Progression-free Survival Research Articles

CTNI-42. A BIOMARKER-GUIDED PHASE 2 STUDY OF DB107-RRV (A RETROVIRAL REPLICATING VECTOR) COMBINED WITH DB107-FC (FLUCYTOSINE EXTENDED-RELEASE TABLETS) IN PATIENTS WITH RECURRENT GLIOBLASTOMA OR ANAPLASTIC ASTROCYTOMA: A CLINICAL PROTOCOL

Abstract INTRODUCTION Despite significant advances in understanding the basic pathogenesis of glioblastoma, the median survival of patients has minimally changed in the past 25 years with a 5-year survival rate of <7%. Because of the dismal prognosis, attention has shifted to alternative adjuvant treatment modalities including gene/viral-based therapy. The first clinically tested replicating retroviral vector DB107-RRV (vocimagene amiretrorepvec, formerly Toca511) was assessed in a randomized Phase 3 study (NCT02414165) to evaluate the intracranial administration of DB107-RRV with subsequent oral administration of DB107-FC (5-fluocytosine extended-release tablets) in patients with recurrent HGG. Although the primary endpoint of overall survival (OS) in the intent-to-treat population was not met (median OS=11.07 months, DB107-RRV+ DB107-FC arm and 12.22 months for the SOC arm (HR=1.06; 95% CI:[0.83, 1.35], p=0.6154)), post-hoc analysis identified a subgroup of patients (responders) who demonstrated a marked survival benefit from the Phase III clinical trial (Toca 5, NCT02414165). Using a non-invasive genotyping pipeline, a novel biomarker, DGM7, was identified among responders that confers an improved prognosis: (DB107-RRV+DB107-FC is 18.3 months vs. 12.0 months in the SOC group (HR=0.50; 95% CI:[0.28, 0.89], p= 0.0167)). DGM7 is present in the blood of approximately 20-30% of HGG patients. METHODS This is a Phase 2, single-site, open-label, single-arm study to assess the oral administration of DB107-FC in combination with DB107-RRV in DGM7+ patients with recurrent/progressive HGG. Key inclusion criteria include presence of the DGM7 biomarker in blood, patient age 18–75 with histologically proven, measurable (MRI) recurrent/progressive HGG, and no radiation therapy for at least 12 weeks without histopathologic/MRI progression confirmation. The primary endpoint of this study will be progression-free survival at 6 months (PFS6) and OS of DB107-RRV+DB107-FC in DGM7+ patients with recurrent/progressive HGG compared to the historical study arm SOC/DGM7+ from NCT02414165.

SURG-10. SUPRATOTAL RESECTION: AN EMERGING CONCEPT OF GLIOBLASTOMA MULTIFORME SURGERY—SYSTEMATIC REVIEW AND META-ANALYSIS

Abstract The severe neurologic tumor known as glioblastoma (GBM), also referred to as a grade IV astrocytoma, is rapidly progressive and debilitating. Supratotal resection (SpTR) is an emerging concept within glioma surgery, which aims to achieve a more extensive resection of the tumor than is possible with conventional techniques. We performed a language-independent search of PubMed, Scopus, and Cochrane CENTRAL to identify all available literature up to August 2022 of patients undergoing SpTR assessing survival outcomes in comparison to other surgical modalities. After screening for exclusion, a total of 13 studies, all retrospective in design, were identified and included in our meta-analysis. SpTR was associated with significantly increased overall survival (hazard ratio 0.77, 95% CI 0.71–0.84; P < 0.01, I2 = 96%) and progression-free survival (hazard ratio 0.2, 95% CI 0.07–0.56; P = 0.002, I2 = 88%). SpTR is associated with greater overall survival and PFS when compared with other glioblastoma surgeries like GTR or SubTR.

