We conducted a randomized surgical window-of-opportunity trial (NCT04606316) in recurrent, resectable glioblastoma. Between 2021 and 2024, 71 patients were screened, and 63 were randomized (intention-to-treat [ITT] population), and 58 received study treatment. Patients received pre-surgical immune checkpoint blockade (ICB) with dual anti-PD1 nivolumab + anti-CTLA4 ipilimumab (Arm 1), nivolumab alone (Arm 2), or placebo (Arm 3). Following surgery, Arms 1 and 3 received dual ICB, while Arm 2 continued nivolumab until progression or unacceptable toxicity. The primary endpoint, tumor-infiltrating lymphocyte (TIL) density, was met for Arm 1, as neoadjuvant dual ICB significantly increased TIL density compared with untreated control (Arm 3). As a secondary endpoint, median overall survival in the ITT population was 402 days (95% CI, 265–571) among patients who received dual ICB (Arms 1 and 3) and 273 days (95% CI, 166–506) for those assigned to nivolumab alone (Arm 2). No unanticipated toxicities were observed. Exploratory analyses showed that dual ICB elicited robust intratumoral and systemic immune activation, including increased interferon-related gene expression in blood. Higher TIL density and early systemic interferon-signature induction were associated with improved survival, whereas tumor mutational burden was not. Our results demonstrate pharmacodynamic activity of dual ICB in glioblastoma, with survival outcomes comparing favorably to similar studies. Here the authors report clinical and immunological outcomes of a randomized surgical window-of-opportunity trial designed to test whether dual immune checkpoint blockade targeting PD-1 and CTLA-4 could overcome the adaptive immune resistance previously reported with single-agent anti-PD-1 therapy in patients with surgically resectable recurrent glioblastoma.

CTO, an oral brain penetrant inhibitor of calcium signaling pathways was evaluated in rHGG and ndGBM. Intracellular Ca2+ homeostasis is altered in cancer cells and results in abnormal gene expression and immune evasion.Primary objectives of safety, dose-limiting toxicity (DLT) and recommended phase 2 dose were reported [Omuro et al. JCO 2018]. This analysis presents secondary outcome of overall survival (OS) and comparison with historical controls. In a 3+3 design, CTO was given daily p.o. in: i) rHGG: CTO (219-812.5mg/m2/d and in 6 pts 600mg/day) and TMZ (150 mg/m2 x 5 every 28 d). OS was compared to phase III in rHGG treated with lomustine . (N=259)ii) ndGBM: CTO (219-481 mg/m2) and standard of care TMZ/RT [Stupp et al. NEJM 2005] OS was compared to phase III in ndGBM treated with SOC (N=1,339). i) rHGG (N=26 pts): CTO was well tolerated (no DLT) and median OS (mOS) was 10.5 mo with 95% CI (8.0, 14.8) and 1-year OS of 47.4%, compared to lomustine treated pts with mOS 7.0 months (6.1, 7.7) and 1-year OS of 25.4%, p=0.0126.ii) ndGBM: All pts (N=15) had GBM (methylated MGMT gene in 33%; EGFR in 27%). In SOC+CTO pts, treatment was well tolerated, mOS was 37.8 mo (95% CI 20.9, 51.9) and a 2-yr survival of 69%, compared to historical control mOS of 15.8 mo 95% CI (15.1, 16.5) and 2-yr OS of 28.4%, p=0.006. Addition of CTO to TMZ or TMZ/RT respectively was safe with no DLT. Survival in both recurrent HGG and newly diagnosed GBM patients compares favorably with historical controls. Phase 2 randomized trials are planned. Thomas Kaley, Elena Pentsova, Cameron Brennan, Debyani Chakravarty, Lindsey Myers, Nancy Keith, Adam Newton, Kathryn Beal, Robert Aiken, Antonio Omuro, Priya Kumthekar, Rashida A. Karmali. Carboxyamidotriazole orotate (CTO) with temozolomide (TMZ) for recurrent high-grade gliomas (rHGG) and in combination with TMZ/RT->TMZ in newly diagnosed glioblastoma (ndGBM): Long term follow-up of phase IB trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB081.

