Progressive Low-grade Glioma Research Articles

NCOG-33. MTOR INHIBITORS AS ADJUVANT TARGETED THERAPY IN PEDIATRIC PATIENTS WITH PROGRESSIVE OR REFRACTORY LOW-GRADE GLIOMA: A SINGLE-CENTER RETROSPECTIVE STUDY

Abstract Low grade gliomas (LGG) represent about one-third of all pediatric central nervous system tumors, with about half having disease progression despite upfront surgery and adjuvant therapies. Current treatments for LGG progression either produce toxic side effects (i.e., radiation therapy) or do not generate durable responses. Targeted agents are an effective way of attacking tumors with identified genetic mutations, but in some cases, a complete response can be subverted by the heterogeneity of tumors. Additionally, most tumors do not carry any targetable mutations. Temsirolimus and everolimus are mTOR inhibitors that have previously been shown to be well-tolerated in early clinical studies in pediatric solid tumors. We performed a retrospective study to look at the toxicity profile of mTOR inhibitors when given in combination therapy and treatment response in patients with progressive or refractory LGG. We examined 20 patients with a diagnosis of LGG including mixed glioma and glioneuronal tumors who received treatment at our institution from 2016-2024 with targeted therapy, of which 8 patients also received temsirolimus or everolimus. Of these 8 patients, 2 had partial response, 2 had minor response, 3 had stable disease, and 1 had progressive disease. The average number of cycles received was 13.6 (range 3-24). Most observed side effects were grade 2 or less, including nausea, transaminitis, myelosuppression, diarrhea, and hyperlipidemia while grade 3/4 toxicities that required dose modification included mucositis, hyperglycemia, and hyperlipidemia. Overall, the addition of temsirolimus to treatment regimens of pediatric patients with heavily pretreated refractory LGG prolonged progression free survival by an average of 478 days with only one patient progressing while on therapy. These results demonstrate feasibility and preliminary efficacy of adding mTOR inhibitors as adjuvant therapy in this patient population. There is dire need of large prospective collaborative studies in the future.

LMIC-02. FREQUENCY OF NTRK FUSIONS IN PEDIATRIC LOW GRADE GLIOMAS. DATA FROM A SINGLE CENTER IN MONTERREY, MEXICO

Abstract BACKGROUND Neurotrophic tyrosine receptor kinases (NTRK 1-3)fusions have been identified in a range of pediatric cancer. Among children with cancer NTRK fusions can be detected in less than 1% of cases. Low grade gliomas (LGG) are the most pediatric brain tumors and the frequency of NTRK fusions reported is between 0.4 -4.3%. NTRK2 fusions are the most commonly reported in pediatric brain tumors. METHOD We describe the characteristics of patients analysed. Due to limited access to Next Generation Sequencing (NGS) only patients with recurrent, progressive, metastatic or midline location LGG were tested during 2021-2022. Positivity to Pan-Trk immunohistochemistry was needed to proceed to confirmation with NGS. 10 patients with LGG were included. Median age of patients at baseline was 4.7 (range,1-12) years. 10/10 showed positivity to Pan-Trk stain and NTRK fusions were detected in 6/10 patients, 3/6 had NTRK1 fusions, 2/6 NTRK2 fusion and 1 with NTRK3 fusion.. All 4 patients without NTRK fusions are off therapy (more than 1 year survellaince) and 2/4 were treated with surgery only. All patients with NTRK fusions are still on treatment due to progressive disease, 4/6 patients have required 2 or more surgeries and 5/6 patients have needed 2 or more chemotherapy regimens. CONCLUSION This small cohort of patients represents a highly selected population with LGG and the frequency of NTRK fusions resulted significantly higher than expected (6 out of 10 patients tested). This finding could reflect a clinical or prognostic significance, it will be important to analyze a larger cohort of patients that share these same clinical characteristics to determine its real value as a prognostic marker in these heavily treated patients. There is well known molecular alterations that predict outcome in patients with LGG. NTRK targeted therapy already exists with proven efficacy although access may limits its use.