CTNI-35. EVALUATE THE SAFETY AND PRELIMINARY EFFICACY OF THE COMBINATION OF NAVIFUS SYSTEM WITH RE-IRRADIATION FOR RGBM PATIENTS

Abstract The blood-brain barrier (BBB) remains the major obstacle in treating patients with malignant brain tumors. Radiation therapy (RT) is the mainstay adjuvant modality regardless of the BBB, but its effectiveness is hindered by the hypoxic microenvironment. Focused ultrasound (FUS) combined with systemic microbubbles has been shown to open the BBB and potentially increase regional perfusion. However, no clinical study has investigated the combination of RT with FUS-BBB opening (RT-FUS). Here, we report an interim analysis of an ongoing single-arm, prospective, pilot study (NCT04988750) combining RT-FUS for recurrent malignant high-grade glioma patients, where re-RT was considered for disease control. FUS-BBB opening was conducted within 2 hours before RT. Treatment responses were evaluated by objective response rate (ORR) using magnetic resonance imaging, progression-free survival, overall survival, and adverse events (AEs). In this pilot clinical trial, an interim analysis of six recurrent malignant high-grade glioma patients who underwent a total of 24 RT-FUS treatments was presented. Three patients experienced rapid disease progression after RT-FUS, while the other three patients had at least stable disease after RT-FUS, with or without salvage chemotherapy or targeted therapy. There were no FUS-related AEs, but re-RT-related grade three radiation necrosis was observed. The interim analysis of this ongoing clinical trial showed that the combination of RT-FUS was safe, with no FUS-related adverse effects. Two more cases will be recruited in this trial. A comprehensive analysis of radiation dosimetry and FUS energy distribution is expected after completing the final recruitment.

CTIM-26. PHASE II STUDY OF AZELIRAGON IN COMBINATION WITH RADIATION THERAPY IN NEWLY DIAGNOSED PATIENTS WITH MGMT-UNMETHYLATED GLIOBLASTOMA

Abstract BACKGROUND Myeloid-derived suppressor cells (MDSCs) exacerbate immunosuppression and immune exhaustion in glioblastoma (GBM) and promote resistance to chemoradiotherapy. Preclinical data demonstrate that inhibiting the receptor for advanced glycation end-products (RAGE) pathway using azeliragon, when combined with radiation therapy (RT), can modulate MDSC accumulation in the tumor microenvironment and improve tumor control. CAN-401 is a phase II study evaluating the safety and preliminary clinical efficacy of combining azeliragon with RT for newly diagnosed IDH-wildtype MGMT-unmethylated glioblastoma (GBM). METHODS This multi-institutional, single-arm, open-label phase II study combines azeliragon with RT (60 Gy/30 fractions). Azeliragon is administered orally with a loading dose of 30 mg twice daily for 6 days before RT, followed by 20 mg daily during and after RT. If more than one dose-limiting toxicity occurs during the safety run-in of 6 patients, additional patients will be treated at de-escalated dose levels using the rolling six design. The study hypothesizes that azeliragon and RT will improve median progression-free survival (PFS) to 9.7 months compared to historical control of 5.7 months, corresponding to a hazard ratio of 0.58. The study aims to enroll 30 evaluable patients. RESULTS From December 2023 to May 2024, 10 patients were enrolled and treated with 20 mg of azeliragon daily, including 6 patients in the safety run-in. No dose-limiting toxicity was observed, hence no dose de-escalation was needed. The most common treatment-related adverse events (AEs) were grade 1, including fatigue and lymphopenia. There were no dose modifications or discontinuations due to treatment-related AEs. Enrollment is ongoing, and updated clinical outcomes will be reported. CONCLUSIONS Azeliragon at 20 mg per day with concurrent RT is well tolerated in patients with GBM. The phase II study is currently enrolling across 8 institutions in the United States (NCT05986851).