Background:Clinical outcomes in patients with glioblastoma and low Karnofsky Performance Scale (KPS) in the inpatient setting are rarely described. Limited survival data and high symptom burden complicate decision-making. This study describes patient-centered outcomes in functionally debilitated patients with newly diagnosed glioblastoma following cancer-directed treatment. Methods:We retrospectively reviewed charts of patients with newly diagnosed glioblastoma who received radiotherapy (RT) while hospitalized. Patient, tumor, and treatment characteristics were included in univariable Cox regression and logistic models to assess associations with overall survival (OS) and discharge home. Multivariable models included factors significant on univariable analysis. OS was estimated by the Kaplan-Meier method. Results:Of 52 patients (median age: 68 years, range: 21-85), median KPS was 50 (range: 30-60). All underwent RT and 50 (96%) received concurrent temozolomide; 12 (23%) received bevacizumab, and 46 (88%) completed planned RT. Median length of stay (LOS) was 29 days (range: 20-65). Only 40% of patients were able to participate in decision-making. Specialty palliative care consultation was provided to 16 (31%). Median OS was 5.82 months. In multivariable analysis, lower KPS remained the sole factor significantly associated with increased risk of death (P = .002) and decreased odd of discharge home (P = .02). Conclusion:Inpatient treatment for functionally disabled patients with glioblastoma was associated with prolonged LOS and poor outcomes. These findings highlight opportunities for early incorporation of specialty palliative care to multimodal cancer-directed therapies to optimize symptom management, elicit patient values and preferences, and facilitate goal-concordant decision-making. Prospective studies are necessary to identify predictors of functional recovery and treatment options.

Background: Primary central nervous system lymphomas (PCNSL) is an aggressive subtype of diffuse large B-cell lymphoma with poor outcomes. Prognosis is especially poor for patients over age 60 years and with relapsed/refractory (R/R) disease. While the currently available therapies provide acceptable response rates in the R/R setting, they are not durable. Similar to PCNSL, the management of secondary CNSL (SCNSL) is challenging and usually involves high dose methotrexate-based (HD-MTX) chemotherapy with limited options for those who progress/relapse following HD-MTX based therapies. Bruton's tyrosine kinase (BTK) is a central signaling nodule of the B-cell receptor signaling pathway and therefore a promising therapeutic target in CNSL. Ibrutinib, a first-in-class BTK inhibitor has established activity in both primary and secondary CNSL with response rates around 50-60%, but the median PFS is short (~4-5 months). Hence, novel combination approaches utilizing ibrutinib backbone are needed to provide durable remissions. Epcoritamab is a subcutaneously administered IgG1-bispecific antibody (BsAb) that recognizes the B-cell antigen CD20 on malignant cells and the T-cell antigen CD3, thus facilitating T-cell mediated cytotoxicity of CD20-expressing malignant cells. PCNSLs are sensitive to CD20 targeting as previously demonstrated by increased response rates when adding the monoclonal anti-CD20 antibody rituximab to other therapies such as ibrutinib. Therefore, combining epcoritamab with ibrutinib might provide a novel therapeutic approach that would work synergistically to improve outcomes in patients with R/R CNSL. We hypothesize that epcoritamab can be safely used in CNSL patients when combined with ibrutinib. Patients with R/R CNSL are at higher risk of clinical deterioration, particularly when treated with a BsAb that might increase inflammation and edema in the CNS resulting in worsening clinical and neurologic deficits. Ibrutinib has been shown to induce significant tumor reduction within 2-4 weeks of therapy. Hence, the treatment schema includes a 'priming’ phase for patients with a 2-week introduction course of ibrutinib to significantly reduce tumor size and reduce the risk of epcoritamab associated cytokine release syndrome as well as immune effector cell-associated neurotoxicity syndrome and to prevent rapid deterioration of neurologic function from the recurrent/refractory disease. Study Design and Methods: EIFEL (NCT07082868) is a multicenter, single-arm, open-label, non-randomized phase 1b study. Eligible patients are 18 years or older with histologically confirmed R/R PCNSL and SCNSL after one prior line of systemic therapy. Patients must have adequate end-organ function. Patients who received external beam radiation therapy to the CNS within 21 days of the first dose of the study drug are excluded. The study consists of a safety lead-in (Cohort A) of 6 patients with either R/R PCNSL or R/R SCNSL followed by dose expansions for R/R PCNSL (Cohort B1) and R/R SCNSL (Cohort B2) with 10 patients each. Ibrutinib will start at 560 mg daily as single agent for 2 weeks followed by combination therapy for 12 cycles (28-day cycle) with ibrutinib dosed at 560 mg daily and subcutaneous epcoritamab dosed at the FDA-approved dosing schedule for DLBCL. Single agent epcoritamab will then be continued until completion of cycle 26. The primary objective is to determine the safety and tolerability of epcoritamab in combination with ibrutinib in CNSL patients. Secondary objectives include frequency and severity of adverse events, overall response rate and complete response rate following C6, duration of response, median PFS and PFS at 16 weeks, 24 weeks and 48 weeks, overall survival, and evaluating CSF pharmacokinetics of epcoritamab for PCNSL and SCNSL patients. Diagnostic tissue, peripheral blood and CSF samples from different timepoints are collected for planned exploratory analysis including evaluation of T-cell function, and ctDNA testing.

