Shi, Wenyin

Abstract Background Meningiomas exhibit clinical heterogeneity. Radiotherapy (RT) remains the only adjuvant therapy, but tumor-control is variable, and biomarkers are limited. NRG/RTOG-0539 is the first prospective phase 2 trial to stratify meningioma patients for adjuvant RT based on clinical risk. Here, we apply modern molecular tools to this cohort and identify correlates of RT response. Methods Tumor tissue from 100 RTOG-0539 patients was profiled using DNA methylation arrays, RNA sequencing, and whole-exome sequencing. Recurrence scores, Molecular Groups, gene expression, and copy number alterations were compared across clinical groups and between RT responders and non-responders; non-response was defined as progression or death within 3 years. Results Modern grading criteria, including brain invasion, TERT mutation, CDKN2A/B deletion, and 1p/1q status, would reclassify 10% of tumors and alter treatment group assignment in 7%. Non-responders to RT exhibited more frequent 1p and 14q loss, and more copy number alterations. Transcriptomic and epigenetic profiling revealed immune-related signatures in responders and cell cycle–related pathways in non-responders, several of which overlapped with targets of vorinostat, a histone deacetylase inhibitor previously validated in aggressive meningioma models. The Proliferative Molecular Group was an independent predictor of post-RT recurrence in multivariable analysis, outperforming WHO grade. Conclusion Multi-omic analysis of the NRG/RTOG-0539 cohort shows that updated WHO grading criteria, incorporating molecular and cytogenetic features, improve risk stratification. However, molecular classification, particularly the Proliferative group, remains an independent and stronger predictor of RT response. These findings support integrating molecular biomarkers alongside modern grading frameworks to guide treatment and trial design in meningioma. Clinical Trial Information NCT00895622.

Abstract BACKGROUND Glioblastoma (GBM) is an aggressive central nervous system (CNS) malignancy with poor prognosis. TTFields are electric fields that exert physical forces to disrupt cellular processes critical for cancer cell viability. TTFields therapy is approved for recurrent and newly diagnosed GBM, and pleural mesothelioma. We report long-term safety data from pediatric, adult and elderly patients with CNS malignancies receiving TTFields, from a global post-marketing surveillance (PMS) dataset. METHODS Unsolicited PMS data were collected from patients receiving TTFields (October 2011–October 2022). AEs were categorized using MedDRA version 25.1, and data stratified by age group (< 18, 18–65, and > 65 years). RESULTS Overall, 25,898 patients from the US, Europe, Israel, and Japan were included. Of these, 93 (0.4%) were < 18 years (pediatric), 17,817 (69%) were 18–65 years (adult), and 7,808 (30%) were > 65 years (elderly). Two-thirds (66%) of all patients were male. Demographic characteristics were therefore consistent with a typical GBM population. Of pediatric patients, 62% experienced ≥ 1 AE, with 53% related to TTFields. This was comparable in adults (72% and 56%, respectively), and elderly patients (75% and 57%, respectively). The most common TTFields-related AEs were skin reaction (pediatric: 39%; adult: 42%; elderly: 45%), heat (warmth) sensation (pediatric: 14%; adult: 12%; elderly: 12%), and electric (tingling) sensation (pediatric: 10%; adult: 15%; elderly: 10%). All-cause serious AEs occurred in 14%, 21% and 25% of pediatric, adult and elderly patients, respectively. No systemic toxicities were reported, regardless of age. CONCLUSIONS These long-term, real-world PMS data demonstrate that TTFields has a tolerable safety profile in pediatric, adult and elderly patients with CNS malignancies, with no new safety signals in any age group. Most AEs were localized skin reactions which are manageable. These data provide supportive evidence of the safety and broad applicability of TTFields, regardless of patient age.