NCMP-11. FACTORS INFLUENCING MANAGEMENT STRATEGY AND CLINICAL OUTCOMES IN LOW-GRADE IDH-MUTANT ASTROCYTOMA: A 10-YEAR INSTITUTIONAL CASE SERIES

Abstract BACKGROUND Low-grade IDH-mutant astrocytomas are rare primary brain tumors that typically affect young adults and slowly progress to more aggressive lesions when untreated. Since lengthy follow-up is required to identify high-risk subgroups and useful therapeutic strategies, consensus recommendations after maximal safe resection are still based on low-level evidence and remain unclear. METHODS Retrospective chart review of all adult patients with a pathological diagnosis of low-grade (grade 2) IDH-mutant astrocytoma from 2013–2023 at a multi-site tertiary care center was performed. Cases without confirmatory IDH-mutation testing or at least 6-month follow-up imaging were excluded. RESULTS A total of 32 patients were included with a mean age of 35.6 years (range: 18–69) and 15 (46.9%) females. Mean follow-up was 40.3 months (range: 8.1–120.7). Preoperative average maximal tumor diameter was 4.1cm (range: 1.4–7cm) with 18 (56.3%) cases involving eloquent cortex. Gross total resection (GTR) was achieved in 12 (37.5%) cases. Observation was the most prevalent postoperative management strategy (n=21, 65.6%), followed by temozolomide-based chemoradiation (n=5, 15.6%), temozolomide alone (n=2, 6.3%), PCV (n=2, 6.3%), radiation alone (n=1, 3.1%), and carboplatin (n=1, 3.1%). Progression of disease (POD) was eventually seen in 17 (53.1%) cases with a median progression-free survival (PFS) of 41.9 months. While GTR was protective against POD (OR:0.14, p=0.019*), initial postoperative management with adjuvant chemotherapy and/or radiation was not (OR:1.09, p=0.907). Additionally, seizures during the follow-up period were significantly associated with POD and a reduced PFS (median 32.5 versus 71.7 months, HR:3.88, p=0.013*). There were no differences in EOR or tumor localization between patients who did and did not have seizures during follow-up. CONCLUSIONS Although limited by sample size, this 10-year series confirms the importance of maximizing EOR for low-grade IDH-mutant astrocytoma and suggests that seizures during follow-up can identify high-risk cases that may benefit from more aggressive treatment.

BIOM-43. SOMATICTP53, PIK3R1, NF1 ORTERT MUTATIONS ARE ASSOCIATED WITH INFERIOR CLINICAL OUTCOME IN H3K27M-ALTERED DIFFUSE MIDLINE GLIOMA: AN INTERNATIONAL, MULTI-INSTITUTIONAL STUDY

Abstract BACKGROUND H3K27-altered diffuse midline gliomas (DMGs) have poor prognosis with no standard of care therapy beyond radiation (RT). While RT prolongs survival, not all patients respond. Molecular biomarkers can be a strategy to predict RT response and thus patient outcomes. METHODS We performed a retrospective analysis of patients with biopsy-proven H3K27M-altered DMG between 2013-2023 from six US medical centers and the DMG Center in Zurich. Patients with tumor genomic sequencing and completion of RT were eligible. Genomic alterations were evaluated for somatic mutations, fusions, and chromosomal instability. Cox proportional hazard models were used to evaluate associations between genomic alterations and survival. Multivariate analysis included all significant variables at P <0.1 in initial analysis, including age at diagnosis, tumor location, TP53 and PIK3R1 alterations. RESULTS 297 patients (135 female; median age 8.3 years; range 0.2-71.4 years) were included. Median progression-free survival (PFS) and overall survival (OS) was 7.6 months (95%CI: 6.9-8.6) and 14.0 months (95%CI: 12.9-15.7). In univariate analysis, TP53 or PIK3R1 status correlated with shorter OS (TP53-mutant 12.5 vs. TP53-wildtype 17.5 months; HR=1.5; 95%CI: (1.1-2.0), P= 0.005); (PIK3R1-mutant 12.6 vs. 14.5 months; HR=1.9, 95%CI: (1.1-3.4), P = 0.03). Multivariate analysis corroborated TP53-mutant status with poorer OS (HR=1.5; 95%CI: (1.2-2.0), P= 0.003). Subgroup univariate analysis of pontine DMG patients showed poorer OS with TP53, NF1, or TERT mutations (TP53-mutant 11.9 vs. 15.2 months; HR= 1.6; 95%CI: (1.1-2.3), P= 0.02); (NF1-mutant 8.4 vs. 13.6 months; HR= 2.3; 95%CI: (1.1-5.0), P=0.03); (TERT 8.5 vs. 13.6 months; HR= 2.5; 95%CI: (1.1-5.7), P= 0.03). Subsequent multivariate analysis corroborated the association of TERT mutations with poorer OS in pontine DMG (HR=2.5; 95%CI:1.05, 5.9, P= 0.03). CONCLUSIONS This is the largest cohort of H3K27M-altered DMG patients with volumetric imaging analysis ongoing. Taken together, our data suggests these genetic alterations can risk-stratify patients for RT and future investigations of radiosensitizers targeting these alterations may improve survival.