Our previous study of neoadjuvant PD-1 immune checkpoint blockade (ICB) in surgically-accessible recurrent glioblastoma suggested that single-agent PD-1 blockade induced adaptive immune responses that may have paradoxically inhibited functional anti-tumor immune responsiveness. To address this, we performed a surgical-window-of-opportunity trial in resectable, relapsed glioblastoma patients (n=60). Patients received either dual ICB (Arm 1, n=25) with ipilimumab (3 mg/kg) and nivolumab (240 mg), single-agent PD-1 ICB (Arm 2, n=25) with nivolumab (240 mg/kg), or a placebo infusion (Arm 3, n=10) prior to surgical resection. Following surgery, Arms 1 and 3 received dual ICB, while Arm 2 continued on nivolumab until progression or unacceptable toxicity. We collected blood and tumor tissue from all patients and performed RNA and TCR sequencing, along with multiplexed immunofluorescence, to evaluate intratumoral and systemic immune response. Dual ICB induced greater T-cell/interferon-related gene expressions in tumor compared with PD-1 ICB or a placebo infusion. It also resulted in the highest TIL density, as assessed by TCR sequencing. In a multivariate analysis, TIL density strongly correlated with survival outcomes. In PBMCs, dual ICB induced robust interferon gene signatures, and early upregulation of these signatures immediately following treatment was associated with longer survival. However, alongside interferon signaling, monocyte-related signatures also significantly increased following dual ICB, and their persistently elevated levels during adjuvant treatment cycles were linked to poorer outcomes. The median overall survival of patients who received dual ipilimumab+nivolumab was 405 days (95% CI, 265 to NA), while that of single agent nivolumab was 275 days (95% CI, 166 to NA). Our results demonstrate a clear pharmacodynamic effect of dual ICB in glioblastoma and the survival times compare favorably with similar clinical studies done in the same population. Moreover, our transcriptional analysis underscores the importance of balancing immune activation and chronic inflammation in shaping ICB responsiveness.

2032 Background: Leptomeningeal metastases (LM), the spread of cancer to the cerebrospinal fluid (CSF), is associated with high morbidity and mortality. LM employ the iron-binding transporter and receptor system, lipocalin-2/SLC22A17, to scavenge iron from the CSF to sustain their metabolic needs. In preclinical models of LM, intrathecal administration of deferoxamine (IT-DFO), an iron chelator, resulted in reduction of LM growth and improvement of survival. We evaluated this novel treatment strategy in this first-in-human clinical trial in patients with solid tumor LM. Methods: This is a phase 1a, single-institution, clinical trial to determine safety and maximum tolerated dose (MTD) of IT-DFO in patients with LM. Eligibility criteria included LM from any solid tumor, age ≥ 18 years, Karnofsky Performance Status ≥ 60, life expectancy ≥ 8 weeks, and Ommaya reservoir. Patients were enrolled in an accelerated 3+3 dose escalation design with a primary endpoint of dose-limiting toxicity (DLT), defined as a grade 3 non-hematologic or grade 4 hematologic toxicity in the first cycle of treatment. All patients received IT-DFO twice weekly (cycle 1), once weekly (cycle 2), then once every two weeks (cycle 3+) in 28-day cycles. Patients were monitored for LM progression by neurological examination, neuraxial magnetic resonance imaging, and CSF cytology as per modified Response Assessment in Neuro-Oncology LM criteria. Results: A total of 8 patients received treatment with IT-DFO from May 2022 to January 2025 at the time of data cut-off. The median age at enrollment was 50 years (range, 26-69). The primary malignancy included breast (n = 4), lung (n = 2), colon (n = 1), and sarcoma (n = 1). Patients were treated with IT-DFO at doses of 10 mg (level 1, n = 4) and 30 mg (level 2, n = 4). IT-DFO was well tolerated, and the majority of adverse events (AEs) were grade 1-2. The most common any grade AEs were vomiting (50%), nausea (37.5%), chills (25%), myalgias (25%), and tremor (25%). Two patients experienced DLTs at 30 mg (grade 3 vomiting, grade 3 syncope). No grade 4-5 AEs were observed. The MTD was determined to be 10 mg. In this heterogenous heavily pretreated population, median overall survival for the evaluable cohort (n = 7) was 10.0 months (95% CI, 6.5 – NA). Conclusions: IT-DFO is a novel, well tolerated investigational treatment for LM. A phase 1b dose expansion study at a dose of 10 mg is currently underway to better define safety and efficacy endpoints. Clinical trial information: NCT05184816 .

