Nghiemphu, Phioanh L.

Abstract IDH-wildtype diffuse astrocytic gliomas with lower-grade histological features alongside specific genomic alterations (e.g., TERT promoter mutation, EGFR amplification, gain Chr7/loss Chr10) are presently diagnosed as glioblastoma, IDH-wildtype (GBM) under WHO 2021 criteria. Previous analyses categorized these into “early/evolving” or “surgically undersampled” GBMs. However, it remains unclear whether these tumors share identical clinical and prognostic features with histologic GBM. Data from IDH-wt molecular GBMs across six institutions were aggregated. Astrocytic IDH-wt tumors of any grade that lacked necrosis or microvascular proliferation on initial histopathology yet exhibited molecular alterations consistent with WHO 2021 GBM diagnosis, were included. Recursive partitioning analysis (RPA) was used to categorize patients into risk groups based on overall survival (OS). Among the 264 patients included, the median age was 60 years (IQR: 51-67), with 162 (61%) being male. Additionally, 210 (80%) were diagnosed since 2016, and 216 (82%) received chemoradiation plus adjuvant temozolomide (GBM-SOC). The median follow-up period was 3.9 years (95% CI: 3.4, 4.6). Identified univariate risk factors for worse survival included older age, biopsy-only status, EGFR amplification, absence of initial adjuvant treatment, low post-operative KPS, and tumor histologic grade of 3. RPA divided patients into four distinct survival groups (p<0.0001). The “best” risk group comprised lower grade (<=2) tumors (n=58, median OS (mOS): 40 months (95% CI: 33, NA)). The “second best” group included Grade 3 patients receiving GBM-SOC without steroids during initial RT (n=139, mOS: 25 months (95% CI: 22, 28)). The “second worst” group encompassed Grade 3 patients who were on steroids during initial RT while receiving GBM-SOC (n=38, mOS: 15 months (95% CI: 13, 20)). The “worst” group contained Grade 3 tumors that had not undergone SOC (n=29, mOS: 9 months (95% CI: 4, 26)). These data show that histologic features and treatment are strong indicators of patient outcomes.

Abstract INTRODUCTION Brigatinib is an oral ALK inhibitor that inhibits multiple tyrosine kinases. We previously published outcomes of patients with NF2-related schwannomatosis treated with brigatinib for a median of 10.4 months. We report updated results of these patients with extended follow-up. METHODS This multicenter, phase II, open-label study included participants ≥12 years with NF2-SWN and progressive target tumors (baskets: VS, NVS, meningioma, or ependymoma). Patients were treated with brigatinib 180 mg daily. Patients discontinued treatment upon progression of target tumors but could continue treatment with isolated progression of non-target tumors if deemed clinically acceptable by the treating team and patient. One target and up to 5 non-target tumors were followed in each participant. Tumor response was evaluated by MRI every 3 months in year 1 and every 6 months thereafter with radiographic response (RR) defined as ≥20% decrease in volume compared to baseline. RESULTS Forty participants were treated for a median of 23 months (range, 3-40 months). Updated imaging data is available on 162 tumors (45 VS, 59 non-VS, 53 meningiomas, and 5 ependymomas). RR rate for all tumors was 28% and was 31% for non-VS, 28% for meningioma, 22% for VS, and 60% for ependymomas. The 12-month freedom from tumor progression was 77.1% for all tumors, 81.5% for non-VS, 78.1% for meningioma, 69.2% for VS, and 100.0% for ependymoma. The 24-month freedom from tumor progression was 73% for all tumors, 81.3% for non-VS, 72.4% for meningioma, 62.4% for VS, and 100.0% for ependymoma. There were no grade 4/5 treatment-related adverse events (AEs). The most common AEs were diarrhea (65%), nausea (40%), muscle cramps (40%), hypertension (35%), increased LDH (35%), increased AST (33%), and increased ALT (25%). CONCLUSION Brigatinib treatment was associated with high rates of tumor stability at 24 months across multiple tumor types in patients with NF2-related schwannomatosis.