NFS-05. INCIDENCE OF BEVACIZUMAB ASSOCIATED TOXICITY IN CHILDREN WITH LOW GRADE GLIOMA WITH AND WITHOUT NF1

Abstract BACKGROUND Low grade gliomas (LGG), both sporadic & Neurofibromatosis1 (NF1) associated, are the commonest pediatric brain tumors. When surgically unresectable, they may become progressive/ symptomatic and require chronic oncological treatment. Bevacizumab (BVZ; Avastin), a recombinant humanized monoclonal antibody to VEGF, has shown efficacy both as a single agent or combined with chemotherapy as second/ third line treatment of progressive LGG especially in the optic pathway. BVZ can be associated with adverse effects including hypertension (HTN) and proteinuria. Children with NF1 have known increased tendency to hypertension however there is no data comparing the frequency of side effects from BVZ in patients with or without NF1. METHODS Retrospective study of all LGG cases treated with BVZ diagnosed 2010-2023 in a tertiary oncology center. We graded hypertension, proteinuria, cardiac function, retinopathy & bleeding according to the CTCAE v5.0 in NF1 and non-NF1 patients. RESULTS 16 children with LGG were treated with BVZ; 7 had NF1. 75% optic glioma, 25% other. All received BVZ as second or third line treatment in combination with chemotherapy. In the non NF1 group, 77% patients developed grade 2 HTN on BVZ treatment; none required medical intervention. 6 had grade 1 elevation of protein-creatinine ratio (median 0.38). In the NF1 group, 71% developed grade 2 or 3 HTN on BVZ treatment including a patient with aortic coarctation (CoA) who had worsening of previous HTN, 2 required antihypertensive therapy (p non-significant HTN non NF1 vs. NF1). Only 1 NF1 patient developed proteinuria. No patients in either group stopped BVZ prematurely for toxicity. Hypertension was reversible after cessation of BVZ in all except the patient with CoA. CONCLUSIONS Hypertension is more common than previously reported in both NF1 and non-NF1 patients treated with BVZ for LGG. Blood pressure should be monitored and treated appropriately. BVZ is safe in young patients with NF1.

NIMG-47. LONGITUDINAL TRAJECTORIES FROM SERIAL SURVEILLANCE MRI IMAGING OF PROGRESSIVE IDH MUTANT LOW-GRADE GLIOMA PATIENTS

Abstract BACKGROUND Most patients with isocitrate dehydrogenase mutant (IDHm) low-grade glioma (LGG) undergo active MRI surveillance after initial surgery. Timely biopsy referral during surveillance is a complex trade-off between avoiding the harms of unnecessary surgery and early detection of transformation. Serial surveillance MRIs could be leveraged to develop dynamic imaging markers, yet prior research has primarily focused on the prognostication of pre-treatment images. We piloted the feasibility of an automated pipeline using patient-specific imaging trajectories. METHODS We retrospectively identified 12 progressive IDHm LGG patients and collected serial surveillance MRIs. A previously developed segmentation model was fine-tuned on a subset of T2/FLAIR images (n=49) before automated tumor segmentation was performed on all MRIs. We extracted geometric and topological tumor features, including volume, cross product, and Euler Characteristic Transform, from each MRI. We used piecewise linear regression to quantify feature trajectories and identify change points in feature growth rates. RESULTS Twelve patients received 14 biopsies/repeat resections (10 with transformation, 4 without) and 282 MRIs (median per patient: 17, range: 10-40). All biopsies/repeat resections were preceded by a change point in tumor volume trajectory, indicating an increase in tumor growth rate preceding clinician-determined MRI progression and biopsy referral. The mean increase in volume growth rate, pre to post change point, was 2.3cm3/month (SE: 0.9) in biopsies/repeat resections with transformation, compared to 1.1cm3/month (SE: 0.6) in biopsies/repeat resections without transformation. Among the ten patients with transformation, the median time from IDHm LGG diagnosis to transformation was 64.8 months (range: 38.6-141.1), and the median time between volume change point and transformation was 15.6 months (range: 4.6-28.2). DISCUSSION This pilot study suggests that feature trajectories from serial MRIs of IDHm LGG patients may advance the detection and treatment of transformed lesions by 12-18 months. Larger studies can corroborate these findings and inform clinical decision-making.

Clinical activity of pan-RAF inhibitor tovorafenib in the registrational pediatric low-grade glioma arm of the phase 2 FIREFLY-1 (PNOC026) study.