Disclosure: A.L. Lin: Bristol-Myers Squibb. V. Rudneva: None. R.J. Young: Guerbet, ICON plc, NordicNeuroImaging, Olea, RadMD, Servier, Turing Medical. T. Kaley: None. I. Mellinghoff: None. M.T. Donoghue: None. V. Tabar: Blue Rock Therapeutics. E.B. Geer: Chiesi, Recordati, Sparrow, Xeris, Crinetics, HRA Pharmaceuticals, Lundbeck. Background: Pituitary neuroendocrine tumors (PitNETs) that progress following surgery and radiotherapy are in need of additional treatment options. Responses to immune checkpoint inhibitors (ICIs) have been described; however, the feasibility of ICI therapy and biomarkers of response have not been formally assessed. Methods: We performed a single center, prospective, phase 2 trial investigating the activity of ipilimumab and nivolumab in PitNET patients. The primary endpoint was objective response using the iRANO response criteria. We then explored genetic biomarkers of response to ICI in 13 patients with PitNETs, who were treated with ICI, on or outside of the trial. Results: 10 patients with a PitNET were enrolled, including 5 corticotroph, 4 lactotroph, and 1 somatotroph tumor; of which 9/10 (4 metastatic and 5 non-metastatic) patients were evaluable for the primary endpoint. While no objective responses were observed, tumor shrinkage was seen in 2/9 patients. In a biomarker discovery cohort, comprised of 7 tumors treated on trial and 6 tumors treated off trial, temozolomide hypermutation and mismatch repair deficiency (MMRd) were associated with immunological response. In 3 tumors sequenced pre- and post-ICI treatment, we identified evidence of immunoediting, characterized by loss of MMRd and/or a decrease in tumor mutational burden. Conclusion: This study demonstrates the safety and feasibility of ICI treatment in refractory PitNETs. We also identified MMRd and temozolomide hypermutation as potential biomarkers of response to ICI. Overall, our data suggests that ICIs might provide an additional treatment option for PitNET; this should be evaluated more broadly in future studies. Presentation: Saturday, July 12, 2025

Prostate specific membrane antigen (PSMA)-directed therapeutics have revolutionized treatment of metastatic prostate cancer. However, this target is expressed by numerous tumor types. Given potential for strong PSMA expression within glioma neovasculature, we are exploring a PSMA-anchored adjuvant theranostic strategy incorporating PSMA PET imaging and radiopharmaceutical therapy (RPT) for malignant glioma neovessels and microscopic disease. This is a phase I, trial-in-progress of adjuvant [177Lu]Lu-PSMA-617 for newly diagnosed, isocitrate dehydrogenase (IDH) wildtype gliomas following upfront standard-of-care temozolomide and external beam radiotherapy (EBRT). The primary outcome is safety, and primary endpoint is descriptive toxicity up to 8 weeks post first infusion of [177Lu]Lu-PSMA-617. Eligible patients have IDH1-R132H wildtype grade II-IV glioma with immunohistochemistry confirmation of PSMA expression. Eligible patients undergo screening [68Ga]Ga-PSMA-PET/MR scan performed 2 weeks post-EBRT. If PSMA avidity exceeds background brain parenchyma, the patient will receive 2 cycles of 7.4GBq of [177Lu]Lu-PSMA-617 spaced 4 weeks apart, in combination with standard adjuvant temozolomide (150-200 mg/m2 per cycle). Dosimetric assessment will be performed during the first cycle of [177Lu]Lu-PSMA-617 RPT, including serial single photon emission CT (SPECT) imaging of the head. Four weeks post-cycle 2, patients will undergo repeat [68Ga]Ga-PSMA-PET/MR. If residual PSMA avidity above background, patients can receive up to 4 additional monthly cycles of [177Lu]Lu-PSMA-617 spaced 4 weeks apart, in combination with standard adjuvant temozolomide. Patients will undergo regular safety assessments, frequent bloodwork, quality of life surveys and imaging every 2mo. A second [68Ga]Ga-PSMA-PET scan will be performed at progression. This phase I study offers a novel approach to integrate RPT for a disease with substantial unmet need. The trial is undergoing IRB approval and slated to open in the next month. At the conference, we will share study design details and early patient experience/data.