CTIM-07. A PHASE II, OPEN LABEL, SINGLE ARM STUDY OF NIVOLUMAB FOR RECURRENT OR PROGRESSIVE IDH MUTANT GLIOMAS WITH PRIOR EXPOSURE TO ALKYLATING AGENTS

Abstract BACKGROUND Somatic mutations in isocitrate dehydrogenase 1 (IDH1) are an important prognostic factor in patients with gliomas. IDH-mutant gliomas are prone to develop hypermutation after exposure to alkylating agents; in other solid tumors, hypermutation may be a predictive biomarker for PD-1 inhibitor response. In this study, we hypothesize that this specific subgroup of patients would clinically benefit from nivolumab as measured by overall response rate (ORR), duration of response (DOR), median progression-free survival (PFS), and overall survival (OS). METHODS Patients aged 18 years and older with recurrent/progressive IDH-mutant (WHO Grades 2-4) gliomas and prior exposure to alkylating agents were included. Nivolumab was given 240 mg q2w for 8 cycles, then 480 mg q4w until progression, toxicity, study withdrawal, or completion at 2 years. Efficacy was evaluated by ORR of partial (PR) and complete responses (CR) per RANO criteria; low-grade glioma RANO criteria was used for patients with non-enhancing disease. Secondary endpoints included median PFS, median OS, DOR. Toxicity and survival were followed every 3 months until death/study completion. RESULTS Thirty-three patients (66.7% male) were evaluable at study completion. Histology consisted of oligodendroglioma (N=11; 55% Grade 3) and astrocytoma (N=22; 36% Grade 3, 32% Grade 4). Median number of prior lines of systemic therapy was 1 (range 1-6). Median dexamethasone dose at screening was 0 mg (range 0-4). ORR was 9% with two PR and one CR, median DOR 33 months. 11 (32%) patients had stable disease (7 stable for 6+ months) with median PFS 2.2 months and median OS 29.1 months. There were two treatment-related Grade 3 adverse events (lymphopenia and hypotension). One patient discontinued treatment for Grade 2 transaminitis. CONCLUSIONS Though the primary endpoint was not met, three patients have ongoing CR and PR at 54+, 33+ and 24+ months. Future combination therapies with PD-1 inhibitors may increase efficacy in recurrent IDH-mutant gliomas.

CTIM-06. OUTCOME OF PATIENTS WITH RECURRENT MEDULLOBLASTOMA AND EPENDYMOMA TREATED WITH PEMBROLIZUMAB, AN IMMUNE CHECKPOINT INHIBITOR: A PEDIATRIC BRAIN TUMOR CONSORTIUM STUDY (PBTC045)

