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AbstractBackgroundKnowledge of the temporal evolution among plasma Alzheimer’s biomarkers and PET will inform disease pathophysiology and appropriate implementation of plasma biomarkers (Therneau, NeuroImage 2021; Betthauser, Brain 2022). This study investigates the relative timing of progression of plasma p‐tau181, p‐tau217, GFAP, and amyloid PET on individual and population levels.MethodWe included 957 participants from the Mayo Clinic Study of Aging with clinical diagnoses of cognitively unimpaired (n = 732), MCI (n = 205), and Alzheimer’s clinical syndrome dementia (n = 20). An accelerated failure time (AFT) model was fit with amyloid (PiB) PET, plasma p‐tau217 (Meso Scale Discovery, Lilly), plasma p‐tau181, and GFAP (Simoa, Quanterix HD‐X) as quad‐variate endpoints, and sex, APOE genotype status, and education as covariates. The model output included a per subject adjustment or time‐shift for each biomarker indicating how much earlier or later it was estimated to progress relative to the average participant, the correlation (R) between adjustments for each pair of biomarkers, and the impact of covariates on each biomarker’s timing. Secondly, we estimated progression at a given age for selected cutpoints.ResultTemporal trajectories for each biomarker are shown in Figure 1. Individual‐level adjustments between plasma p‐tau217 and amyloid PET were highly correlated, R = 0.69(0.64‐0.74); how early or late an individual progressed on plasma p‐tau217 explained 48% of the variation in relative timing of amyloid PET progression. Associations of plasma p‐tau181 and GFAP with amyloid PET individual adjustments were moderate and low, respectively (Figure 2). Using the chosen cutpoints, the estimated order of biomarker progression was GFAP, amyloid PET, plasma p‐tau181, and plasma p‐tau217 (Figure 3).ConclusionOn the individual level, the strong association of the relative timing of progression of plasma p‐tau217 and amyloid PET supports that these processes are mechanistically related. The relatively lower associations of the timing of p‐tau181 and GFAP with amyloid PET likely reflect a lower biological association and greater measurement noise for p‐tau181. The individual adjustments, the primary output of this model, are independent of cutpoints. On the population level, relative timing of biomarker change is highly dependent on the cutpoints applied. This true for any analysis that employs cutpoints, regardless of the approach.

Background: Despite the development and approval of effective therapies for multiple myeloma (MM), MM remains an incurable disease. Moreover, patients with high-risk cytogenetics, like translocation t(4;14), continue to have a poor prognosis compared to standard-risk patients. No novel agents have been approved specifically for this population. There remains an unmet need for precision therapies for MM that can target specific drivers of high-risk MM like t(4;14). Multiple myeloma SET domain-containing protein (MMSET) overexpression observed in 100% of patients with t(4;14) acts through the MMSET-H3K36me2 axis, which promotes malignant transformation through regulation of multiple oncogenic programs. KTX-1001, a methyl transferase inhibitor, is a novel, first-in-class, potent, oral, small molecule that inhibits MMSET and the methylation of lysine K36. KTX-1001 had favorable drug-like properties, demonstrated in vivo activity, and was well tolerated in non-clinical studies. Based on these data, KTX-1001 is now being studied in a Phase 1 dose escalation and expansion study in relapsed and refractory multiple myeloma (RRMM). Study Design and Methods: This multi-country, Phase 1, open-label study (NCT05651932) is designed to assess the safety, tolerability, and initial clinical activity of KTX-1001. The study will also examine the recommended phase 2 dose (RP2D), pharmacokinetics (PK) and pharmacodynamics (PD). Part A of this trial includes an accelerated titration, followed by 3+3 dose escalation with backfill of cohorts for dose optimization prior to moving to Part B, which is an expansion phase at the RP2D (please see Figure 1 for study design schematic). The expansion phase will only include patients with t(4;14). KTX-1001 will be administered orally daily and given until disease progression, unacceptable toxicity, or withdrawal from the study. Estimated enrollment for Parts A and B will be approximately 60 patients. The study will enroll patients with RRMM who have received ≥3 prior lines of therapy, including a proteasome inhibitor (PI), immunomodulatory drug (IMiD), and anti-CD38 antibody. Patients must have measurable disease, be ≥18 years of age, have an Eastern Cooperative Oncology Group score of ≤2, and adequate bone marrow, liver, and kidney function. Key exclusion criteria include history of or current plasma cell leukemia, active central nervous system (CNS) disease, or active unstable cardiovascular function. The primary endpoints of safety and tolerability include incidence of dose-limiting toxicity (DLTs), treatment-emergent adverse events (AEs), and treatment-related AEs. Secondary endpoints include plasma concentrations of KTX-1001 and efficacy outcomes such as objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Exploratory biomarker and pharmacodynamic assessments will also be performed. The sample size was not determined by formal statistical methods but will be sufficient to provide preliminary information on safety, PK, PD, and efficacy. Statistical analyses will be primarily descriptive. Conclusion: This Phase 1 study will evaluate a potential treatment for RRMM utilizing KTX-1001, which is a novel, first-in-class, potent, oral small-molecule MMSET inhibitor. The study is open and actively enrolling patients at centers in the United States, Spain, France, and Canada.

