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Abstract BACKGROUND Breast cancer is one of the most common cancers associated with brain metastases (BM). Up to 50% of patients with metastatic triple-negative breast cancer (TNBC) develop BM which portends a poor prognosis, with a median survival of 4.4-7.3 months. There is a lack of effective systemic therapy. Irinotecan is a topoisomerase-1 inhibitor with a response rate of 5-23% in advanced breast cancer. Nal-IRI is an intravenous liposomal formulation of irinotecan, with greater efficacy in tumor growth inhibition and the ability to cross the blood brain barrier (BBB) than irinotecan, resulting in a prolonged survival in preclinical TNBC BM models. Additionally, Nal-IRI has demonstrated promising anti-tumor activity in patients with TNBC- BM in a phase-I trial (NCT01770353). Pembrolizumab is a humanized anti-PD-1 monoclonal antibody which has shown efficacy in TNBC. The purpose of this study is to evaluate whether the combination of Nal-IRI and pembrolizumab can provide a synergic effect to control the CNS disease and prolong survival in TNBC with progressive BM. METHODS This is a phase II, single arm trial with a safety lead-in to evaluate the efficacy of nal-IRI (50-70mg/m2 IV Q2W) in combination with pembrolizumab (400mg IV Q6W). Simon’s 2-stage design is used, with 18 patients in the 1st stage and additional 24 at 2nd stage for a total of 42. The first 6 patients will serve as a safety lead-in. Key eligibilities include: histologically/cytologically confirmed TNBC with new or progressive BM; prior immunotherapy is allowed but not prior nal-IRI/irinotecan; prior sacituzumab-govitecan is permitted if disease stable for ≥16-week while on therapy and ≥24-week washout prior to starting trial; measurable disease; and ≤4 prior lines of therapy in the metastatic setting. The primary endpoint is CNS disease control rate (DCR) at 6 months using RANO-BM criteria. Secondary endpoints include CNS and non-CNS ORR, PFS and OS. (ClinicalTrials.gov: NCT05255666)

Abstract INTRODUCTION High grade gliomas (HGG) are devastating diseases with largely unchanged survival outcomes despite decades of research. Recent studies suggest the interleukin 13 receptor subunit alpha 2 (IL-13Rα2) is selectively upregulated in up to 80% of HGG, including glioblastoma (GBM) and diffuse midline gliomas (DMG) harboring H3K27 alterations. Immunotoxins targeting IL-13Rα2 have been demonstrated as safe and have shown some benefit for patients with HGG in previous phase I/II and III clinical trials. We hypothesized that by using GB-13 (IL13.E13K-PE4E), a novel peptide-toxin that binds IL-13Rα2 with high specificity and possesses a Pseudomonas exotoxin moiety, we would enhance the anti-tumor effects of this immunotherapy for HGG in vitro and in vivo while decreasing off-target toxicity. METHODS We examined the pharmacological effects of GB-13 in multiple patient-derived cell lines and rodent models of HGG. GBM and DMG lines were used to confirm IL-13Rα2 expression and sensitivity towards GB-13. Tumor naïve rats were evaluated for toxicity, and orthotopic PDX mice were used to monitor tumor size and survival following loco-regional infusion of GB-13. RESULTS GB-13 induced a potent cytotoxic response strongly predicated on IL-13Rα2 expression in vitro. No treatment-related adverse effects were noted after 7-day continuous intracranial infusion of GB-13 in tumor naïve rats. Further, in IL-13Rα2-upregulated orthotopic PDX mice, direct intratumoral administration of GB-13 via convection-enhanced delivery abrogated tumor growth and prolonged survival. CONCLUSIONS Given these promising results as well as the critical need for novel therapies in CNS malignancies, we are progressing to human trials using GB-13 targeting recurrent HGG. Ongoing safety studies in tumor-bearing animals will be able to define dose levels for the initial adult study-arm and the following pediatric study-arm. In this Phase 1 clinical trial, we hypothesize that loco-regional infusion of GB-13 will safely enhance tumor clearance by causing selective killing of IL-13Rα2-upregulated HGG cells.

Abstract SETDB1 is a key regulator of lineage-specific genes and endogenous retroviral elements (ERVs) through its deposition of repressive H3K9me3 mark. Apart from its H3K9me3 regulatory role, SETDB1 has seldom been studied in terms of its other potential regulatory roles. To investigate this, a genomic survey of SETDB1 binding in mouse embryonic stem cells across multiple libraries was conducted, leading to the unexpected discovery of regions bereft of common repressive histone marks (H3K9me3, H3K27me3). These regions were enriched with the CTCF motif that is often associated with the topological regulator Cohesin. Further profiling of these non-H3K9me3 regions led to the discovery of a cluster of non-repeat loci that were co-bound by SETDB1 and Cohesin. These regions, which we named DiSCs (domains involving SETDB1 and Cohesin) were seen to be proximal to the gene promoters involved in embryonic stem cell pluripotency and lineage development. Importantly, it was found that SETDB1-Cohesin co-regulate target gene expression and genome topology at these DiSCs. Depletion of SETDB1 led to localized dysregulation of Cohesin binding thereby locally disrupting topological structures. Dysregulated gene expression trends revealed the importance of this cluster in ES cell maintenance as well as at gene ‘islands’ that drive differentiation to other lineages. The ‘unearthing’ of the DiSCs thus unravels a unique topological and transcriptional axis of control regulated chiefly by SETDB1.

