IWAMOTO, FABIO MASSAITI

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 (<18 years), and n=7,808 (30.2%) were elderly patients (>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 BACKGROUND Standard of care (SOC) and patient survival in glioblastoma have changed little in the past 17 years. We evaluated in a phase 3 trial whether adding an autologous tumor lysate-loaded dendritic cell vaccine (murcidencel) to SOC extends survival. Patients and METHODS Newly diagnosed glioblastoma patients were randomized 2:1 to either murcidencel or placebo. Under a crossover design, all patients could receive murcidencel following tumor recurrence. All parties remained blinded regarding treatments before recurrence. Patients thus received murcidencel at new diagnosis (nGBM) or at recurrence (rGBM) following crossover from placebo. The primary and secondary endpoints compare overall survival (OS) with contemporaneous, matched external controls. Four sets of analyses were conducted to ensure rigorous matching of the controls, reduce biases, and confirm the robustness of the results. RESULTS 331 patients were enrolled. With the crossover, 89% received murcidencel. Median OS (mOS) for nGBM patients (n = 232) was 19.3 months from randomization (22.4 months from surgery) with murcidencel vs. 16.5 months from randomization in the controls (HR = 0.80, p = 0.002). Survival at 48 months from randomization was 15.7% vs. 9.9%, and at 60 months was 13% vs. 5.7%. For rGBM (n = 64), mOS was 13.2 months from relapse vs. 7.8 months in the controls (HR = 0.58, p < 0.001). Survival at 24 months post-recurrence was 20.7% vs. 9.6%, and at 30 months post-recurrence was 11.1% vs 5.1%. In nGBM patients with methylated MGMT (n = 90), mOS was 30.2 months from randomization (33 months from surgery) with murcidencel vs. 21.3 months from randomization in the controls (HR = 0.74, p = 0.027). The treatment was well tolerated, with only 5 serious adverse events deemed at least possibly related to the vaccine. CONCLUSION Clinically meaningful and statistically significant survival extension was seen in both nGBM and rGBM patients treated with murcidencel and SOC compared with contemporaneous, matched external controls who received SOC alone.

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 > 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.

Abstract BACKGROUND Radiation Therapy Oncology Group 9802 was a phase III trial for patients with centrally confirmed LGG (WHO grade II). Participants ³ 40 years or those with neurosurgeon defined less than gross total resection (GTR) were randomized to radiotherapy (RT) +/- PCV. In a separate cohort, adults age < 40 years with neurosurgeon defined GTR were observed by MRI every 6 months without adjuvant therapy. At last report, outcome for the observation cohort was immature with median follow-up of only 4.4 years. Here, we present mature outcomes for the observation arm. METHODS Eligible adults (as above) were observed by MRI every 6 months. OS and PFS were estimated by Kaplan-Meier method and estimated hazard ratios to characterize the prognostic variables. RESULTS There were 111 eligible patients (median age 30; median KPS = 100). Median follow-up was 16.1 years with 71 (64%) alive at the last follow-up. 79 patients (71%) had progressed with median PFS of 6.9 years. 5, 10, and 15 year-PFS and OS rates were 54%, 39%, 28% and 94%, 77%, and 65%. 1p19q status was codeleted in 32%, IDH1/2 mutant in 78% and MGMT promoter methylated in 39% of tested cases. Multivariate Cox analyses showed that preoperative tumor size ³ 4 cm (HR = 2.43 for PFS, p = 0.001; HR = 2.58 for death, p = 0.016) and residual disease on imaging ³ 1 cm (HR = 2.97 for PFS, P < 0.001; HR = 2.02 for death, p = 0.05) were associated with worse outcomes. Analyses based on molecular results will be presented. CONCLUSION A subset of low-grade gliomas can be observed after the initial resection based on younger age, smaller tumor size, and no residual disease on neuroimaging. This can likely be further refined by prognostic molecular markers. Patients with the most favorable prognostic factors can avoid or delay the acute and long-term side effects of RT and chemotherapy for several years.

