Background: Glioblastoma (GBM) has a median survival of <2 years. Pexidartinib (PLX3397) is a small-molecule inhibitor of CSF1R, KIT, and oncogenic FTL3, which are implicated in GBM treatment resistance. Results from glioma models indicate that combining radiation therapy (RT) and pexidartinib reduces radiation resistance. We added pexidartinib to standard-of-care RT/temozolomide (TMZ) in patients with newly diagnosed GBM to assess the therapeutic benefit of altering the tumor microenvironment with pexidartinib. Methods: In this open-label, dose-escalation, multicenter, Phase 1b/2 trial, pexidartinib was administered in combination with RT/TMZ followed by adjuvant pexidartinib + TMZ. During Phase 1b, pexidartinib was given 5 or 7 days/week at multiple dosing levels. The primary Phase 1b endpoint was the recommended Phase 2 dose (RP2D). Phase 2 patients received the RP2D with the primary endpoint of median progression-free survival (mPFS). Secondary objectives were median overall survival (mOS), pharmacokinetics, and safety. Results: The RP2D of pexidartinib was 800 mg/day for 5 days/week during RT/TMZ, followed by 800 mg/day for 7 days/week with adjuvant TMZ. mPFS was 6.7 months (90% CI: 4.5, 11.5) for the modified intention-to-treat population. The actual mOS was 13.1 months (90% CI: 11.5, 24.5), and the mOS corrected for comparison with matched historical controls was 18.8 months (95% CI: 12.6, 28.0). Conclusions: This trial established the RP2D of pexidartinib in combination with RT/TMZ and adjuvant TMZ. Pexidartinib was generally safe and well tolerated. Although the study regimen with pexidartinib was not efficacious, pharmacodynamic studies showed modulation of systemic markers that could lead to alteration of the tumor microenvironment.

Key Points. 1. We identified a new pediatric type of PCNS-LBCL that has distinct molecular features compared to PCNS-LBCL occurring in adults.2. Pediatric PCNS-

A post-operative MRI (MRI_post-op) performed within 72 h is routinely used for radiation treatment planning in glioblastoma (GBM) patients, with radiotherapy starting about 4–6 weeks after surgery. Some patients undergo an additional pre-radiotherapy MRI (MRI_pre-RT) about 2–6 weeks after surgery. We sought to analyze the incidence of rapid early progression (REP) between surgery and initiation of radiotherapy seen on MRI_pre-RT and the impact on radiation target volumes. Patients with GBM diagnosed between 2018 and 2020 who had an MRI_post-op and MRI_pre-RT were retrospectively identified. Criteria for REP was based on Modified RANO criteria. Radiation target volumes were created and compared using the MRI_post-op and MRI_pre-RT. Fifty patients met inclusion criteria. The median time between MRI_post-op and MRI_pre-RT was 26 days. Indications for MRI_pre-RT included clinical trial enrollment in 41/50 (82%), new symptoms in 5/50 (10%), and unspecified in 4/50 (8%). REP was identified in 35/50 (70%) of patients; 9/35 (26%) had disease progression outside of the MRI_post-op-based high dose treatment volumes. Treatment planning with MRI_post-op yielded a median undertreatment of 27.1% of enhancing disease and 11.2% of surrounding subclinical disease seen on MRI_pre-RT. Patients without REP had a 38% median volume reduction of uninvolved brain if target volumes were planned with MRI_pre-RT. Given the incidence of REP and its impact on treatment volumes, we recommend using MRI_pre-RT for radiation treatment planning to improve coverage of gross and subclinical disease, allow for early identification of REP, and decrease radiation treatment volumes in patients without REP.