10004 Background: Pediatric low-grade gliomas (LGGs) are the most common brain tumors of childhood. Genomic alterations of BRAF ( KIAA1549-BRAF fusions, 50–60% and BRAF V600E mutations, 5–15%) are the most frequent oncogenic drivers in pLGGs. Tovorafenib is an investigational, oral, selective, brain-penetrant, small molecule, type II pan-RAF inhibitor. Tovorafenib has demonstrated clinically meaningful responses in 24/35 patients (2 CR, 7 PR and 15 SD) in the pediatric phase 1B PNOC014 (NCT03429803) trial in patients with RAF-altered cancers (Wright, SNO 2022). Methods: FIREFLY-1 (NCT04775485) is a multicenter phase 2 study evaluating the efficacy and safety of tovorafenib monotherapy in patients with BRAF-altered cancers. Registrational arm 1 of FIREFLY-1 includes patients 6 months–25 years of age with recurrent or progressive LGG previously treated with ≥1 prior line of systemic therapy. Tovorafenib 420 mg/m2 (not to exceed 600 mg) is administered weekly, in 28-day cycles, (tablet or liquid suspension formulation) until progression. The primary endpoint of arm 1 is ORR, as defined by Response Assessment in Neuro-Oncology (RANO) criteria and determined by blinded independent review. Results: As of September 28, 2022, arm 1 had enrolled 77 patients and is fully accrued. All patients had ≥6 months of follow-up. Median age at enrollment was 8 years (range 2–21). Patients were pretreated with a median of 3 prior lines of systemic therapy (range: 1–9); 60% had received prior MAPK pathway-targeted agents. The most common tumor site was optic pathway (51%). Sixty-four patients harbored a BRAF fusion/rearrangement (83%) in their tumors, and 13 (17%) had a BRAF V600E mutation. Median duration of tovorafenib treatment is 8.4 months (range 0.7–16.8), with 59 patients (77%) remaining on treatment at the time of data cutoff. Per independent assessment in 69 RANO-evaluable patients, ORR was 64%, [3 CR, 41 PR (10 unconfirmed) and 19 SD] with a clinical benefit rate of 91%. Responses were achieved in tumors with BRAF fusions and V600E mutations, including those previously treated with MAPK inhibitors. The most common treatment-related adverse events (TRAEs) of any grade were hair color changes (75%), increased creatine phosphokinase (64%), anemia (46%), fatigue (42%) and maculopapular rash (42%). Tovorafenib dose modifications occurred in 16 (21%) and discontinuations in 2 (3%) patients due to TRAEs. Updates from a longer follow-up on the 77 patients in arm 1 will be presented at the meeting. Conclusions: Tovorafenib was generally well tolerated and showed encouraging evidence of antitumor activity in children and young adults with recurrent/progressive BRAF-altered pLGG. LOGGIC/FIREFLY-2 (NCT05566795), a global, phase 3 trial is evaluating once-weekly tovorafenib monotherapy in newly-diagnosed patients with pLGG harboring a known activating RAF alteration. Clinical trial information: NCT04775485 .

Evaluating Focal Areas of Signal Intensity (FASI) in Children with Neurofibromatosis Type-1 (NF1) Treated with Selumetinib on Pediatric Brain Tumor Consortium (PBTC)-029B

Understanding the effect of selumetinib on FASI may help elucidate the biology, proliferative potential, and role in neurocognitive changes for these NF1-associated lesions. Patients with NF1-associated LGG and FASI treated with selumetinib on PBTC-029B were age-matched to untreated patients with NF1-associated FASI at Cincinnati Children's Hospital Medical Center. Paired bidirectional measurements were compared over time using nonparametric tests. Sixteen age-matched pairs were assessed (age range: 2.8-16.9 years, 60% male). Initial FASI burden was not different between groups (median range 138.7 cm2 [88.4-182.0] for the treated subjects vs. 121.6 cm2 [79.6-181.9] for the untreated subjects; p = 0.98). Over a mean follow-up of 18.9 (±5.9) months, the LGG size consistently decreased with treatment while no consistent change among the treated or untreated FASI size was seen. At the paired time points, the median treated LGG decreased significantly more than the treated FASI (-41.3% (LGG) versus -10.7% (FASI), p = 0.006). However, there was no difference in the median size change in the treated versus untreated FASI (-10.7% (treated FASI) versus -17.9% (untreated FASI), p = 0.08). Among the treated subjects, there was no correlation between the change in LGG and FASI (r = -0.04, p = 0.88). Treatment with selumetinib did not affect the overall FASI size in children with NF1 treated for progressive low-grade glioma.

Use of Trametinib in Children and Young Adults With Progressive Low-grade Glioma and Glioneuronal Tumors.

Low-grade gliomas/glioneuronal tumors comprise one-third of all pediatric-type CNS tumors. These tumors are generally caused by activating mutations in the mitogen-activated protein kinase (MAPK) pathway. Targeted drugs, such as trametinib, have shown promise in other cancers and are being utilized in low-grade gliomas. A retrospective chart review was conducted to evaluate radiographic response, visual outcomes, tolerability, and durability of response in progressive circumscribed low-grade gliomas treated with trametinib. Eleven patients were treated with trametinib. The best radiographic response was 2/11 partial response, 3/11 minor response, 3/11 stable disease, and 3/13 progressive disease. In the patients with partial or minor response, the best response was seen after longer durations of therapy; 4 of 5 best responses occurred after at least 9 months of therapy with a median of 21 months. Patients with optic pathway tumors showed at least stable vision throughout treatment, with 3 having improved vision on treatment. Trametinib is effective and well-tolerated in patients with progressive low-grade glioma. Best responses were seen after a longer duration of therapy in those with a positive response. Patients with optic pathway lesions showed stable to improved vision while on treatment.