Abstract BACKGROUND Children with recurrent medulloblastoma and ependymoma typically have a dismal prognosis. Immune checkpoint blockade has revolutionized treatment of some resistant cancers. PBTC045 is a safety and preliminary efficacy study of pembrolizumab, a PD-1 inhibitor, in children with recurrent/progressive brain tumors. Here we present the strata that included children with recurrent/progressive ependymoma and medulloblastoma. METHODS Eligibility included patients aged 1-21 years old with recurrent/progressive ependymoma or medulloblastoma and with functional scores ≥70, no greater than physiologic steroid usage and standard washout periods, among other eligibility criteria. Pembrolizumab was administered at 2mg/kg IV every three weeks. Tumor tissue (if available) and serum were collected for correlative studies. Primary endpoints included toxicity and response, and two stages were planned requiring objective responses for potential expansion. RESULTS Patients with progressive ependymoma (Stratum D, n=13) or medulloblastoma (Stratum E, n=14, one ineligible) were enrolled. The median age at diagnosis was 3.37 years (range, 1-12.7) and 7 years (range, 2.2-13.1), respectively. The median age at study entry was 8.5 years and 11.4 years, respectively. There were no first-stage objective responses in either stratum, and thus the expansion arms were not initiated. Grade 3 or greater treatment-related adverse events included rash (n=1), anemia (n=1) and neutropenia (n=2), with no dose-limiting toxicities. The median progression-free survival (PFS) for ependymoma and medulloblastoma were 1.38 months (range, 1.08-1.51) and 1.41 months (range, 1.22-3.45), respectively. Immune correlative analyses are ongoing. CONCLUSIONS Immune checkpoint inhibition holds potential for CNS cancer treatment, and as a single agent, is well tolerated. However, in the current study, checkpoint inhibition monotherapy does not appear to significantly prolong survival or induce radiographic responses in children with recurrent/progressive ependymoma or medulloblastoma. Potential incorporation of checkpoint inhibitors into treatment for these patients will likely require combinatorial approaches that may be informed by the correlative science.

CTNI-32. A MULTICENTER PHASE 1 TRIAL OF TUCATINIB, TRASTUZUMAB, AND CAPECITABINE WITH STEREOTACTIC RADIOSURGERY IN PATIENTS WITH BRAIN METASTASES FROM HER2 POSITIVE BREAST CANCER (TUTOR)

Abstract BACKGROUND Nearly 20-40% of HER2+ breast cancer patients develop brain metastases (BMs), where stereotactic radiosurgery (SRS) is standard-for-care for local control. Tucatinib, an oral HER2-selective TKI, is safe and efficacious in HER2+ breast cancer in combination with capecitabine and trastuzumab. Synergism between these 3 drugs (TCT) and radiation may enhance DNA damage. This phase 1 trial aims to evaluate TCT plus SRS for HER2+ breast cancer BMs (BCBM). METHODS TUTOR is a pre-registered (NCT05553522), single-arm, multicenter, ongoing, phase 1 trial that aims to determine the safety and efficacy of TCT+SRS in HER2+ BCBM patients. Patients with age 18-80 years, ECOG score 0-2, normal organ function, and ≤10 newly-diagnosed BMs are being enrolled at six US centers. Any number of prior systemic therapies are allowed, except tucatinib and capecitabine. Key exclusion criteria include leptomeningeal metastases, intra-tumoral or peri-tumoral hemorrhage, and BMs ≤5 mm of optic chiasm/nerve. Primary endpoint is maximum tolerated dose (MTD) of tucatinib, in this 3 + 3 de-escalation study starting at dose level (DL) 300 mg BID. DL-1 is 250 mg BID, and DL-2 is 200 mg BID. Secondary endpoints include efficacy as determined by response rate, intracranial progression-free survival (PFS), extracranial PFS, and overall survival. Neurocognitive outcomes are assessed using Hopkins Verbal Learning, Controlled Oral Word Association, Trail Making, and Grooved Pegboard Tests. Toxicities are assessed using CTCAE v5.0. Quality of life is assessed using Functional Assessment of Cancer Therapy with Brain Tumor module. Patients are administered tucatinib with SRS as per treating radiation oncologist, followed by tucatinib for two weeks, i.e. dose-limiting toxicity (DLT) period, followed by TCT until progression or intolerable toxicity. DLTs are defined by Grade 3 or 4 thrombocytopenia, grade 4 anemia, grade 4 neutropenia lasting >7 days, febrile neutropenia, and any non-hematologic toxicity of grade ≥3 (excluding alopecia). Cohort expansion at MTD to 40 patients is planned. Patient enrollment started in February 2023 and remains ongoing.

Clinical features, treatment options and outcomes in primary cutaneous B-cell lymphomas: a real-world, multicenter, retrospective study.