Abstract AIMS Glioblastoma (GBM) has a poor prognosis, which is compounded by an increase in treatment-related toxicity with age. TTFields are electric fields that exert physical forces to disrupt cellular processes critical for cancer cell viability. Subgroup analysis of the phase 3 EF-14 study demonstrated TTFields therapy to be well-tolerated in patients ≥65 years with newly diagnosed (nd) GBM. We report safety data in elderly patients from a global post- marketing surveillance (PMS) analysis of patients with central nervous system (CNS) malignancies receiving TTFields. METHOD PMS data was collected from patients receiving TTFields (October 2011–March 2022) in North America, Europe, Middle East, Africa, and Japan. Adverse events (AEs) were categorized using MedDRA version 25.1. RESULTS Overall, 25,898 patients were included (diagnoses: ndGBM [68%], recurrent GBM [26%], anaplastic astrocytoma/oligodendroglioma [4%], other [2%]). Of these, 7808 patients (30%) were elderly (>65 years). 75% of elderly patients experienced ≥1 AE, with 57% related to TTFields; comparable frequencies to the overall population (73% and 56%, respectively). The most common treatment-related AE in elderly patients was skin reaction (45%; overall population: 43%). Incidence of treatment-related fall and fracture in elderly patients was 1% and <1%, respectively. Incidence of treatment-related ‘quality-of-life decreased’ was 2% (elderly and overall). No systemic toxicities were reported, regardless of age group. CONCLUSIONS These real-world data demonstrate TTFields has a tolerable safety profile in elderly patients with CNS malignancies, consistent with elderly subgroup data from EF-14, and with no new safety signals. Most AEs were localised, manageable, mild–moderate skin reactions.

Abstract BACKGROUND TTFields are electric fields that exert physical forces to disrupt cellular processes critical for cancer cell viability and tumor progression. TTFields therapy is approved for adults with recurrent (r) and newly diagnosed (nd) glioblastoma (GBM), based on the phase 3 EF-11 (TTFields 200 kHz) and EF-14 studies (TTFields therapy 200 kHz + temozolomide), respectively, which showed clinical benefit without increase in systemic adverse events (AEs). Pediatric patients were not included in the EF-11 and EF-14 studies. Here, we present pediatric safety data from an updated global post-marketing surveillance (PMS) analysis of patients with brain tumors treated with TTFields therapy, over an 11-year timeframe. METHODS Unsolicited PMS data from patients with brain tumors who received TTFields therapy from October 2011-March 2022 in North America, Europe, Middle East, Africa, and Japan were included. AEs were categorized using MedDRA version 25.1. RESULTS Overall, 25,898 patients were included. Diagnoses were ndGBM (68%), rGBM (26%), anaplastic astrocytoma/oligodendroglioma (4%) and other (2%). Two-thirds of patients were male. The analysis included 93 (0.4%) pediatric/adolescent patients (<18 years). In pediatric patients, 62% experienced ≥1 AE, with 53% related to TTFields therapy; these values were comparable with the overall population (73% and 56%, respectively). The most common treatment-related AEs in pediatric patients were: skin reaction (39%), heat sensation (14%), and headache (12%); and in the overall population were: skin reaction (43%), electric sensation (14%), and heat sensation (12%). CONCLUSIONS This long-term, global, real-world data analysis, including pediatric patients with brain tumors, demonstrates a tolerable safety profile of TTFields therapy, consistent with pivotal clinical studies. There were no major differences in AEs between pediatric and adult patients and no new safety signals identified in the pediatric population. Consistent with the overall dataset, most AEs in pediatric patients were localized mild–moderate skin events, which are typically easily managed.