Efficacy of different salvage regimens in progressive unresectable pediatric low-grade glioma.

Multiple salvage chemotherapy regimens are used in progressive low-grade glioma (LGG), with no single regimen being more effective than any other. In the present study, different salvage therapies were compared with regard to the response rate, overall survival (OS) rate, event-free survival (EFS) rate and visual outcome in 70 patients with pediatric LGG. Age was found to significantly affect the EFS and OS rates (P<0.001). The visual outcome was the same between the three regimens. The 2-year EFS and OS rates of the vincristine/carboplatin, monthly carboplatin and weekly vinblastine regimens were 64.7 and 70.6%, 71.0 and 85.0%, and 56.0 and 62.7%, respectively (P=0.6 for EFS; P=0.56 for OS). Overall, the present study demonstrated that age had a significant impact on survival. The three salvage regimens used were equally effective with regard to the radiological response and visual outcome. However, further randomized controlled trials are required to detect the optimal salvage therapy.

LGG-09. A Nationwide Service Evaluation of Safety, Radiologic and Visual Outcome Refining Bevacizumab-based Treatments in Children with Progressive Low-Grade Glioma

INTRODUCTION: Bevacizumab/Irinotecan is currently 3rd-line treatment in the UK for progressive Paediatric Low-Grade Glioma (PLGG) based on limited evidence. A nationwide service evaluation was conducted to review its safety and efficacy amongst a larger cohort. METHODS: Data from children with PLGG receiving Bevacizumab-based Treatments (BBT) from 11 UK Centres (2009-2020) were reviewed. Radiological and visual outcomes were based on standardized measurements. Clinical-radiological correlation was investigated. Time to progression from BBT stop, progression free-survival (PFS) curves and multivariate analysis of prognostic factors (p 0.05) were performed. RESULTS: 88 children with PLGG (88% OPG, 24% NF1) had BBT for radiological (43%), visual (20%) or combined (27%) progression, after 40 months (median) from diagnosis. Amongst OPG cases, visual acuity (VA) per eye (better/worse) before BBT was logMAR 0.0-0.3 (23/7) 0.3 - 1.0 (27/20), > 1.0 (14/18) and LP/NLP (8/27), with 19/8 children respectively blind (LP/NLP) in one or both eyes. Bevacizumab 10 mg/kg every 14 days (median 24 doses) was given as 3rd line+ with Irinotecan (85%) or alongside 1st/2nd line chemo (15%) leading to remarkable radiological (88%) and visual (74%) responses (stable or improved) within 3-6 months, with limited toxicity. 12% progressed on treatment, and 8% died unrelated to BBT. After initial response 65% progressed at a median of 8 months (4 - 23) after BBT, resulting in 3-year-all-causes-PFS of 16% and 3-yr-visual-PFS of 45% from start of BBT. Visual concordance with MRI was poor (36%) but increases (47%) when better-eye determines visual outcome. Lack of NF1 and diencephalic syndrome (DS) at presentation were independent negative prognostic factors for PFS. CONCLUSIONS: A remarkable but transient effect of BBT has been confirmed. Visual > radiological responses can be sustained after BBT. Variations in current BBT strategies justifies further research, including the potential upfront use alongside conventional first-line chemotherapy as sight-saving strategy.

LGG-28. Rapid symptomatic improvement for a patient treated with BRAF inhibition for BRAFV600E mutated ganglioglioma

BACKGROUND: Biologically targeted agents such as the BRAF inhibitor dabrafenib are now used to treat progressive low-grade glioma (LGG), but the effect of these agents on the neurologic symptoms that accompany LGGs is poorly understood. CASE: A 21-year-old male was diagnosed with medullary ganglioglioma (GG) after presenting with persistent vertigo and positional headaches. Immunohistochemistry was consistent with BRAF V600E mutation and dabrafenib was started. The patient had resolution of his neurologic symptoms within 3 weeks of treatment initiation; surveillance MRI several months later demonstrated interval decrease in tumor size. The patient remained on therapy for 2 years. Several days after planned drug discontinuation the patient had re-emergence of persistent vertigo that impaired his ability to work. Repeat imaging two months later demonstrated an increase in tumor size and solid enhancement along tumor margins. He was restarted on dabrafenib. Within one week, he again had complete resolution of his vertigo. DISCUSSION: Gangliogliomas are comprised of mixed neuronal and glial components and associated with epilepsy, headache and other localizing neurologic symptoms. In this report, we describe clinical and radiographic response from single-therapy dabrafenib in a patient with BRAF V600E+ GG, along with a very rapid resolution of neurologic symptoms upon initiation of the drug and recrudescence shortly following cessation of therapy. The symptoms subsided within a week of restarting dabrafenib, suggesting a separate, more rapid mechanism of symptom reversal than decline in tumor size. BRAF mutations have been identified in both the neuronal and glial components of ganglioglioma, suggesting that dabrafenib may provide symptomatic relief via inhibition of abberant neuronal processes. CONCLUSION: BRAF inhibitors can rapidly improve neurological symptoms via a rapid, not yet fully elucidated mechanism. Kinetics of this response suggest it is independent of effects on tumor volume and the degree of compression to tissue surrounding the tumor.

