reduction and/or intermittent dose interruption. CONCLUSION Our data supports the use of trametinib for both upfront and relapsed/refractory pediatric LGG.

scholarly journals TMOD-23. A NOVEL BRAF V600E LOW-GRADE GLIOMA MOUSE MODEL HIGHLIGHTS EXOMIC AND TUMOR IMMUNE ALTERATIONS AND DIFFERING THERAPEUTIC RESPONSES IN LOW- AND HIGH-GRADE GLIOMAS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii232-ii233
Author(s):  
Anne Marie Barrette ◽  
Lasse Meyer ◽  
Yoko Hirata ◽  
Stefan Grossauer ◽  
Edbert Lu ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Low Grade Glioma ◽  
Braf V600e ◽  
Common Mutation ◽  
Low Grade ◽  
High Grade ◽  
Checkpoint Inhibition ◽  
Immune Infiltrate ◽  
Low Grade Gliomas

Abstract Pediatric low-grade glioma (pLGG), the most common brain cancer in children, is difficult to treat especially at recurrence. The BRAF V600E mutation is the second most common mutation in pLGG, and in a high-risk group for progression is associated with deletion of the tumor suppressor CDKN2A. A better understanding of the factors contributing to progression, in particular the role of the immune infiltrate is needed, but studies have been hindered by the lack of low-grade glioma mouse models. We utilized transgenic mice with a cre-activatable (CA) allele of BRAF V600E to generate endogenous models for low-grade gliomas. We found that BRAF V600E expression cooperates with hemizygous CDKN2A deletion to induce low-grade gliomas, with tumors forming at a greater latency than by homozygous deletion. Cell line derivatives from low-grade lesions continue to grow slower upon orthotopic injection than those we previously derived from high-grade tumors. Murine LGG can progress to higher grade tumors within the mouse lifespan and we observe exomic changes and alterations in the tumor immune infiltrate associated with progression, the details of which will be discussed at the meeting. High-grade cells’ phenotypic changes within in vivo passage are accompanied by exomic changes. The high-grade glioma immune infiltrate is altered by dual MAPK pathway inhibition with dabrafenib and trametinib. Adding dual immune checkpoint inhibition by anti-PD-L1 and anti-CTLA-4 antibodies significantly extends survival of dabrafenib-trametinib dual treatment. Human BRAF V600E mutant tumors reportedly have a higher tumor immune infiltrate than that of BRAF wildtype gliomas, consistent with our murine RESULTS: Here we present a novel model for BRAF V600E mutant gliomas in mice that has a frequent rate of progression, similar to human BRAF V600E mutant gliomas, and an active immune infiltrate in high grade tumors which makes them susceptible to the immunostimulatory effects of dual checkpoint inhibition.

scholarly journals LGG-18. EVEROLIMUS TREATMENT IN PEDIATRIC PATIENTS AFFECTED BY LOW-GRADE GLIOMAS (pLGG) NON-TSC, BRAF v600-WT

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii369-iii369
Author(s):  
Antonella Cacchione ◽  
Evelina Miele ◽  
Maria Chiara Lodi ◽  
Andrea Carai ◽  
Giovanna Stefania Colafati ◽  
...  
Keyword(s):  
Adverse Event ◽  
Disease Progression ◽  
Mapk Pathway ◽  
Brain Mri ◽  
Mammalian Target Of Rapamycin ◽  
Low Grade ◽  
Duration Of Treatment ◽  
Tumor Biopsy ◽  
Low Grade Gliomas ◽  
Personalized Approach