2049 Background: Glioblastoma (GBM) has a poor prognosis. Standard treatments are associated with systemic toxicity, further increasing the disease burden in this patient population. Tumor Treating Fields (TTFields) are electric fields that disrupt cancer cell processes which affect cancer cell viability, and are generated by a portable, wearable device which is locoregional and noninvasive. TTFields therapy was approved by the FDA for the treatment of newly diagnosed (nd) and recurrent (r) GBM based on the phase 3 EF-14 (TTFields therapy 200 kHz + temozolomide) and EF-11 (TTFields 200 kHz) studies, respectively. TTFields therapy is also approved for pleural mesothelioma. We report an updated global, post-marketing surveillance (PMS) safety analysis of patients with CNS malignancies treated with TTFields therapy over an 11-year timeframe. This analysis represents the largest dataset of TTFields therapy use to date. Methods: Unsolicited safety data were collected from routine post-marketing activities for patients (N = 25,898) in North America, Europe, Middle East and Africa and Japan, from October 2011 to March 2022. AEs were stratified by diagnosis, age, and sex and categorized using MedDRA version 25.1. Results: Diagnoses were ndGBM (68%), rGBM (26%), anaplastic astrocytoma/oligodendroglioma (4%) and other (2%). Baseline demographics were reflective of real-world practice: median (range) age was 59 (3–103) years; two-thirds of patients were male. Most (69%) patients were 18–65 years; 0.4% were < 18 years, and 30% were > 65 years. All-cause and TTFields-related AEs occurred in 18,798 (73%) and 14,599 (56%), patients, respectively. The most common device-related AE was skin reaction (43% patients overall). There were no major differences in occurrence of this AE between pediatric, adult, and elderly groups (39%, 42%, and 45%, respectively), or between males and females (41% and 46%, respectively). The incidence of device-related skin reactions was higher in ndGBM than rGBM (46% vs 34%, respectively), in line with previous reports. Only 405 (2%) of patients overall reported an AE of treatment-related ‘quality-of-life decreased’. In line with the phase 3 studies, there were no treatment-related systemic AEs. Conclusions: In this updated global PMS safety analysis, TTFields therapy demonstrated a tolerable safety profile in patients with CNS malignancies, with no new safety findings. In line with previous real-world and clinical data, most AEs were localized, non-serious skin events, which were consistent between age groups. Such events can typically be managed easily using prophylaxis and topical therapies, together with optimization of caregiver techniques. Importantly, no TTFields therapy-related systemic AEs were detected.

Abstract Patients with glioblastoma (GBM) face poor outcomes; the 5-year survival rate is 7% with standard of care treatments, which are frequently associated with systemic toxicity. Tumor Treating Fields (TTFields) are electric fields that disrupt critical cancer cell processes. The TTFields therapy device consists of a portable electric field generator and arrays placed on the patient’s scalp, thus delivery is locoregional and noninvasive. Currently, TTFields therapy is approved for recurrent and newly diagnosed GBM, based on the phase 3 EF-11 (TTFields 200 kHz) and EF-14 studies (TTFields therapy 200 kHz + temozolomide), respectively. These studies confirmed that TTFields therapy had a tolerable safety profile with mild-to-moderate localized skin adverse events (AEs) being the most common related AEs. Here, we present an updated analysis of the largest global real-world evidence dataset of patients with brain tumors receiving TTFields therapy over an 11-year time period. Unsolicited safety data were obtained from routine post-marketing activities, including published literature and interactions with patients, caregivers, and healthcare professionals. Safety data were grouped according to age, diagnosis, and sex. AEs were categorized using MedDRA version 25. Data from 25,898 patients were included in this analysis; median age was 59 years (range: 3-103) for patients with known age. Diagnoses were ndGBM (67.7%), rGBM (26.1%), anaplastic astrocytoma/oligodendroglioma (4.2%) and other (2.1%). Most (n=17,817, 68.8%) patients were 18-65 years of age; n=93 (0.4%) were pediatric/adolescent patients (&lt;18 years), and n=7,808 (30.2%) were elderly patients (&gt;65 years). For 130 patients (0.5%) age was not known. Two-thirds of patients were male, which reflects the preponderance of CNS tumors in males. Most patients were based in North America (72.1%), followed by Europe, the Middle East and Africa (23.3%), and Japan (4.6%). Overall, 72.4% of patients experienced at least one AE, with 55.9% being related to TTFields therapy. The most common AEs (overall and related to TTFields therapy) were skin reactions (42.0%), electric (tingling) sensations (13.5%), and heat (warmth) sensations (11.8%). The percentage of patients experiencing ≥1 AE in the pediatric/adolescent, 18-65, and elderly groups was 63.4%, 74.6%, and 68.4%, respectively. The percentage of females and males experiencing ≥1 AE was 75.2% and 70.9%, respectively. These long-term, real-world data from the largest global dataset of patients with brain tumors using TTFields therapy to date demonstrate a tolerable safety profile consistent with pivotal clinical studies. There were no new safety signals, and most AEs were manageable localized mild-moderate skin events that can be resolved. The distribution of AEs between age and sex was similar, with broad applicability among different patient groups. Citation Format: Maciej M. Mrugala, Wenyin Shi, Fabio Iwamoto, Rimas V. Lukas, Joshua D. Palmer, John H. Suh, Martin Glas. Patients with glioblastoma (GBM) treated with tumor treating fields (TTFields) therapy: post-marketing safety data over the last decade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3221.