Abstract BACKGROUND Mirdametinib is the first FDA-approved MEK1/2 inhibitor for both adults and children (≥2y) with symptomatic NF1-PN. In ReNeu, symptomatic improvement and PN volume reductions were observed at the earliest assessments (~91 and ~152 days, respectively) and were sustained. This analysis evaluated time to first onset and resolution of commonly reported TRAEs in the ReNeu trial. METHODS Data cutoff (DCO) was September 20, 2023. Median time to first onset and resolution (days) for common TRAEs (≥15%) were evaluated for prepubescents (≥2 to <12y, n=32), postpubescents (≥12 to <18y, n=24), younger adults (≥18 to ≤50y, n=48), and older adults (>50y, n=10). RESULTS Common TRAEs were mostly grades 1 to 2 (83%). In prepubescents, median day (range) of onset was 32 (14, 263) for vomiting, 71 (19, 386) for dermatitis acneiform, 123 (1, 663) for diarrhea, 124 (52, 775) for paronychia, and 127 (2, 663) for nausea. For postpubescents, median day (range) of onset was 8 (1, 438) for diarrhea, 8 (2, 574) for nausea, 12 (1, 252) for dermatitis acneiform, 28 (2, 354) for vomiting, and 110 (43, 245) for paronychia. In younger adults, median day (range) of onset was 5 (1, 352) for nausea, 8 (2, 15) for dermatitis acneiform, 9 (2, 73) for diarrhea, and 29 (1, 264) for vomiting. For older adults, median day (range) of onset was 4 (1, 286) for diarrhea, 9 (2, 15) for nausea, and 13 (2, 38) for dermatitis acneiform. Time to resolution was variable between TRAEs and among patients in all age groups; 90% resolved completely by DCO. Among all patients, 18 had a TRAE of asymptomatic ejection fraction decrease, with all but one resolving by DCO. CONCLUSIONS Overall, common TRAEs arose before treatment benefits and were generally resoluble by DCO. Proactively managing TRAEs may improve treatment experience and adherence.

PURPOSE Pharmacologic therapies for neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PNs) are limited; currently, none are US Food and Drug Administration–approved for adults. METHODS ReNeu is an open-label, multicenter, pivotal, phase IIb trial of mirdametinib in 58 adults (≥18 years of age) and 56 children (2 to 17 years of age) with NF1-PN causing significant morbidities. Patients received mirdametinib capsules or tablets for oral suspension (2 mg/m 2 twice daily, maximum 4 mg twice daily), regardless of food intake, in 3 weeks on/1 week off 28-day cycles. The primary end point was confirmed objective response rate (ORR; proportion of patients with a ≥20% reduction of target PN volume from baseline on consecutive scans during the 24-cycle treatment phase) assessed by blinded independent central review (BICR) of volumetric magnetic resonance imaging. RESULTS Twenty-four of 58 adults (41%) and 29 of 56 children (52%) had a BICR-confirmed objective response during the 24-cycle treatment phase; in addition, two adults and one child had confirmed responses during long-term follow-up. Median (range) target PN volumetric best response was –41% (−90 to 13) in adults and –42% (−91 to 48) in children. Both cohorts reported significant and clinically meaningful improvement in patient- or parent proxy-reported outcome measures of worst tumor pain severity, pain interference, and health-related quality of life (HRQOL) that began early and were sustained during treatment. The most commonly reported treatment-related adverse events were dermatitis acneiform, diarrhea, and nausea in adults and dermatitis acneiform, diarrhea, and paronychia in children. CONCLUSION In ReNeu, the largest multicenter NF1-PN trial reported to date, mirdametinib treatment demonstrated significant confirmed ORRs by BICR, deep and durable PN volume reductions, and early, sustained, and clinically meaningful improvement in pain and HRQOL. Mirdametinib was well-tolerated in adults and children.