FIREFLY-1 (PNOC 026): A phase 2 study to evaluate the safety and efficacy of tovorafenib (DAY101) in pediatric patients with RAF-altered recurrent or progressive low-grade glioma or advanced solid tumors.

TPS10062 Background: RAF gene fusions ( BRAF and RAF1) and BRAF V600E mutations are oncogenic drivers found on a mutually exclusive basis in most pediatric low-grade gliomas (LGGs). In addition, RAF fusions ( BRAF and RAF1) have also been identified in other pediatric solid tumors. Tovorafenib (DAY101) is an investigational, oral, highly selective, CNS-penetrant, small molecule, type II pan-RAF inhibitor. In contrast to type I BRAF inhibitors, tovorafenib does not induce RAS-dependent paradoxical activation of the MAPK pathway. In the phase 1 PNOC014 study in pediatric patients with recurrent/progressive LGG, tovorafenib was well tolerated and 7/8 patients with tumor harboring RAF fusions had meaningful clinical benefit. Recently, a child with a novel SNX8-BRAF fusion spindle cell sarcoma demonstrated a rapid and deep response when treated with tovorafenib. Methods: FIREFLY-1 (NCT04775485) is an open-label, multicenter, phase 2 study evaluating the safety and efficacy of tovorafenib monotherapy in pediatric patients with RAF-altered recurrent or progressive LGG or advanced solid tumors. The initial design included only patients with LGG (arm 1). Two new arms have now been added; arm 2 will allow tovorafenib treatment for patients with LGG harboring an activating RAF alteration after completion of enrollment to arm 1 and prior to tovorafenib regulatory approval; arm 3 will enroll patients with advanced solid tumors harboring an activating RAF fusion. Eligible patients are 6 months to 25 years of age, who have received ≥1 prior line of systemic therapy with documented radiographic progression, have evaluable and/or measurable disease by appropriate criteria, a Karnofsky or Lansky performance score of at least 50, and adequate organ function. Patients are excluded if their tumor has other driver mutations, they have neurofibromatosis type 1, central serous retinopathy, retinal vein occlusion, clinically significant active cardiovascular disease, or are currently being treated with a strong CYP2C8 inhibitor or inducer other than those allowed per protocol. Approximately 140 patients in total will be enrolled including 60 in arm 1, 60 in arm 2 and 20 in arm 3. Tovorafenib will be administered at 420 mg/m2 (not to exceed 600 mg) weekly (days 1, 8, 15 and 22) for 26, 28-day cycles (in the absence of disease progression or unacceptable toxicity). They may then continue tovorafenib or enter a drug holiday period. The primary endpoint is overall response rate, as defined by the RANO criteria (arm 1) or RECIST v1.1 (arm 3) and as determined by an independent radiology review committee. Secondary endpoints (arms 1 and 3) include safety and tolerability, pharmacokinetics, duration of response, time to response and progression-free survival. Tovorafenib is available in tablet or liquid suspension formulations. Clinical trial information: NCT04775485.

The role of irinotecan-bevacizumab as rescue regimen in children with low-grade gliomas: a retrospective nationwide study in 72 patients.

At least half of children with low-grade glioma (LGG) treated with first line chemotherapy experience a relapse/progression and may therefore need a second-line chemotherapy. Irinotecan-bevacizumab has been recommended in this setting in France after encouraging results of pilot studies. We performed a retrospective analysis to define the efficacy, toxicity and predictors for response to the combination on a larger cohort. We reviewed the files from children < 19 years of age with progressive or refractory LGG treated between 2009 and 2016 in 7 French centers with this combination. 72 patients (median age 7.8 years [range 1-19]) received a median of 16 courses (range 3-30). The median duration of treatment was 9 months (range 1.4-16.2). 96% of patients experienced at least disease stabilization. The 6-month and 2-year progression-free survivals (PFS) were 91.7% [IC 95% 85.5-98.3] and 38.2% [IC 95% 28.2-51.8] respectively. No progression occurred after treatment in 18 patients with a median follow-up of 35.6 months (range 7.6-75.9 months). Younger patients had a worse PFS (p = 0.005). Prior chemoresistance, NF1 status, duration of treatment, histopathology or radiologic response did not predict response. The most frequent toxicities related to bevacizumab included grades 1-2 proteinuria in 21, epistaxis in 10, fatigue in 12 and hypertension in 8 while gastro-intestinal toxicity was the most frequent side effect related to irinotecan. Bevacizumab-irinotecan has the potential of disease control clinically and radiographically in children with recurrent LGG whatever their previous characteristics; in many cases however these responses are not sustained, especially in younger children.