Abstract BACKGROUND MAPK pathway is the hallmark of pediatric low grade gliomas (pLGGs); hyperactivation of mTOR (mammalian target of rapamycin) might be a suitable biomarker for therapeutic response. We investigated the feasibility of Everolimus, mTOR inhibitor, in patients affected by pLGGs. METHODS Patients 1 to 18 years old, diagnosed with pLGG, with a positive tumor biopsy for mTOR/phospho-mTOR and radiological and / or clinical disease progression, treated at Bambino Gesù Children’s Hospital in Rome were evaluated. Tumor DNA methylation analysis was performed in 10 cases. Exclusion criteria included: Tuberous Sclerosis patients, Sub Ependymal Giant Astrocytoma. Everolimus was administered orally at a dose of 2.5 mg or 5 mg daily based on body weight. Patients were evaluated with brain MRI every 4, 8 and 12 months after treatment start and every six months thereafter. RESULTS 16 patients were enrolled from September 2014 and 2019. The median age was 7.5 years old. All patients had at least one adverse event. Events rated as severe (grade 3/4) were reported in 6 patients. Stomatitis was the most frequent adverse event. One patient discontinued treatment due to grade 4 toxicity (ulcerative stomatitis and fatigue). The median duration of treatment was 21 months (4–57 months). Brain MRI evaluations have showed disease stability in 11 patients, partial response in 2 patients and disease progression in 3 patients. CONCLUSIONS Everolimus has proven to be well tolerated and effective treatment in terms of disease stability in patients with pLGGs. It’s also an excellent example of chemo-free personalized approach.

scholarly journals HGG-02. ADOLESCENT AND YOUNG ADULT (AYA) GLIOMA WITH BRAF V600E-MUTANTATION

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii344-iii344
Author(s):  
Yui Kimura ◽  
Yukitomo Ishi ◽  
Yuko Watanabe ◽  
Yoshiko Nakano ◽  
Shigeru Yamaguchi ◽  
...  
Keyword(s):  
Braf Inhibitor ◽  
Clinical Information ◽  
Early Recurrence ◽  
Pleomorphic Xanthoastrocytoma ◽  
Adolescent And Young Adult ◽  
Braf V600e ◽  
Low Grade ◽  
Diffuse Astrocytoma ◽  
Genetic Features ◽  
Epithelioid Glioblastoma

Abstract BACKGROUND Biological features of pediatric glioma differ significantly from those of adult glioma, and limited data are available on those of AYA patients. Here, we focused on AYA patients with glioma, especially those harboring BRAF V600E mutation, and investigated their clinical and genetic features. METHOD: We retrospectively analyzed AYA patients with brain tumors harboring BRAF V600E, who were treated in two hospitals in Japan. RESULTS Clinical information was available for 14 patients. The median age at diagnosis was 25 years (range: 15–38). Five patients were diagnosed with glioblastoma (GBM), including one epithelioid type. These patients were over 25. Although one patient with GBM died of the disease 6.9 years after initial diagnosis, the remaining patients were alive. Two patients were alive without recurrence at 38 and 51 months after the treatment. The patient with epithelioid glioblastoma experienced early recurrence. The remaining nine patients (64%) were diagnosed with low-grade glioma, including ganglioglioma, pilocytic astrocytoma, diffuse astrocytoma, oligodendroglioma, pleomorphic xanthoastrocytoma, and polymorphous low-grade neuroepithelial tumor of the young. No patients died of the disease, and four patients are alive without recurrence after initial operation without adjuvant treatment. Two patients are (epithelioid glioblastoma and ganglioglioma) currently undergoing treatment with a BRAF inhibitor for recurrent tumors. DISCUSSION Although the number of this study is limited, our study suggested that the prognosis of AYA patients with BRAF-V600E positive GBM may not be as dismal as that of children or adults.

scholarly journals LGG-50. INTEGRATED MOLECULAR AND CLINICAL ANALYSIS OF 1,000 PEDIATRIC LOW-GRADE GLIOMAS UNCOVERS NOVEL SUBGROUPS FOR CLINICAL RISK STRATIFICATION

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii375-iii376
Author(s):  
Uri Tabori ◽  
Scott Ryall ◽  
Michal Zapotocky ◽  
Julie Bennett ◽  
Liana Nobre ◽  
...  
Keyword(s):  
Risk Stratification ◽  
Clinical Presentation ◽  
Mapk Pathway ◽  
Clinical Analysis ◽  
Genetic Alterations ◽  
Low Grade ◽  
Who Grade ◽  
Low Grade Gliomas ◽  
Younger Age ◽  
Risk Categories