Abstract INTRODUCTION The timing of plasma biomarker changes is not well understood. The goal of this study was to evaluate the temporal co‐evolution of plasma and positron emission tomography (PET) Alzheimer's disease (AD) biomarkers. METHODS We included 1408 Mayo Clinic Study of Aging and Alzheimer's Disease Research Center participants. An accelerated failure time (AFT) model was fit with amyloid beta (Aβ) PET, tau PET, plasma p‐tau217, p‐tau181, and glial fibrillary acidic protein (GFAP) as endpoints. RESULTS Individual timing of plasma p‐tau progression was strongly associated with Aβ PET and GFAP progression. In the population, GFAP became abnormal first, then Aβ PET, plasma p‐tau, and tau PET temporal meta‐regions of interest when applying cut points based on young, cognitively unimpaired participants. DISCUSSION Plasma p‐tau is a stronger indicator of a temporally linked response to elevated brain Aβ than of tau pathology. While Aβ deposition and a rise in GFAP are upstream events associated with tau phosphorylation, the temporal link between p‐tau and Aβ PET was the strongest. Highlights Plasma p‐tau progression was more strongly associated with Aβ than tau PET. Progression on plasma p‐tau was associated with Aβ PET and GFAP progression. P‐tau181 and p‐tau217 become abnormal after Aβ PET and before tau PET. GFAP became abnormal first, before plasma p‐tau and Aβ PET.

Abstract BACKGROUND Diffuse hemispheric glioma (DHG) is an uncommon infiltrating glioma, defined in the World Health Organization 2021 guidelines by a mutation in the H3F3A gene at codon 34 (H3.G34). DHG primarily affects children and young adults. Due to its rarity, there is paucity of knowledge regarding factors affecting overall survival (OS). We retrospectively assessed our institutional experience and present a review of the literature. METHODS We searched our institution’s pathology records to identify six cases of DHG. Demographic, clinical, diagnostic, treatment, and outcome data were recorded. We next searched for published articles regarding DHG cases via PubMed through May 2023. Four-hundred-fifty-four published individual cases of H3.G34 glioma were identified, 204 of which were hemispheric/supratentorial tumors with OS data reported, providing a combined 210 cases for analysis. 132 of these cases included MGMT promoter methylation status. 111 included extent of surgical resection. Kaplan-Meier and Cox regression survival analysis was performed. RESULTS Age range for DHG patients was 7-66 years (median 17). Median OS was 18.5 months (95% CI, 17-25). Greater extent of surgical resection and presence of MGMT promoter methylation were associated with better prognosis. Median OS for biopsy alone was 12 months (95% CI, 10-NA), subtotal resection was 16 months (95% CI, 14-23), and gross total resection was 27 months (95% CI 23-NA) – log-rank p< 0.001. OS for MGMT promoter unmethylated was 14 months (95% CI 12-22), MGMT promoter methylated was 24 months (95% CI, 17-30) – log-rank p=0.028. Contrary to previous reports, patient age was not found to impact prognosis (using 18, 21, and 40 years as cutoffs or as a continuous variable with Cox regression). CONCLUSION Extent of surgical resection and MGMT promoter methylation status are important prognostic factors for DHG. Unlike many primary brain tumors, survival does not appear to be significantly impacted by age.