LGG-08. TREATMENT OUTCOMES AND TOLERABILITY OF TRAMETINIB IN PROGRESSIVE CIRCUMSCRIBED LOW-GRADE GLIOMAS

Circumscribed low-grade gliomas comprise roughly one-third of pediatric CNS tumors. Most of these tumors are caused by activating mutations in the mitogen-activated protein kinase (MAPK) pathway. Drugs targeting the MAPK pathway are effective in other cancers and are being utilized in low-grade gliomas. We describe treatment outcomes and toxicities in a series of thirteen low-grade glioma patients treated with trametinib. We performed a retrospective chart review to evaluate response on T2/FLAIR MRI images per updated RANO criteria, visual outcomes, tolerability, and durability of response in progressive low-grade glioma patients treated with trametinib. Thirteen patients age 22 months to 34 years were included. Best radiographic response on therapy included 2/13 partial response, 3/13 minimal response, 5/13 stable disease, and 3/13 progressive disease. Diagnoses included pilocytic astrocytoma (n=6), desmoplastic infantile ganglioglioma (DIG; n=1), and low-grade glial neoplasms (n=2). Molecular drivers included BRAF:KIAA1549 fusion (n=3), V600E mutation (n=1), and somatic NF1 mutation (n=1). Three patients had germline NF1. In patients with partial or minimal response, best response was seen after longer durations of therapy; 4 of 5 best responses occurred after at least 12 months on therapy. Five patients completed prescribed therapy. Three patients remain stable off therapy at 6, 12, and 21 months; two patients recurred at 1 and 10 months off therapy. Skin manifestations were the predominant form of toxicity. This was more severe in older males, and symptoms improved with intermittent dosing. All patients with optic pathway tumors showed at least stable vision throughout treatment, with some patients having dramatic improvement. Trametinib is effective and well-tolerated in patients with low-grade glioma. Dermatologic toxicity can be mitigated by intermittent dosing. Best responses tended to occur later in therapy, sometimes after relatively stable MRIs. Patients with optic pathway lesions showed stable to improved vision even in the absence of significant radiographic response.

LGG-52. BINIMETINIB IN CHILDREN WITH PROGRESSIVE OR RECURRENT LOW-GRADE GLIOMA NOT ASSOCIATED WITH NEUROFIBROMATOSIS TYPE 1: INITIAL RESULTS FROM A MULTI-INSTITUTIONAL PHASE II STUDY

BACKGROUNDRAS/RAF/MEK/ERK pathway activation is the primary driver for most pediatric low-grade gliomas (LGG). Binimetinib is an orally bioavailable MEK1/2 inhibitor found to have significant central nervous system penetration in a preclinical model.OBJECTIVEThe primary objective of this multi-institutional open-label phase II study was to assess preliminary efficacy of binimetinib in progressive pediatric LGG. The study included strata for both neurofibromatosis type I (NF1) and non-NF1 associated tumors, as well as a target validation (surgical) stratum. NF1 and surgical strata remain open to enrollment and will be reported separately.METHODSChildren aged 1–18 years with previously treated recurrent or progressive LGG were eligible. The dose of binimetinib was 32 mg/m2/dose twice daily. Partial and minor responses were defined, respectively, as 50% and 25% decrease in maximal two-dimensional measurements.RESULTSFifty-seven eligible patients without NF1, median age 8 years, were enrolled and began treatment; 26 were female; 28 had documented KIAA1549-BRAF fusion. Eleven patients discontinued drug in the first year due to toxicity, and an additional 27 required dose reduction. The most common drug-attributable grade 3 toxicities included creatine kinase elevation (n=9 patients), rash (n=8), and truncal weakness (n=8). Truncal weakness improved or resolved with dose reduction or cessation. Grade 4 toxicities included creatine kinase elevation (n=2) and transient colitis (n=1). Of 44 patients with preliminary response data available, 22 (50%) showed a minor (n=7) or partial (n=15) response.CONCLUSIONBinimetinib is active, with manageable toxicities, in children without NF1 with progressive LGG.