PURPOSE Patients with progressive or recurrent meningiomas have limited systemic therapy options. Focal adhesion kinase (FAK) inhibition has a synthetic lethal relationship with NF2 loss. Given the predominance of NF2 mutations in meningiomas, we evaluated the efficacy of GSK2256098, a FAK inhibitor, as part of the first genomically driven phase II study in recurrent or progressive grade 1-3 meningiomas. PATIENTS AND METHODS Eligible patients whose tumors screened positively for NF2 mutations were treated with GSK2256098, 750 mg orally twice daily, until progressive disease. Efficacy was evaluated using two coprimary end points: progression-free survival at 6 months (PFS6) and response rate by Macdonald criteria, where PFS6 was evaluated separately within grade-based subgroups: grade 1 versus 2/3 meningiomas. Per study design, the FAK inhibitor would be considered promising in this patient population if either end point met the corresponding decision criteria for efficacy. RESULTS Of 322 patients screened for all mutation cohorts of the study, 36 eligible and evaluable patients with NF2 mutations were enrolled and treated: 12 grade 1 and 24 grade 2/3 patients. Across all grades, one patient had a partial response and 24 had stable disease as their best response to treatment. In grade 1 patients, the observed PFS6 rate was 83% (10/12 patients; 95% CI, 52 to 98). In grade 2/3 patients, the observed PFS6 rate was 33% (8/24 patients; 95% CI, 16 to 55). The study met the PFS6 efficacy end point both for the grade 1 and the grade 2/3 cohorts. Treatment was well tolerated; seven patients had a maximum grade 3 adverse event that was at least possibly related to treatment with no grade 4 or 5 events. CONCLUSION GSK2256098 was well tolerated and resulted in an improved PFS6 rate in patients with recurrent or progressive NF2-mutated meningiomas, compared with historical controls. The criteria for promising activity were met, and FAK inhibition warrants further evaluation for this patient population.

Abstract BACKGROUND PCV+RT substantially prolongs survival in AO patients, but long-term CF and QOL implications are unclear. We compared CF and QOL by treatment arm in RTOG 9402 participants and evaluated the impact that baseline characteristics had on CF, QOL, and survival. METHODS CF and QOL were evaluated using the Mini Mental State Exam (MMSE) and Brain-Quality of Life (B-QOL) scale at baseline and annually. Scores were analyzed between treatment arms at each time point for patients with ≥ 10 years of follow-up data. Shared parameter models evaluated MMSE and B-QOL scores and survival for all patients. RESULTS 42/148 (28.4%) participants in PCV+RT and 20/143 (14%) in RT alone arms survived ≥ 10 years. 35/42 and 39/42 (PCV+RT) and 18/20 and 17/20 (RT) participants completed baseline B-QOL and MMSE assessments, respectively. B-QOL scores did not differ between treatment groups at any time-point. Among 16 patients (10 PCV+RT, 6 RT) who completed year 10 MMSE evaluations, mean MMSE score at 10 years was higher in the RT arm (29.83 [95% CI 22.1, 30.0] vs. 26.50 [95% CI 29.4, 30.0], P= 0.04). Change in MMSE and B-QOL scores from baseline did not differ significantly between treatment groups at any time. In shared parameter models including all patients with baseline assessments, MMSE and B-QOL scores decreased over time (MMSE P= 0.0189, B-QOL P= 0.0005), but this did not differ by treatment group (MMSE P= 0.5727, B-QOL P= 0.3592). Younger age and higher KPS predicted better scores (MMSE P < 0.0001, P = 0.0002; B-QOL P = 0.0043, P = 0.0007). PCV+RT predicted better survival in both models. CONCLUSIONS PCV+RT improves survival in AO. Shared parameter models show decrease in MMSE and B-QOL over time. However, relative to RT alone, the addition of PCV did not impact change in CF and QOL over time.