Abstract Glioblastoma (GBM) is the most common and aggressive form of brain tumor in adults. Despite maximal surgical resection, irradiation, and chemotherapy, median overall survival (OS) for recurrent GBM (rGBM) remains at only 30 weeks. GBM tumors have an immune-suppressive microenvironment with low numbers of tumor-infiltrating lymphocytes (TILs). Interleukin 7 (IL-7) plays a key role in T cell homeostasis and survival, with IL-7 inducing T cell expansion in lymphopenic conditions. Efineptakin alfa (NT-I7), a long-acting IL-7, has been shown to increase effector CD8 T cells and reduce suppressor T-regulatory cells in murine GBM models, with subsequently improved OS. We recently completed a Phase I study in newly diagnosed GBM patients which showed that NT-I7 is safe, well-tolerated, and increased absolute lymphocyte counts (ALCs), and determined maximum tolerated dose for Phase II. We hypothesized that NT-I7 may not only mitigate GBM treatment-associated immune suppression, but also potentiate the effect of immune checkpoint blockade, leading to an increase in TILs and improved survival. The purpose of this study is to evaluate the safety and efficacy of combining NT-I7 and pembrolizumab in rGBM patients. This is an open-label, single arm one-stage Phase II study of NT-I7 and pembrolizumab as neoadjuvant and adjuvant therapy with surgery for adult patients with rGBM. We plan to enroll 30 evaluable patients, including a 6-patient safety run-in. The primary endpoint is the 9-month OS rate. Secondary endpoints include progression-free survival, objective response rate, changes in ALC, and adverse events profile. The correlative endpoints include studies to assess the anti-glioma immune response, changes in T cell subsets and functionality, peripheral cytokine quantification, and immunohistochemical analysis of GBM tissue. Longitudinal cerebrospinal fluid proteomics is optional. This study opened in Jan 2023. Six (6) of the planned thirty (30) patients had been enrolled by time of submission.

Abstract Sequencing efforts have identified key oncogenic drivers and transcriptomic subtypes of high-grade gliomas (HGGs), but this knowledge has not resulted in individualized therapy or improved patient outcomes. Here, we used a functional genomics approach combining integrated genomic/transcriptomic analyses with patient-derived 3D micro-cancers (mCancers) to rapidly identify individualized therapeutic vulnerabilities and determine predictive response biomarkers. 30 primary/recurrent HGGs, including 20 glioblastomas, 5 astrocytomas, and 5 oligodendrogliomas, were included for drug testing. mCancers recapitulated the structural and molecular alterations, cellularity, and heterogeneity, of parental patient tumors. A total of 119 single-agent drugs and 183 drug combinations were tested, while a pre-selected drug panel comprising 25 glioma-relevant treatment strategies was tested across all cases. In general, mCancer efficacy corresponded well to historical responses to previously tested agents (EGFR, HDAC inhibitors, etc.). Combined, strong efficacy (i.e. >70% growth inhibition at Cmax) of single treatments targeting deregulated receptor tyrosine kinase (RTK), p53/apoptosis, cell cycle, DNA damage repair, IDH, or telomere maintainance pathways, was observed in 14 out of 30 cases. Surprisingly, transcriptional signatures, but not specific genetic alterations, were found to stratify drug responses. For example, mCancers enriched for the most aggressive mesenchymal (MES) and glycolytic/plurimetabolic (GPM) transcriptional subtypes exhibited stronger response to the BET inhibitor JQ1 (and other clinical BET inhibitors) and the DNA-PKcs/mTOR dual inhibitor CC-115. This therapeutic vulnerability was associated with enrichment of YAP/TAZ signaling, and the glioblastoma stem cell G-STEM signature. Notably, individual combination strategies were effective across tumors, with strong responses ranging from 38% to 77% of all tumors tested. Overall, this study underscores the value of functional genomics in identifying novel vulnerabilities of HGGs and associated response biomarkers. It also highlights the need for further clinical validation of several novel therapies and especially drug combination strategies with strong efficacy in the ex vivo setting.