Abstract INTRODUCTION NF2-related schwannomatosis (NF2-SWN) predisposes affected individuals to vestibular schwannomas (VS), non-vestibular schwannomas (NVS), meningiomas, and ependymomas. The rarity of NF2-SWN and the presence of multiple tumor types has impeded clinical trials. We conducted a multi-center, adaptive, platform-basket trial to screen multiple drugs against progressive NF2-SWN tumors. We report the final analysis of the first treatment arm with brigatinib, an oral ALK inhibitor that inhibits multiple tyrosine kinases. METHODS This study enrolled participants ≥ 12 years with NF2-SWN and progressive target tumors (baskets: VS, NVS, meningioma, or ependymoma Radiographic response (RR) was defined as ≥ 20% decrease in target tumor volume from baseline. The primary outcome was RR rate. Secondary outcomes included safety, hearing response, and RR in non-target tumors. Tumor response was evaluated by MRI every 3 months in year 1 and every 6 months thereafter. In stage 1, 20 participants received brigatinib 180 mg daily. Interim analysis suggested activity in NVS and meningioma. Thus, an additional 20 participants with progressive meningioma or NVS were enrolled in stage 2. RESULTS Forty participants (median age 26 years, 12 pediatric, 28 female) were treated. Prior treatment included surgery (90%), radiation therapy (20%) and chemotherapy (55%). Target tumors included 10 VS, 9 NVS, 19 meningiomas, and 2 ependymomas. Overall RR rate was 10% for all target tumors (22% for non-VS, 11% for meningioma, 0% for VS, and 0% for ependymomas). There were no grade 4 or 5 treatment-related adverse events (AEs). The most common AEs were diarrhea (63%), nausea (40%), muscle cramps (33%), increased LDH (35%), increased AST (33%), and increased ALT (23%). CONCLUSION Brigatinib treatment was associated with RR in NVS and meningiomas in a heavily pretreated cohort of participants with progressing NF2-SWN tumors. This novel design provides unique ability to assess treatments for hereditary syndromes with multiple primary tumors.

The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of the following adult CNS cancers: glioma (WHO grade 1, WHO grade 2–3 oligodendroglioma [1p19q codeleted, IDH- mutant], WHO grade 2–4 IDH- mutant astrocytoma, WHO grade 4 glioblastoma), intracranial and spinal ependymomas, medulloblastoma, limited and extensive brain metastases, leptomeningeal metastases, non–AIDS-related primary CNS lymphomas, metastatic spine tumors, meningiomas, and primary spinal cord tumors. The information contained in the algorithms and principles of management sections in the NCCN Guidelines for CNS Cancers are designed to help clinicians navigate through the complex management of patients with CNS tumors. Several important principles guide surgical management and treatment with radiotherapy and systemic therapy for adults with brain tumors. The NCCN CNS Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel’s most recent recommendations regarding molecular profiling of gliomas.

Abstract BACKGROUND The Food and Drug Administration recently issued guidance on conducting qualitative research to support patient-focused drug development. In prior FDA submissions, qualitative data has been critical to demonstrate the content validity of and meaningfulness of change in quantitative trial endpoints. Qualitative patient interviews embedded within neuro-oncology trials can supplement traditional quantitative measures by providing nuanced information on patients’ treatment priorities, benefit/risk assessments, and quality of life. METHODS We interviewed people with neurofibromatosis 2 (NF2) in stage one of the brigatinib arm of a multicenter, phase II, adaptive platform-basket trial for progressive NF2-related tumors (NCT04374305). Transcripts were coded by two analysts using a hybrid inductive/deductive framework; cross-cutting themes were generated using the Framework Method. RESULTS 16/20 trial enrollees participated in interviews May 2021-March 2022. The radiographic response rate (volume shrinkage ≥20% from baseline) at 6 months for target and non-target tumors was 5% and 22%, respectively. However, most participants rated their change in overall status as minimally (10/16) or much (3/16) improved. Several participants acknowledged their tumor size had not changed significantly but felt tumor stability was an improvement over previously accelerated growth rates; this importantly allowed them to avoid or postpone future surgery. Participants also valued prevention of symptomatic decline, minimal impact of side effects on social roles and activities, the convenience of oral medication, and the sense of hope and agency gained from participating in a trial. CONCLUSIONS Virtual, in-depth qualitative interviews were feasible across multiple sites and provided unique information on NF2 patients’ conceptualization of clinical benefit. Qualitative interviews embedded within neuro-oncology trials can reveal 1) whether trial design and choice of outcome measures align with patient priorities; 2) whether and how new treatments improve patients’ quality of life; and 3) what degree of change in quantitative measures such as radiographic progression are clinically meaningful.