Glioblastoma (GBM) is the most common malignant brain tumor. Despite multimodality treatment with surgical resection, radiation therapy, chemotherapy, and tumor treating fields, recurrence is universal, median observed survival is low at 8 months and 5-year overall survival is poor at 7%. Immunotherapy aims to generate a tumor-specific immune response to selectively eliminate tumor cells. In treatment of GBM, immunotherapy approaches including use of checkpoint inhibitors, chimeric antigen receptor (CAR) T-Cell therapy, vaccine-based approaches, viral vector therapies, and cytokine-based treatment has been studied. While there have been no major breakthroughs to date and broad implementation of immunotherapy for GBM remains elusive, multiple studies are underway. In this review, we discuss immunotherapy approaches to GBM with an emphasis on molecularly informed approaches.

2068 Background: There is a lack of effective therapy for recurrent high-grade meningiomas who relapsed after prior radiation therapy (RT). ETCTN 10186 is a phase I/II study to evaluate the feasibility and preliminary clinical efficacy of combining reirradiation using fractionated radiosurgery with nivolumab plus or minus ipilimumab for recurrent high-grade meningiomas. The preliminary results from the phase I portion are reported here. Methods: Recurrent grade II-III meningioma patients were treated with radiosurgery plus nivolumab with or without ipilimumab. Key eligibility criteria include age ≥ 18 years; ECOG score ≤ 2; tumor diameter 1-5 cm; prior radiation dose ≤ 70 Gy; normal organ function; no active autoimmunity. During the phase I portion, eligible patients were treated according to treatment-escalation schema following the modified 3+3 design (Table 1). The maximum tolerated combination (MTC) will be the regimen at which ≤ 1/6 patients experience dose-limiting toxicity (DLT) within 8 weeks of the start of study therapy. During the phase II portion, a total of 24 evaluable patients will be enrolled at the MTC using Simon’s MiniMax two-stage design. The primary endpoint of the phase I portion is to determine the MTC. Objective radiological responses (ORRs) are defined as per the Macdonald criteria. One cycle of immunotherapy is defined as 4 weeks of nivolumab with or without concurrent ipilimumab. Results: From 7/2019 to 3/2021, 13 patients were enrolled in the phase I, including 6 with regimen A and 7 with regimen B (Table). The median prior RT dose was 56 Gy (18-70) at a median interval of 2.8 years (1.3-13.3). There was no DLT in either cohort, so regimen B was deemed the MTC. The median cycles of immunotherapy completed were not significantly different between cohort A and B (11 vs. 6, p = 0.41, respectively). Three cohort A patients and 2 cohort B patients completed all planned doses of immunotherapy. Most patients stopped due to progression, and only one cohort B patient stopped due to treatment-related toxicity (grade 3 hypophysitis and encephalitis after 6 cycles of immunotherapy). After a median follow-up of 11.1 months, there have been 5 progressions and 4 deaths. The 6 month-PFS and 12 month-PFS rates are 62% and 54%, respectively. Two ORRs have been reported by institutional assessment, and central radiology review is ongoing and will be reported. Conclusions: Reirradiation using fractionated radiosurgery with nivolumab plus or minus ipilimumab are well tolerated for radiation-relapsed high-grade meningiomas. Phase II study of regimen B is currently enrolling. Clinical trial information: NCT03604978. [Table: see text]