LGG-30. TRAMETINIB-ASSOCIATED HYPONATREMIA IN A CHILD WITH LOW GRADE GLIOMA IS NOT SEEN FOLLOWING TREATMENT WITH ALTERNATIVE MEK INHIBITOR

Molecularly targeted therapy with MEK inhibitors is increasingly being incorporated into the treatment of pediatric low-grade gliomas (LGGs). Trametinib is an orally available MEK1/2 inhibitor that has demonstrated tumor control in LGGs with BRAF alterations. Safe expansion of MEK inhibitor therapy within the pediatric patient population demands adequate understanding of and surveillance for potential MEK-inhibitor specific toxicities, especially among young children. Hyponatremia has been reported in adult patients receiving BRAF/MEK inhibitor combination treatment as well as in two pediatric patients with known diabetes insipidus treated with trametinib monotherapy. To our knowledge, single-agent trametinib has not previously been reported to be associated with hyponatremia in children in the absence of an underlying endocrinopathy. We present a case of hyponatremia associated with trametinib use in an infant with progressive LGG without known endocrine dysfunction, which recurred after significant dose reduction. Therapy with an alternative MEK1/2 inhibitor, binimetinib, provided excellent tumor response without hyponatremia. Hyponatremia is a rare but serious side effect of trametinib, even without underlying pituitary dysfunction. Infants and patients lacking the ability to quickly regulate fluid intake in response to osmolality changes are at particular risk of suffering severe consequences from hyponatremia and should be monitored closely with initiation of trametinib. Switching to a different drug within the same class may offer an alternative to significant dose reduction or discontinuation due to this toxicity.

IMG-05. INITIAL RADIOGRAPHIC ASSESSMENT OF DWI AND ADC VALUES IN CHILDREN AND YOUNG ADULTS TREATED WITH DAY101 (TAK-580) FOR RECURRENT LOW-GRADE GLIOMAS (LGG) HARBORING MAPK ALTERATIONS

BACKGROUNDApparent diffusion coefficient (ADC) is a quantitative measure reflecting observed net movement of water calculated from a diffusion-weighted image (DWI), correlating with tumor cellularity. The higher cellularity of high-grade gliomas results in diffusion restriction and reduced ADC values, whereas the lower cellularity of low-grade gliomas (LGGs) gives higher ADC values. Here we examine changes in ADC values in patients with LGGs treated with the type 2 RAF inhibitor DAY101 (formerly TAK580).METHODSHistorical, baseline, and on-treatment brain MRIs for 9 patients enrolled on a phase 1 study of DAY101 in children and young adults with radiographically recurrent or progressive LGG harboring MAPK pathway alterations were obtained, de-identified and independently evaluated for ADC changes. Time points included baseline, first follow-up, and best response. Data processing of ADC estimates was performed using pmod molecular image software package. ADC changes were displayed as a histogram with mean values. Results were based upon a single read paradigm.RESULTSThere was a clear shift to lower ADC values for the solid component of tumors, reflecting changes in cellularity and tissue organization, while necrosis correlated with a shift toward higher ADC values. DWI reveals reduced ADCs in responding tumors, with the percent change in ADC from baseline correlating with deeper RANO responses.CONCLUSIONDWI analysis reveals reductions in ADC values that correlates with treatment response and a shift toward more normal cellularity in tumors treated with DAY101. Changes in ADC may represent a novel imaging biomarker, reflecting biological response to DAY101 treatment.

Current Salvage Treatment Strategies for Younger Children (

Pediatric low-grade gliomas (LGGs) are the most common brain tumors in children. Treatment of pediatric LGG can often be challenging, particularly when not resectable and refractory or recurrent following standard chemotherapy regimens. There is no current accepted standard of care salvage regimen for progressive LGG after the failure of first-line chemotherapy. A web-based survey was distributed to pediatric cancer centers throughout North America to inquire regarding institutional preferences of salvage treatment strategies after initial chemotherapy for LGG in children less than 10 years of age, as well as molecular testing preferences. Highlights from the survey results were as follows: vincristine/carboplatin (VC) and vinblastine (VBL) were the top 2 preferred salvage regimens for non-BRAF-altered pediatric LGG. BRAF and MEK inhibitors were the most preferred salvage regimens for BRAF V600e-mutated and BRAF fusion-positive pediatric LGG, respectively. VC ranked second. As high as 47.8% of North American centers would use conformal radiation for younger children with non-neurofibromatosis type 1 LGG after failing 2 to 3 chemotherapy regimens. Overall, 87% (87%) of North American institutions obtain some type of routine molecular testing for non-neurofibromatosis type 1-associated pediatric LGG cases. Less than 60% of centers obtain routine H3 K27M molecular testing for pediatric LGG with a midline location.