Abstract Pediatric low-grade gliomas (pLGG) are primarily driven by genetic alterations in the RAS/MAPK pathway, most commonly involving BRAF of NF1. Despite their molecular convergence, pLGG often show unexplained variability in their clinical outcome. To address this, we molecularly characterized a cohort of >1,000 clinically annotated pLGG. 84% of cases harbored a detectable driver mutation. The remaining 16% of patients nonetheless showed RAS/MAPK pathway up-regulation at the RNA level. The clinical presentation and outcome of pLGG appeared highly variable and linked to the alteration type: re-arrangement or SNV. Re-arrangement-driven tumors were diagnosed at a younger age (6.6 versus 10.9 years, p<0.0001), enriched for WHO grade I histology (88% versus 66%, p<0.0001), infrequently progressed (27% versus 46%, p<0.0001), and rarely resulted in death (3 versus 13%, p<0.0001) as compared to SNV-driven tumors. These included the rarest molecular drivers of pLGG, for which we now have the clinicopathologic features of including MYB, MYBL1, FGFR2 fusions, FGFR1-TACC1, FGFR1 SNVs, IDH1 p.R132H, and H3.3 p.K27M. Utilizing this information, we suggest novel risk categories of pLGG that effectively predicted patient outcome. Low-risk tumors progressed infrequently and rarely succumbed to their disease (10-year PFS of 71% and OS of 98%). Intermediate-risk pLGG had a 10-year PFS and OS of 35% and 90%, respectively. High risk pLGG almost invariably progressed (10-year PFS of 0%) and these patients often succumbed to their disease (10-year OS of 41%). These data highlight the biological and clinical differences between pLGG subtypes and offers molecular based risk stratification to these cancers.

scholarly journals LGG-17. SYNERGISTIC ACTIVITY OF MAPK INHIBITOR CLASSES REVEALED BY A NOVEL CELL-BASED MAPK ACTIVITY PEDIATRIC LOW-GRADE GLIOMA ASSAY

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii369-iii369
Author(s):  
Diren Usta ◽  
Romain Sigaud ◽  
Juliane L Buhl ◽  
Florian Selt ◽  
Viktoria Marquardt ◽  
...  
Keyword(s):  
Cell Lines ◽  
Mapk Pathway ◽  
Braf V600e ◽  
Vector System ◽  
Luciferase Reporter ◽  
Low Grade ◽  
Brafv600e Mutation ◽  
Pathway Activity ◽  
Combination Treatments ◽  
Braf Fusion

Abstract Pilocytic astrocytomas (PAs) and other pediatric low-grade gliomas (pLGGs) exhibit aberrant activation of the MAPK signaling pathway caused by genetic alterations, most commonly KIAA1549:BRAF fusions, BRAF V600E and NF1 mutations. In such a single-pathway disease, novel drugs targeting the MAPK pathway (MAPKi) are prime candidates for treatment. We developed an assay suitable for pre-clinical testing of MAPKi in pLGGs, aiming at the identification of novel MAPK pathway suppressing synergistic drug combinations. We generated a reporter plasmid (pDIPZ) expressing destabilized firefly luciferase driven by a MAPK-responsive ELK-1-binding element, packaged in a lentiviral vector system. We stably transfected pediatric glioma cell lines with a BRAF fusion (DKFZ-BT66) and a BRAFV600E mutation (BT-40) background, respectively. Measurement of MAPK pathway activity was performed using the luciferase reporter. pERK protein levels were detected for validation. We performed a screen of a MAPKi library and calculated Combination Indices of selected combinations. The MAPKi library screen revealed MEK inhibitors as the class inhibiting the pathway with the lowest IC50s, followed by ERK and second generation RAF inhibitors. Synergistic effects in both BRAF-fusion and BRAFV600E mutation backgrounds were observed following combination treatments with different MAPKi classes (RAFi/MEKi, > RAFi/ERKi > MEKi/ERKi). We have generated a novel reporter assay for medium- to high-throughput pre-clinical drug testing of MAPKi in pLGG cell lines. MEK, ERK and next-generation RAF inhibitors were confirmed as potential treatment approaches for KIAA1549:BRAF and BRAFV600E mutated pLGGs. Synergistic suppression of MAPK pathway activity upon combination treatments was revealed using our assay in addition.