2058 Background: Immunotherapies targeting the programmed cell death-1 (PD-1) pathway in recurrent glioblastoma (rGBM) have failed. We hypothesize that combining therapies targeting multiple immunosuppressive pathways with cytotoxic and antiangiogenic therapies will improve survival. Here, we evaluate the safety and efficacy of an anti-PD-1 monoclonal antibody (retifanlimab), hypofractionated radiotherapy (HFRT), and bevacizumab, with or without an oral IDO1 inhibitor (epacadostat), in patients with rGBM in a nonrandomized, noncomparative sequential two-arm Phase II study. Methods: This is an open-label Phase II study of 2 sequential cohorts (Table). Cohort A first examines retifanlimab + bevacizumab + HFRT in patients with IDH1/2-WT rGBM. After a toxicity monitoring period, Cohort B, which adds epacadostat, starts enrolling. Key inclusion criteria includes dexamethasone ≤ 4 mg/day at registration and candidacy for reirradiation. Previous bevacizumab use for radiation necrosis is permitted. The primary endpoint is OS probability at 9 months (OS-9). Secondary endpoints include PFS, OS, and toxicity. Exploratory endpoints include immunological phenotyping of blood and tissue. An increase of OS-9 from 38% (bevacizumab alone) to 60% is considered clinically relevant. Results: From 6/2020 to 12/2021, we have completed accrual for cohort A and the interim analysis results are presented here: 25 patients with rGBM enrolled, with 23 evaluable. Median age is 64.3 years (42.1-81.8), 30.4% female, 30.4% MGMT promotor methylated, median KPS 90 (range 70-100), baseline dexamethasone 0 mg (range 0-4) with 52.2% of patients on dexamethasone during the first 3 cycles, median baseline ALC 1,000 cells/µl (range 300-3,700). Patients received a median of 6 cycles to date (range 2-20). Median follow-up is 11.97 months per the reverse Kaplan-Meier method. Interim analysis shows a median PFS of 9.9 months (95%CI: 5.5 to not reached (NR)) and median OS of 12.2 months (95%CI 7.3-NR). Notably, Cohort A met the primary endpoint with an OS-9 of 71.4% (95%CI: 46.7% -86.1%). No dose limiting toxicities have been yet observed. Two treatment-related grade 3 toxicities have occurred (myositis, hypertension). Cohort B enrollment is ongoing, and correlative studies pending. Conclusions: Interim analysis suggests retifanlimab combined with HFRT and bevacizumab in patients with rGBM is well-tolerated and had encouraging OS and PFS at the time of data cutoff. Cohort B, which adds epacadostat, is currently enrolling. Clinical trial information: NCT03532295. [Table: see text]

Abstract Background Treatment options for unresectable new and recurrent glioblastoma remain limited. Laser ablation has demonstrated safety as a surgical approach to treating primary brain tumors. The LAANTERN prospective multicenter registry (NCT02392078) data were analyzed to determine clinical outcomes for patients with new and recurrent IDH wild-type glioblastoma. Methods Demographics, intraprocedural data, adverse events, KPS, health economics, and survival data were prospectively collected and then analyzed on IDH wild-type newly diagnosed and recurrent glioblastoma patients who were treated with laser ablation at 14 US centers between January 2016 and May 2019. Data were monitored for accuracy. Statistical analysis included individual variable summaries, multivariable differences in survival, and median survival numbers. Results A total of 29 new and 60 recurrent IDH wild-type WHO grade 4 glioblastoma patients were treated. Positive MGMT promoter methylation status was present in 5/29 of new and 23/60 of recurrent patients. Median physician-estimated extent of ablation was 91%-99%. Median overall survival (OS) was 9.73 months (95% confidence interval: 5.16, 15.91) for newly diagnosed patients and median post-procedure survival was 8.97 months (6.94, 12.36) for recurrent patients. Median OS for newly diagnosed patients receiving post-LITT chemo/radiation was 16.14 months (6.11, not reached). Factors associated with improved survival were MGMT promoter methylation, adjuvant chemotherapy within 12 weeks, and tumor volume <3 cc. Conclusions Laser ablation is a viable option for patients with new and recurrent glioblastoma. Median OS for IDH wild-type newly diagnosed glioblastoma is comparable to outcomes observed in other tumor resection studies when those patients undergo radiation and chemotherapy following LITT.

Abstract Background Patients with glioblastoma (GBM) have a poor prognosis and limited effective treatment options. Bevacizumab has been approved for treatment of recurrent GBM, but there is questionable survival benefit. Based on preclinical and early clinical data indicating that CD105 upregulation may represent a mechanism of resistance to bevacizumab, we hypothesized that combining bevacizumab with the anti-CD105 antibody TRC105 may improve efficacy in recurrent GBM. Methods Phase I dose-escalation/comparative randomized phase II trial in patients with GBM. During phase I, the maximum tolerated dose (MTD) of TRC105 in combination with bevacizumab was determined. In phase II, patients were randomized 1:1 to TRC105 and bevacizumab or bevacizumab monotherapy. Patients received TRC105 (10 mg/kg) weekly and bevacizumab (10 mg/kg) every 2 weeks. Efficacy, as assessed by progression-free survival (PFS), was the primary endpoint; safety, quality of life, and correlative outcomes were also evaluated. Results In total, 15 patients were enrolled in phase I and 101 in phase II; 52 patients were randomized to TRC105 with bevacizumab and 49 to bevacizumab monotherapy. The MTD was determined to be 10 mg/kg TRC105 weekly plus bevacizumab 10 mg/kg every 2 weeks. An increased occurrence of grade ≥3 adverse events was seen in the combination arm, including higher incidences of anemia. Median PFS was similar in both treatment arms: 2.9 months for combination versus 3.2 months for bevacizumab monotherapy (HR = 1.16, 95% CI = 0.75–1.78, P = .51). Quality of life scores were similar for both treatment arms. Conclusions TRC105 in combination with bevacizumab was well tolerated in patients with recurrent GBM, but no difference in efficacy was observed compared to bevacizumab monotherapy.