Abstract Purpose: Adavosertib is an oral small-molecule inhibitor of Wee1. The Adult Brain Tumor Consortium conducted a phase I study evaluating adavosertib in combination with radiation (RT) and temozolomide (TMZ) in patients with newly diagnosed glioblastoma (GBM), as well as a surgical window-of-opportunity study in recurrent GBM. Patients and Methods: The MTD of adavosertib was determined in adult patients with newly diagnosed GBM using a standard 3+3 design in two separate cohorts: with concurrent RT/TMZ or with adjuvant TMZ. A combination cohort with both concurrent and adjuvant adavosertib at MTD followed. We also performed intratumoral drug distribution studies in patients with recurrent GBM undergoing surgery. Results: As separate cohorts, the MTD for concurrent adavosertib with RT/TMZ was 200 mg daily Monday through Friday × 6 weeks during RT, and the MTD for adjuvant adavosertib with TMZ was 425 mg daily for 5 days of each 28-day cycle. However, six of 12 patients experienced dose-limiting toxicities (DLT) in the combination cohort. The mean ratios of the intratumoral to plasma concentration of adavosertib were 4.18 ± 3.36 for contrast-enhancing tissue and 0.74 ± 0.63 in nonenhancing tissue. Conclusions: Adavosertib at 200 mg daily Monday through Friday × 6 weeks with RT/TMZ and at 425 mg daily on a 5-day/28-day cycle with TMZ had an unacceptable DLT rate. Additional dose levels in combination cohorts resulted in DLT, and we deemed concurrent adavosertib too toxic for further examination. Adavosertib 425 mg daily on a 5-day/28-day cycle with adjuvant TMZ is the recommended phase II dosage. Tissue pharmacokinetics in tissue homogenates and by microdialysis provided complementary information about drug penetration.

Nearly all glioblastomas recur within two years of initial treatment. While most recurrences occur within or near the resection cavity, a substantial minority of recurrences arise distant to the primary tumor site, representing progression of microscopic disseminated disease, and leading to compromised oncologic outcomes. We hypothesized that glioblastoma distant recurrences preferentially occur near white matter tracts associated with the primary site, and that these high-risk regions can be mapped using probabilistic tractography. We identified glioblastoma patients with distant recurrence ≥ 2 cm from the primary site and diffusion tensor imaging prior to recurrence. Probabilistic tractography connection (PTC) maps were produced, initialized from the primary site plus a 1 cm expansion. Low-probability voxels with values less than the mean were eliminated. The distance from PTC map to the recurrent tumor was then evaluated as the primary metric of model performance. The probability of the distant recurrence occurring within 0.5 cm of the PTC map was evaluated with a one-sided binomial distribution. Of 35 glioblastoma distant recurrences identified at median 15.9 months after resection, the median distance from the primary site was 4.5 cm. The median volume of the PTC map was 139 cc, equivalent to 9.7% of the brain volume. The median distance from the PTC map to the recurrent tumor was 0.0 cm (range: 0.0-1.7 cm). Among 35 distant recurrences, 29 (83%) were within 0.5 cm of the PTC map (p=0.0002). We describe a novel technique that uses probabilistic tractography to identify regions of the brain at high risk for glioblastoma distant recurrence. Nearly all distant recurrences occur along mappable white matter tracts, supporting the hypothesis that white matter tracts are a predominant pathway for microscopic dissemination. Mapping of white matter tracts with probabilistic tractography may aid in personalizing neurosurgical and radiotherapeutic treatment planning, improving oncologic control.