scholarly journals LGG-26. DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR (DLGNT) IN CHILDREN: DIFFERENT CLINICAL PRESENTATIONS AND OUTCOMES

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii371-iii371
Author(s):  
Andge Valiakhmetova ◽  
Ludmila Papusha ◽  
Ludmila Yasko ◽  
Alexander Druy ◽  
Alexander Karachunsky ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Braf Inhibitor ◽  
Complete Response ◽  
Mek Inhibitor ◽  
Braf V600e ◽  
Glioneuronal Tumor ◽  
Low Grade ◽  
Conventional Chemotherapy ◽  
Diffuse Leptomeningeal Glioneuronal Tumor ◽  
Braf Fusion

Abstract Diffuse leptomeningeal glioneuronal tumor (DLGNT) is an extremely rare disease, newly recognized in the 2016 WHO classification of tumors of the CNS. Most DLGNTs are low-grade neuroepithelial tumors with variable elements of neuronal/neurocytic and glial differentiation, have diffuse leptomeningeal enhancement on MRI, and typically harbor KIAA1549-BRAF fusions. Other alterations, such as the BRAF V600E substitution, are less common. Here, we present three cases of DLGNT with different presentations and outcomes. The first patient is a 2yr-old male with KIAA1549-BRAF fusion, and was treated with Carbo/VCR chemotherapy after a biopsy, with resultant ongoing stable disease for 3.5 years. The second patient, an 8yr-old male had the BRAF V600E point mutation and was treated with conventional chemotherapy (VCR/carboplatin). On progression, he received the BRAF inhibitor vemurafenib, achieving a complete response which last 14 month. The third patient, a 27 month old male, harbored a KIAA1549-BRAF fusion and was treated at diagnosis with the MEK inhibitor trametinib. The tumor has been radiographically stable in the context of clinical improvement for 21 months since the treatment initiation, ongoing 24 month. In summary, we present further evidence of MAPK pathway alterations in children with DLGNT. We describe a range of molecular presentations and clinical outcomes, including one patient treated with conventional chemotherapy with further stabilization of disease during 3.5 years and two patients who were successfully treated with targeted therapy.

Polymorphous Low-Grade Neuroepithelial Tumor of the Young (PLNTY): Molecular Profiling Confirms Frequent MAPK Pathway Activation

2021 ◽  
Author(s):  
Cristiane M Ida ◽  
Derek R Johnson ◽  
Asha A Nair ◽  
Jaime Davila ◽  
Thomas M Kollmeyer ◽  
...  
Keyword(s):  
Copy Number ◽  
Mapk Pathway ◽  
Braf V600e Mutation ◽  
Mitogen Activated Protein Kinase ◽  
Braf V600e ◽  
Low Grade ◽  
Pathway Activation ◽  
Mitogen Activated Protein ◽  
Copy Number Changes ◽  
Cd34 Expression

Abstract Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a recently described epileptogenic tumor characterized by oligodendroglioma-like components, aberrant CD34 expression, and frequent mitogen-activated protein kinase (MAPK) pathway activation. We molecularly profiled 13 cases with diagnostic histopathological features of PLNTY (10 female; median age, 16 years; range, 5–52). Patients frequently presented with seizures (9 of 12 with available history) and temporal lobe tumors (9 of 13). MAPK pathway activating alterations were identified in all 13 cases. Fusions were present in the 7 youngest patients: FGFR2-CTNNA3 (n = 2), FGFR2-KIAA1598 (FGFR2-SHTN1) (n = 1), FGFR2-INA (n = 1), FGFR2-MPRIP (n = 1), QKI-NTRK2 (n = 1), and KIAA1549-BRAF (n = 1). BRAF V600E mutation was present in 6 patients (17 years or older). Two fusion-positive cases additionally harbored TP53/RB1 abnormalities suggesting biallelic inactivation. Copy number changes predominantly involving whole chromosomes were observed in all 10 evaluated cases, with losses of chromosome 10q occurring with FGFR2-KIAA1598 (SHTN1)/CTNNA3 fusions. The KIAA1549-BRAF and QKI-NTRK2 fusions were associated respectively with a 7q34 deletion and 9q21 duplication. This study shows that despite its name, PLNTY also occurs in older adults, who frequently show BRAF V600E mutation. It also expands the spectrum of the MAPK pathway activating alterations associated with PLNTY and demonstrates recurrent chromosomal copy number changes consistent with chromosomal instability.