Impact of repeated operations for progressive low-grade gliomas

BackgroundMaximal, aggressive resection of diffuse low-grade gliomas (DLGG) is well established as the standard of care in neuro-oncology. The role of repeat resection for tumor progression is unclear. ObjectiveTo assess the role of repeated operation for DLGG, and the effect on malignant transformation and survival. MethodsWe conducted a historical cohort study in which all patients undergoing multiple resections of DLGG between the years 1995–2019 were evaluated for overall survival (OS) and time to transformation (TTT). We then compared the outcome of this group with that of a matched control group comprised of patients who underwent only one operation despite being eligible for repeat surgery at tumor progression, but had received non-surgical oncological therapy or declined additional treatment. ResultsOf 607 patients in our departmental DLGG database, 93 patients underwent 2 or more surgeries and had sufficient follow-up and imaging data to be included in the study group. Thirty-eight patients were included in the matched control group. Early (less than 1 year) progression was associated with decreased survival and shorter TTT in the study group. Patients undergoing multiple resections had significantly longer TTT and OS compared to patients who underwent a single surgery. This effect was especially noted in patients who had radiological evidence of tumor transformation. ConclusionsRepeated resections of LGG are safe and offer survival benefit in select patients. Early progression following resection is associated with worse prognosis. Patients with evidence of radiological transformation may benefit the most from re-resection.

New treatment modalities in NF-related neuroglial tumors.

The management of low-grade gliomas (LGGs) and other neuroglial tumors in children with neurofibromatosis type 1 (NF1) has not changed over the past 2-3 decades. With the widespread utilization of chemotherapy for younger children with progressive LGGs, outcomes have been good for most patients who have required treatment. However, some may progress after the initiation of chemotherapy and others, although radiographically responding or with stable disease, may develop progressive neurologic and visual deterioration. Molecular-targeted therapy has become an option for patients who have progressed after receiving chemotherapy and the mTOR inhibitors and bevacizumab have already shown some degree of efficacy. However, the greatest impact has been the introduction of the MEK inhibitors. A variety of different MEK inhibitors are in clinical trials and have already demonstrated the ability to result in radiographic tumor shrinkage in the majority of children with NF1 and progressive LGGs. Because of this efficacy, the MEK inhibitors have moved rapidly from phase I studies to ongoing phase III studies comparing their benefit directly to that of chemotherapy. The long-term ability of these agents to not only control disease, but improve visual and/or neurological function, as well as their short- and long-term safety, are open questions that can only be answered by well-constructed prospective, often randomized, clinical trials.

RARE-15. OUTCOMES OF TREATMENT OF GLIOMAS IN PATIENTS WITH NEUROFIBROMATOSIS TYPE I TREATED WITH RADIATION THERAPY

Abstract INTRODUCTION Neurofibromatosis type 1 (NF1) is a rare tumor suppressor syndrome that predisposes to nervous system tumors. The optimal treatment of gliomas in adults with NF1 is uncertain. Specifically, little is known about the effectiveness or toxicity of radiation therapy (RT) in this population although it is standard of care for progressive low grade glioma (LGG) or high grade glioma (HGG) in general. We evaluated the tolerability of RT and time to progression (TTP) after completion of RT in people with NF1 diagnosed with glioma in adulthood. METHODS Charts were reviewed for patients with a confirmed NF1 syndrome, LGG or HGG, &gt; 18 years old, receiving RT and followed at Johns Hopkins University between 2009–2019. Secondary outcomes were overall survival (OS) from diagnosis and RT associated toxicity. Progression was defined radiographically; toxicity was graded by CTCAE. RESULTS Eight people (6 males) with median age of 36.5 years (range, 20–63) received RT at median of 56.7Gy either at the time of diagnosis (N=4) or at recurrence (N=4). Three patients (37.5%) had LGG; five (62.5%) had HGG. Tumor locations were brainstem (6) and temporal lobe (2). All patients received concurrent chemotherapy with RT; temozolomide (7) or bevacizumab (1). At median follow-up of 28.3 months (0.9–90.2) from RT completion, 5/8 patients had progression. Of those who progressed, median TTP was 12.7 months (2.5–26.6). The longest period of disease control was 28.9 months. One and two-year OS rates were 87% and 32%, respectively. RT associated toxicities were within the expected range. CONCLUSIONS Overall disease control after RT was variable, with some examples of extraordinary duration of disease control, and RT toxicities were within expected range. Collaborative efforts to examine a larger cohort of adults with NF1 associated gliomas are needed to define optimal care, but these observations suggest RT is a feasible modality.