Abstract Tumor Treating Fields therapy (TTFields; 200 kHz) is a noninvasive, locoregional, antimitotic treatment approved for newly diagnosed glioblastoma (ndGBM), recurrent (r) GBM, malignant pleural mesothelioma, and is being investigated in additional solid tumors. Approval in GBM was based on results of the phase 3 EF-11 (TTFields monotherapy; rGBM) and EF-14 (TTFields therapy/maintenance temozolomide; ndGBM), which showed clinical benefit without an increase in adverse events (AEs). Here we review post-marketing surveillance (PMS) data from patients with brain tumors who received TTFields therapy over an 11-year period. Unsolicited PMS data from patients with brain tumors who received TTFields therapy between October 2011 and March 2022, were included. Overall 23,822 patients were included in this analysis. Most patients (72%) were from North America; 24% from Europe, Middle East and Africa, and 4% from Japan. Birth year was available for 23,784 patients; of these, the average age at treatment start was 57 years (range: 3–103). Diagnoses were ndGBM (67%), rGBM (27%), astrocytoma (WHO grade 3; 4%) and other (2%). Overall, 71% of patients reported ≥ 1 AE, with the most common being skin reaction (42%), electric (tingling) sensation (14%), heat (warmth) sensation (12%), and seizure (11%). Furthermore, 56% of patients reported AEs possibly related to TTFields therapy, with the most frequently reported being skin reaction (42%), electric sensation (14%) and heat sensation (12%), occurring underneath the arrays. Numbers and types of AEs were comparable between age and diagnosis groups. PMS data from &gt; 23,000 patients with brain tumors show that TTFields therapy (200 kHz) is well-tolerated, consistent with the known safety profile; no new safety signals were identified. TTFields therapy is not associated with systemic toxicity; most common possibly-related AEs are localized dermatologic events that can be managed with appropriate prophylaxis and treatment strategies.

PURPOSE Radiation dose to the neuroregenerative zone of the hippocampus has been found to be associated with cognitive toxicity. Hippocampal avoidance (HA) using intensity-modulated radiotherapy during whole-brain radiotherapy (WBRT) is hypothesized to preserve cognition. METHODS This phase III trial enrolled adult patients with brain metastases to HA-WBRT plus memantine or WBRT plus memantine. The primary end point was time to cognitive function failure, defined as decline using the reliable change index on at least one of the cognitive tests. Secondary end points included overall survival (OS), intracranial progression-free survival (PFS), toxicity, and patient-reported symptom burden. RESULTS Between July 2015 and March 2018, 518 patients were randomly assigned. Median follow-up for alive patients was 7.9 months. Risk of cognitive failure was significantly lower after HA-WBRT plus memantine versus WBRT plus memantine (adjusted hazard ratio, 0.74; 95% CI, 0.58 to 0.95; P = .02). This difference was attributable to less deterioration in executive function at 4 months (23.3% v 40.4%; P = .01) and learning and memory at 6 months (11.5% v 24.7% [ P = .049] and 16.4% v 33.3% [ P = .02], respectively). Treatment arms did not differ significantly in OS, intracranial PFS, or toxicity. At 6 months, using all data, patients who received HA-WBRT plus memantine reported less fatigue ( P = .04), less difficulty with remembering things ( P = .01), and less difficulty with speaking ( P = .049) and using imputed data, less interference of neurologic symptoms in daily activities ( P = .008) and fewer cognitive symptoms ( P = .01). CONCLUSION HA-WBRT plus memantine better preserves cognitive function and patient-reported symptoms, with no difference in intracranial PFS and OS, and should be considered a standard of care for patients with good performance status who plan to receive WBRT for brain metastases with no metastases in the HA region.