Selumetinib in patients with tumors with MAPK pathway alterations: Results from Arm E of the NCI-COG pediatric MATCH trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 10008-10008
Author(s):  
Carl E. Allen ◽  
Olive Eckstein ◽  
Paul M. Williams ◽  
Sinchita Roy-Chowdhuri ◽  
David R Patton ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Stable Disease ◽  
Thromboembolic Event ◽  
Mapk Pathway ◽  
Low Grade Glioma ◽  
Braf V600e ◽  
Low Grade ◽  
Match Trial ◽  
Hotspot Mutations ◽  
Clinical Trial Information

10008 Background: The NCI-Children’s Oncology Group (COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) trial assigns patients age 1 to 21 years with relapsed or refractory solid tumors, lymphomas, and histiocytic disorders to phase 2 treatment arms of molecularly-targeted therapies based on genetic alterations detected in their tumor. Arm E evaluated the MEK inhibitor selumetinib (ARRY-142886) in patients whose tumors harbored activating alterations in the MAPK pathway ( ARAF, BRAF, HRAS, KRAS, NRAS, MAP2K1, GNA11, GNAQ hotspot mutations; NF1 inactivating mutations; BRAF fusions). Methods: Patients received selumetinib 25 mg/m2/dose (max 75 mg/dose) PO BID for 28-day cycles until disease progression or intolerable toxicity with response assessments obtained every 2-3 cycles. The primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival (PFS). Patients with low grade glioma were excluded. Results: A total of 21 patients (median age 14 years; range 5-21) were enrolled between 10/2017 and 8/2019, with 20 patients evaluable for response. Diagnoses were high grade glioma (HGG; n = 8), rhabdomyosarcoma (n = 7), adenocarcinoma (n = 2), and one each of MPNST, endodermal sinus/yolk sac tumor, plexiform neurofibroma (PN), and neuroblastoma. MAPK pathway alterations detected consisted of inactivating NF1 mutations (n = 8), hotspot mutations in KRAS (n = 8), NRAS (n = 3), and HRAS (n = 1), and BRAF V600E (n = 2). No objective responses were observed. Three patients had a best response of stable disease (HGG with NF1 mutation, 6 cycles; HGG with KRAS mutation, 12 cycles; PN with NF1 mutation, 13 cycles prior to removal for dose-limiting toxicity). Six-month PFS was 15% (95% CI: 4%, 34%). Adverse events that were deemed possibly, probably, or definitely attributable to study drug included one case each of grade 3 uveitis, lymphopenia, and thromboembolic event; one grade 4 CPK elevation; and one grade 5 thromboembolic event. Conclusions: Selumetinib did not result in tumor regression in this cohort of children and young adults with treatment-refractory tumors with activating MAPK pathway alterations. Of note, two patients with HGG initially had stable disease, but ultimately progressed after 6 and 12 cycles, respectively. Selumetinib has previously demonstrated activity in low grade glioma and PN and is now FDA-approved for PN. The results of our study indicate that MAPK pathway mutation status alone is insufficient to predict response to selumetinib monotherapy. It is likely that selumetinib and other MEK inhibitors will require combination with targeted or cytotoxic agents for optimal efficacy in children with persistent or progressive cancers after front-line chemotherapy. Clinical trial information: NCT03213691. Clinical trial information: NCT03155620.

Sign in / Sign up

Export Citation Format

Share Document