Context Pituitary neuroendocrine tumors (PitNETs) that progress following surgery and radiotherapy are in need of additional treatment options. Responses to immune checkpoint inhibitors (ICIs) have been described; however, the feasibility of ICI therapy and biomarkers of response have not been formally assessed.Objective To evaluate the activity of ICI as a treatment for PitNETs.Methods We performed a single-center, prospective, phase 2 trial investigating the activity of ipilimumab and nivolumab in patients with PitNETs. The primary endpoint was objective response using the iRANO response criteria. We then explored genetic biomarkers of response to ICIs in 13 patients with PitNETs who were treated with ICIs, on or outside of the trial.Results Ten patients with a PitNET were enrolled, including 5 corticotroph, 4 lactotroph, and 1 somatotroph tumor, of which 9/10 (4 metastatic and 5 nonmetastatic) patients were evaluable for the primary endpoint. While no objective responses were observed, tumor shrinkage was seen in 2/9 patients. In a biomarker discovery cohort, comprising 7 tumors treated on trial and 6 tumors treated off trial, temozolomide hypermutation, and mismatch repair deficiency (MMRd) were associated with immunological response. In 3 tumors sequenced pre- and post-ICI treatment, we identified evidence of immunoediting, characterized by loss of MMRd and/or a decrease in tumor mutational burden.Conclusion This study demonstrates the safety and feasibility of ICI treatment in aggressive PitNETs. We also identified MMRd and temozolomide hypermutation as potential biomarkers of response to ICI. Overall, our data suggest that ICIs might provide an additional treatment option for PitNET; this should be evaluated more broadly in future studies.

BACKGROUND:Despite advances in our understanding of the molecular underpinnings of meningioma progression and innovations in systemic and local treatments, recurrent meningiomas remain a substantial therapeutic challenge. The objective of this systematic review and meta-analysis is to provide a historical baseline, contemporary analysis, and propose a "rate of probable interest" to inform future clinical trial design and development on behalf of the Response Assessment in Neuro-Oncology meningioma group. METHODS:PubMed, ClinicalTrials.gov, and ASCOpubs databases were screened for clinical trials evaluating the activity of systemic therapies for adults with recurrent meningiomas. The pooled progression-free survival at 6-months and 1-year (PFS-6 and PFS-1 year) values were calculated using the random effects technique with I2 indices. RESULTS:The pooled PFS-6 and PFS-1 year rates for recurrent WHO grade 1 meningiomas were 43.6% (95% CI: 22.7-67.0%, I2 = 80%) and 21.7% (95% CI: 6.2-53.9%, I2 = 76%), and for grades 2-3 meningiomas, the PFS-6 was 38.0% (95% CI: 28.3-48.8%, I2 = 68%). In the targeted therapy group, PFS-6 and PFS-1 year rates stood at 62.0% (I2 = 58%) and 49.0% (I2 = 63%) for grade 1, while for grades 2-3 tumors, the PFS-6 rates with targeted therapy and immunotherapy were 42.1% (I² = 60%) and 46.0% (I² = 0%), respectively. The benchmarks were set at 67% and 54% for PFS-6 and PFS-1 year for grade 1 tumors, and PFS-6 of 49% for grades 2-3 tumors. CONCLUSIONS:Several studies have reported outcomes in patients with recurrent meningiomas testing a variety of agents with modest, but variable and progressively increasing activity. In this context, we recommend new benchmarks for future trials to define efficacy of future investigational therapies.

PURPOSE:Ibrutinib is a first-in-class inhibitor of Bruton tyrosine kinase. We previously reported the safety and short-term antitumor activity of ibrutinib in 20 patients with relapsed or refractory (r/r) primary central nervous system (CNS) lymphoma (PCNSL) or secondary CNS lymphoma (SCNSL). PATIENTS AND METHODS:We enrolled 26 additional patients with r/r PCNSL/SCNSL into the dose-expansion cohort of the trial into a combined cohort of 46 patients (31 with PCNSL and 15 with SCNSL). Patients received ibrutinib at 560 or 840 mg daily in the dose-escalation cohort and ibrutinib at 840 mg daily in the expansion cohort. The median follow-up was 49.9 and 62.1 months for patients with PCNSL and SCNSL, respectively. We sequenced DNA from available tumor biopsies and cerebrospinal fluid collected before and during ibrutinib therapy. RESULTS:Tumor responses were observed in 23/31 (74%) patients with PCNSL and 9/15 (60%) patients with SCNSL, including 12 complete responses in PCNSL and 7 in SCNSL. The median progression-free survival (PFS) for PCNSL was 4.5 months [95% confidence interval (CI), 2.8-9.2] with 1-year PFS at 23.7% (95% CI, 12.4%-45.1%). The median duration of response in the 23 PCNSL responders was 5.5 months. The median PFS in SCNSL was 5.3 months (95% CI, 1.3-14.5) with a median duration of response of 8.7 months for the 9 responders. Exploratory biomarker analysis suggests that mutations in TBL1XR1 may be associated with a long-term response to ibrutinib in PCNSL (P = 0.0075). Clearance of ctDNA from cerebrospinal fluid was associated with complete and long-term ibrutinib responses. CONCLUSIONS:Our study confirms single-agent activity of ibrutinib in r/r CNS lymphoma and identifies molecular determinants of response based on long-term follow-up.