Immunodeficiency-associated primary CNS lymphoma (ID-PCNSL) represents a clinicopathologically distinct PCNSL subtype, for which large studies and prognostic models are lacking. To address this gap, the International PCNSL Collaborative Group conducted an international retrospective multi-center study, integrating clinical, radiological, and pathological data from 308 ID-PCNSL, diagnosed at 23 participating sites in 7 countries. Pre-existing immunodeficiency included administration of immunosuppressants for transplantation (41.2%) or autoimmunity (36.7%), and HIV infection (21.7%). All tumors were diffuse large B-cell lymphomas, with Epstein-Barr virus (EBV) detected in 79.2%. Immune reconstitution together with rituximab-methotrexate-(RM)-based chemotherapy was associated with highest response rates and prolonged progression-free survival, irrespective of immunodeficiency subtype and EBV status. Survival outcomes were highly variable with a 54-month median overall survival. Multivariable Cox regression identified age (per year increment HR: 1.05 (95%-CI:1.02-1.07); p < 0.001), Karnofsky Performance status (KPS) < 70 (HR: 3.10 (95%-CI:1.67-5.87); p < 0.001), EBV positivity (HR: 3.26 (95%-CI:1.47-7.33); p = 0.004) as prognostic factors for OS. A prognostic score was developed based on the sum of these adverse variables (age > 60 years, KPS < 70, EBV positivity). Stratification by this score yielded median survival times of 135, 29, and 3 months in patients with up to one, two and three unfavorable markers (p < 0.0001). It allowed improved prognostic stratification of ID-PCNSL as compared to the well-established MSKCC and IELSG models developed for immunocompetent PCNSL. Collectively, this large international cohort defines clinicobiologic features of ID-PCNSL and introduces an easily applicable prognostic system with potential to guide future management.

Background: Social determinants of health (SDOHs)—specifically those related to rurality, health care accessibility, and income—may play as-yet-unidentified roles in prognosis for glioma patients, and their impact on access to clinical trials is important to understand. We examined SDOHs of patients enrolled in glioma clinical trials and evaluate disparities in trial participation and outcomes between rural and urban patients. Methods: We retrospectively identified patients enrolled in glioma clinical trials at Huntsman Cancer Institute (HCI) from May 2012 to May 2022 to evaluate clinical trial participation. We used multivariable models to evaluate SDOHs and geographic information system mapping to assess representation across Utah’s counties. We utilized the most recent 10-year datasets of patients treated for glioma at HCI and from the Utah Cancer Registry to analyze survival and incidence, respectively. Results: A total of 570 participants (68 trials) resided in Utah, 84.4% from urban counties, 13.5% from rural counties, and 2.1% from frontier (least-populous) counties. Nineteen counties (65.5%) were underrepresented in trials (enrolled participants vs. eligible), 1 (3.5%) was represented in a near-1:1 ratio, and 9 (31.0%) were overrepresented. Counties with greater enrollment had greater population densities, highest per-capita income, and proximity to HCI. Among patients treated at HCI, patients from rural/frontier counties had equivalent survival with urban patients across nearly all glioma types, including glioblastomas, despite underrepresentation in clinical trials. Conclusions: By highlighting disparities in clinical trial enrollment, our results can support efforts to improve recruitment in underrepresented regions, which can assist providers in delivering equitable care for all patients.

Current treatments grade 2 gliomas are not curative and can be associated with short- and long-term toxicities. Vorasidenib (VOR), an oral, brain-penetrant, dual inhibitor of mutant (m)IDH1/2 enzymes, has shown a tolerable safety profile and preliminary clinical activity in phase 1 studies. In the phase 3 INDIGO study (NCT04164901), patients (pts) were randomized 1:1 to receive VOR 40 mg daily or placebo (PBO) daily in 28-day cycles. Patients were stratified by 1p19q status and baseline tumor size. Key eligibility criteria included: age ≥12; KPS >80; residual or recurrent grade 2 IDH1m or IDH2m oligodendroglioma or astrocytoma; measurable non-enhancing disease; no prior treatment for glioma with most recent surgery 1-5 years from randomization; and not in immediate need of chemotherapy/radiation. Primary endpoint: radiographic progression-free survival (PFS) by blinded independent radiology committee (BIRC). Key secondary endpoint: time to next intervention (TTNI). As of 06 Sep2022, 331 pts were randomized across 10 countries: 168 to VOR and 163 to PBO. Median PFS by BIRC was 27.7 mos with VOR and 11.1 with PBO (HR, 0.39; 95% CI, 0.27, 0.56; 1-sided P=0.000000067). Median TTNI was not reached with VOR and 17.8 mos with PBO (HR, 0.26; 95% CI, 0.15, 0.43; 1-sided P=0.000000019). All-grade adverse events (AEs) occurring in >20% pts receiving VOR vs PBO were alanine aminotransferase increased, COVID-19, fatigue, aspartate aminotransferase increase, headache, diarrhea, nausea. Common grade ≥3 AEs (>5%): ALT increased (9.6% vs 0%). VOR significantly improved PFS by BIRC versus PBO with a manageable safety profile. © 2023 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2023 ASCO Annual Meeting. All rights reserved.