Abstract WSD0922-Fu is an oral, CNS-penetrant, small molecule EGFR inhibitor which potently inhibits EGFR aberrations specific to non-small cell lung cancer (NSCLC) and high-grade astrocytoma (HGA). MC1914 (NCT04197934) is a first-in-human phase 1 trial in patients with EGFR aberrant recurrent HGA and NSCLC. Adult patients with either recurrent EGFR mutant NSCLC with CNS metastases or recurrent EGFR aberrant HGA were enrolled and treated across six cohorts (40 mg once daily to 320 mg twice daily, 28-day cycles) to determine the maximum tolerated dose (MTD). 25 patients (17 HGA, 8 NSCLC) were enrolled (median age = 57 years; 24% female; 36% ECOG 0). All patients with HGA received prior radiation and temozolomide. All patients with NSCLC had previous disease progression on EGFR inhibitor therapy (prior osimertinib 88%). The median duration of WSD0922-Fu exposure among all patients was 55 days (range 3 to >279 days) [NSCLC median = 131 days; HGA median = 51 days]. Common treatment-related adverse events are comparable to other EGFR inhibitors (fatigue, acneiform rash, diarrhea, nausea, pruritis). At Cycle 1 Day 15 for patients treated at MTD (160 mg twice daily), the mean terminal elimination half-life (%CV) in the plasma was 31.6 h (102%) (median 14.5 h). The mean Cmax, Tmax, oral clearance at steady state, and AUC (0-12 h) (%CV) were 4513 ng/mL (50%), 2.0 hr (69%), 6.9 L/hr/m2 (42%), and 28084 h*ng/mL (52%), respectively. Among patients with NSCLC treated at MTD or higher dose levels and with available response data, 100% (5/5) of patients demonstrated clinical benefit (SD + PR) while 60% of patients had partial responses. Intracranial and extracranial efficacy was concordant. Furthermore, prolonged stable disease (9 cycles) was observed in a patient with EGFRvIII mutant GBM. Expansion cohorts are in progress to optimize WSD0922-Fu dose and schedule for future phase 2 development.

Abstract Cerebrospinal fluid (CSF) is emerging as an abundant source of candidate biomarkers, including proteins, for gliomas. Longitudinal CSF access may enable insights into treatment response and resistance. To that end, we have established a growing biobank of CSF samples, many of which have been obtained longitudinally via CSF access devices, such as Ommaya reservoirs, through our ongoing biomarker discovery clinical trials (NCT04692337, 04692324). We have previously presented our initial data demonstrating a conserved proteomic signature of HGG that decreased with resection and increased with recurrence. Since then, samples have been acquired throughout individual patients’ treatment course toward our goal of identifying CSF-derived biomarkers of treatment response. CSF samples obtained prior to, during, and throughout treatment underwent global proteomics analysis via the SomaScan® assay by Somalogic. Fold-changes for each protein were calculated between different timepoints and ranked for each comparison of interest. Treatment with pembrolizumab alone results in increased IL-23 (5.01x), IL-12 (4.25x), lymphocyte activation gene 3 protein (LAG3) (3.26x), and granzyme A (2.93x), suggesting potential for combination with multiple agents. Chemoradiation, with or without pembrolizumab, consistently downregulated NAD kinase, acetyl CoA transferase, and Bcl-2 and upregulated proteins related to neuronal signaling, such as neurexins and cerebellins, in addition to LAG-3, suggesting potential for synergy between chemoradiation and anti-LAG-3 antibodies currently in clinical trials. Interestingly, pembrolizumab and chemoradiation decreased MMP-12 and MMP-9 abundance as compared to chemoradiation alone (0.25x vs. 18.5x; 0.54x vs. 4.99x). Finally, bevacizumab treatment consistently increased VEGF-A (7.32x), VEGF-B (2.21x), and MMP-3 (2.99x) abundance, while decreasing the presence of our previously reported plasma-associated protein signature in CSF. In conclusion, the global CSF proteome can be longitudinally accessed to evaluate response to standard-of-care and experimental therapies. Further studies are ongoing to identify signatures of therapeutic resistance and to assess the impact of novel immunotherapeutic combinations on the CSF proteome.