Leptomeningeal disease (LMD) is a devastating complication of melanoma with a dismal prognosis. We present the case of a young man with stage IV BRAF V600E mutant melanoma with lung, lymph node, and brain metastases initially treated with ipilimumab and nivolumab, who subsequently developed LMD. Upon change to BRAF/MEK targeted therapy with nivolumab, a durable complete response was achieved and remains ongoing, off treatment, 7 years from diagnosis. Management of symptomatic LMD remains a critical unmet clinical challenge, with limited clinical trial data. This exceptional case is instructive, as the first published case of the use of the triplet, and the first durable response with therapy discontinuation, in melanoma LMD. The triple-drug regimen may be considered a viable option in fit patients. This case highlights the potential for long-term disease control and the critical and urgent need to develop clinical trials inclusive of patients with LMD to define the best treatment strategies. We present the case of a young man with stage IV BRAF V600E mutant melanoma with lung, lymph node, and brain metastases initially treated with ipilimumab and nivolumab, who subsequently developed leptomeningeal disease (LMD). Upon change to dabrafenib and trametinib with nivolumab, a durable complete response was achieved and remains ongoing, off-treatment, 7 years from diagnosis. Management of symptomatic LMD remains a critical unmet clinical challenge, with limited clinical trial data. This exceptional case is instructive, as the first published case of the use of the triplet, and the first durable response with therapy discontinuation, in melanoma LMD (Lochrin et al. (2024). Pigment Cell & Melanoma Research. ).image

Abstract GBM AGILE(NCT03970447) is a phase 2/3 Bayesian adaptive registration platform trial testing multiple therapies against a common control. Paxalisib, a PI3K/mTOR inhibitor, is the 3rd arm in the trial to conclude evaluation. METHODS Paxalisib was open to patients with newly diagnosed unmethylated (NDU) and recurrent (RD) glioblastoma, with three possible signatures: NDU, RD, and All(NDU+RD). Arm enrollment occurred Dec2020 through May2022. Control patients were enrolled from study initiation (July2019) and were treated with temozolomide(NDU) or lomustine(RD). GBM AGILE investigational arms have 1 or 2 stages, with adaptive randomization in stage 1 and fixed randomization if arms continue to stage 2. Efficacy is based on OS hazard ratio(HR) of Arm/Control. Efficacy goal is final Bayesian probability ≥ 98% for HR<1.00 in combined Stages. An Arm continues to Stage 2 if Bayesian predictive power (PP) ≥ 0.8. An Arm stops accruing in Stage 1 if it reaches maximal sample size(N) or does not meet a minimum efficacy threshold (PP<0.25 for all signatures when N>50). Clinical cut-off is 12 months after accrual stops. The maximum N for paxalisib was approximately 150(Stage 1) and 50(Stage 2). RESULTS After paxalisib reached >150 patients in Stage 1, accrual stopped [Paxalisib/control N 54/75(NDU), 100/188(RD)]. Neither PP thresholds for moving to Stage 2 nor stopping for minimum efficacy were met. Following an unplanned public disclosure that the arm did not continue to stage 2, clinical cut-off for final analysis (planned May2023) was updated to public disclosure date (August2022). At final analysis mean HRs were 0.89(NDU), 1.25(RD), 1.05(All), probabilities of HR<1.00 of 0.72(NDU), 0.076(RD), 0.398(All). Model estimated median OS paxalisib/control (months) were 14.77/13.84(NDU) and 8.58/10.06(RD). CONCLUSION Paxalisib did not show survival benefit over cumulative control in final primary analysis; additional secondary analyses are being considered. GBM AGILE continues to rapidly and efficiently assess therapies in ND and RD glioblastoma.

Abstract The characterization of genetic alterations in tumor samples has become standard practice for many human cancers to achieve more precise disease classification and guide the selection of targeted therapies. Cerebrospinal fluid (CSF) can serve as a source of tumor DNA in patients with central nervous system (CNS) cancer. We performed comprehensive profiling of CSF circulating tumor DNA (ctDNA) in 711 patients using an FDA-authorized platform (MSK-IMPACT™) in a hospital laboratory. We identified genetic alterations in 489/922 (53.0%) CSF samples with clinically documented CNS tumors. None of 85 CSF samples from patients without CNS tumors had detectable ctDNA. The distribution of clinically actionable somatic alterations was consistent with tumor-type specific alterations across the AACR GENIE cohort. Repeated CSF ctDNA examinations from the same patients identified clonal evolution and emergence of resistance mechanisms. ctDNA detection was associated with shortened overall survival following CSF collection. Next-generation sequencing of CSF, collected through a minimally invasive lumbar puncture in a routine hospital setting, provides clinically actionable cancer genotype information in a large fraction of patients with CNS tumors.

Abstract BACKGROUND Several genetic syndromes have been linked to the development of central nervous system (CNS) tumors; however, the prevalence and clinical significance of germline pathogenic variants in this population remain unclear. METHODS 2,367 patients with a glioma, glioneuronal, or neuronal tumor (WHO grade 1-4) ages 0.2-93.8 years underwent tumor and matched normal sequencing with MSK-IMPACT. Germline variants and copy-number variants affecting 90 well-established cancer predisposing genes were analyzed; the presence of biallelic inactivation was determined using FACETS. RESULTS Eleven percent harbored germline pathogenic mutations in high-, moderate-, and low-penetrance genes. High- and moderate-penetrance genes included CHEK2 (n=32, 1.3%), BRCA2 (n=10; 0.4%), TP53 (n=9; 0.4%), NF1 (n=6; 0.2%), and mismatch repair (MMR) genes (n=20, 0.9%). Low-penetrance genes included monoallelic MUTYH (n=42; 1.8%) and the APC I1307K variant (n=28, 1.2%). Biallelic inactivation was found in all tumors from patients with germline TP53 and NF1 mutations, with lower rates in tumors from patients with a germline MMR alteration (53%). Biallelic inactivation was rare among patients with a germline mutation in homologous recombination pathway (HRD) genes (27%), and in the aforementioned low-penetrance APC (15.3%) and MUTYH (10.2%) variants. All patients with biallelic inactivation of an MMR gene were hypermutated. Biallelic inactivation of MMR genes and TP53 were observed in IDH-mutant astrocytoma and IDH-WT gliomas, while biallelic inactivation of NF1 and somatic IDH1/2 mutation were mutually exclusive. When examining the age at diagnosis among patients with germline alterations, tumors with biallelic inactivation were diagnosed at a younger age compared to tumors with monoallelic alterations (37.7 vs 51.6 years, p=0.002). CONCLUSION Clinical germline sequencing identifies a germline mutation in a high proportion of patients with CNS tumors. Biallelic inactivation was most commonly identified in tumors from patients with germline TP53 or NF1 mutations and were less common in patients with a germline MMR alteration.

Abstract BACKGROUND Patients with meningiomas that have progressed after surgery and/or radiation have limited treatments. Loss of NF2 and CDKN2A/B are common in higher-grade meningiomas and promote meningioma progression. We evaluated the efficacy of abemaciclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, as part of Alliance A071401, a genomically-driven phase II trial in recurrent or progressive meningiomas. METHODS Eligible patients (pts) with grade 2/3 tumors and NF2 mutations or CDK pathway alterations were treated with abemaciclib 200 mg orally twice daily. Two co-primary endpoints were used: progression-free survival at 6 months (PFS6) and response rate (RR); the trial would be declared positive if either endpoint was met. Twenty-four evaluable pts provided ≥85% power to detect a PFS6 ≥41.5% (vs. null 15%; alpha=0.02), and ≥89% power to detect RR ≥20% (vs. null 2.5%; alpha=0.021). RESULTS Of 83 pts screened while the abemaciclib arm was open between September 15, 2021 and October 3, 2022, 36 eligible pts received abemaciclib. The observed PFS6 rate in the first 24 evaluable pts was 54% (95% CI 33-75%), thus the study met PFS6 endpoint. Of all 35 evaluable pts, median PFS was 7.6 months (95% CI 3.6-17.1 months), estimated 6-month PFS was 55% (95% CI 40-75%) and estimated 6-month OS was 88% (95% CI 77-100%). No objective responses were observed. Of the 36 pts who started treatment, two had a grade 4 adverse event at least possibly related to treatment which included ALT elevation(1), AST elevation(1) and vomiting(1). Patients with NF2 alterations (n=24) had favorable PFS6 outcomes (58%, 95% CI 37-78%) compared to those with CDK (n=4, 25%, 95% CI 1-81%) and CDK+NF2 alterations (n=7, 29% 95% CI 4-71%), (Fisher’s Exact p=0.036). CONCLUSIONS Abemaciclib was well-tolerated and resulted in improved PFS6, meeting the trial’s co-primary endpoint. Abemaciclib warrants further investigation for the treatment of patients with progressive meningiomas.