Abstract PURPOSE For large brain metastases, it is unknown whether single fraction stereotactic radiosurgery (sSRS) or multi-fraction stereotactic radiosurgery (fSRS) is optimal. We aimed to compare rates of local progression and necrosis between sSRS and fSRS for large brain metastases. METHODS Patients with intact or resected brain metastases with a target volume ≥ 4.2 cc (corresponding to a diameter ≥ 2 cm) treated with Gamma Knife (GK) or linear accelerator-based SRS from 2014-2022 were included in this retrospective review. RESULTS A total of 343 large brain metastases in 276 patients were included; 171 lesions were treated with sSRS (96% with GK) and 172 lesions with fSRS (100% with linear accelerator). Median lesion volume was 19.8 cc and 8.4 cc for fSRS and sSRS, respectively. Resection was performed prior to SRS in 228 (66%), with the remaining 115 metastases treated intact. There was no difference in rate of local progression between sSRS versus fSRS, or between resected versus intact targets (p >0.8 for both). Cumulative incidence of local progression (with death as a competing risk) at 1 and 3 years for patients receiving sSRS was 24% and 30%, respectively, compared to 22% and 34% for fSRS. FSRS was associated with significantly higher rates of necrosis than sSRS (HR 5.58, 2.38-13.08, p < 0.001). This association remained significant after controlling for target volume. Cumulative incidence of necrosis (with death as a competing risk) at 1 and 3 years for patients receiving sSRS was 1% and 3%, respectively, compared to 10% and 18% for fSRS. Necrosis rates were significantly higher with fSRS for both intact and resected targets (P < 0.02 for both). CONCLUSION While local control for large resected or intact brain metastases appears similar after sSRS or fSRS, this retrospective study shows higher rates of necrosis after fSRS. Prospective validation is needed.

Abstract BACKGROUND Liquid biopsy in glioblastoma (GBM) is hindered by a lack of requisite circulating-free DNA (cfDNA) blood levels in due to the blood-brain barrier (BBB). Real-time image-guided low-intensity focused ultrasound (LIFU) with intravenously administered microbubble oscillators non-invasively causes BBB disruption (BBBD). This clinical trial aimed to evaluate the utility of LIFU for increasing cfDNA in blood for liquid biopsy in GBM. METHODS LIBERATE is an ongoing, prospective, multi-center, self-controlled, ongoing, pivotal trial evaluating the safety and technical efficacy of LIFU for BBBD to increase cfDNA in blood for GBM. Patients aged 18-80 years with suspected GBM planned for tumor biopsy or resection at ten centers in the US are being included. Patients are administered intravenous oscillating microbubbles for enhancing sonication, after which MR-guided BBBD using 220 kHz LIFU device is performed, with real-time acoustic feedback for effective sonication. Pre- and post-procedure, phlebotomies, and MRI brain are performed. The primary study endpoint is defined, per subject, as the ratio between cfDNA levels in blood 1-hour post-LIFU procedure compared to cfDNA level in blood pre-procedure. The primary study hypothesis is that BBBD with LIFU leads to ≥2-fold increase in cfDNA in blood. The secondary hypothesis is that there exists ≥75% concordance between biomarker patterns in the cfDNA sample from 1-hour post-LIFU sample and tumor tissue obtained later. Exploratory endpoints include (1) sensitivity of detection of known somatic mutations in cfDNA from blood samples collected before and after LIFU, (2) estimation of cfDNA levels in samples collected at 30 minutes, 1 hour, 2 hours, and 3 hours post-LIFU to determine the time of greatest yield, (3) correlation of MRI parameters related to BBBD grading and biomarkers in cfDNA from post-LIFU samples. Patient enrollment commenced in 2022, and 13 patients have been recruited by 06/09/2023. Clinical trial information: NCT05383872.