Primary cutaneous B-cell lymphomas (PCBCLs) are rare cutaneous neoplasms with limited literature regarding treatment options and associated treatment outcomes. This study aimed to investigate and present real-world treatment outcomes in patients with PCBCLs. All patients with PCBCL who were treated in five major referral centers for cutaneous lymphoma in Greece over 10 years were retrospectively included with their baseline characteristics and treatment-associated outcomes collected and analyzed. In total, 235 PCBCL patients, of whom 125 (53.2%) were females, were included. The median age at diagnosis was 60 years (IQR 47-72), and the median follow-up duration was 3 years (IQR 1.3-6.4). The most common subtype was primary cutaneous marginal zone lymphoma (PCMZL) (52.3%), followed by primary cutaneous follicle center lymphoma (PCFCL) (40.9%), and primary cutaneous large B-cell lymphoma, leg type (PCDLBCL, LT) with 16 (6.8%) cases. Complete responses (CRs) were observed in 77.3% after first-line treatment. Both radiotherapy (RT) and surgical excision (SE) achieved superior outcomes, with 88.9% and 89% achieving CR, respectively. Relapses occurred in 22.6% of initial complete responders. The median time to the next treatment (TTNT) for the PCMZL and PCFCL was 349 days. RT and topical/intralesional steroids demonstrated longer TTNT compared to SE (445 and 359 vs. 154 days). For PCMZL and PCFCL, the 1-year progression-free survival (PFS) was 84.2% (75.7-89.9) and 85% (75.1-91.2), and the 5-year PFS was 66.5% (55.2-75.5) and 58.8% (44.4-70.7), respectively. PCBCLs have favorable outcomes. RT demonstrates significantly increased TTNT compared to SE, suggesting RT as the preferable option. After careful evaluation, "watch and wait" may be a reasonable option for asymptomatic patients.

BIOM-25. MOLECULAR PROFILING PREDICTS EARLY AND LATE PROGRESSION IN GLIOBLASTOMA

Abstract Patients with glioblastoma experience a wide variation in response to standard treatment, with nearly 30% experiencing tumour progression during treatment, and nearly 6% surviving more than 5 years. To date, there are few non-invasive clinical biomarkers to predict response to first – line treatment. Chemical exchange saturation transfer (CEST) MRI may have the potential to fill this gap. CEST MRI is sensitive to treatment-induced changes and changes in tumor metabolism. Our team has obtained CEST data for patients before, during and after the end of standard chemoradiation treatment, and found that CEST provides markers of early response and can identify early, standard and late progressors before treatment initiation. In this study, we aimed to establish molecular profiles of early, standard and late progressors with IDH wild-type glioblastoma. Patients (n=180) with primary, IDH wild-type glioblastoma were imaged with CEST-MRI at multiple time points throughout standard chemoradiation treatment. DNA and RNA were co-extracted from matched normal and tumour pairs and processed for whole genome sequencing, enzymatic methyl-seq and gene expression analysis using Nanostring. Clinical variables such as age, extent of resection, sex, ECOG status and MGMT promoter methylated were also collected. A survival analysis was conducted using the Kaplan-Meier method with log-rank tests. Univariate and multi-variate hazard ratios for clinical variables were calculated by fitting Cox Proportional Hazards Models. Early progressors reported a median progression-free survival (PFS) of 142 days compared to 832 days in late progressors (p<0.0001). Early progressors also harbored distinct and statistically significant differences in gene expression and genomic alterations, namely in DNA damage repair, glucose transport and arginine metabolism pathways. A gene signature was prognostic of PFS and overall survival. Collectively, this data has the potential to serve as a radiogenomic biomarker to assess treatment response before or within early phases of treatment and allow for individual tailoring of the treatment plan.

Efficacy Analysis of Bronchial Arterial Chemoembolization for Nonsmall Cell Lung Cancer: A Systematic Review and Meta-Analysis.

Objective: This study aims to comprehensively evaluate the efficacy and safety of bronchial arterial chemoembolization (BACE) in the treatment of advanced nonsmall cell lung cancer (NSCLC) through a meta-analysis of single-group rate, providing evidence-based guidance for clinical treatment. Materials and Methods: A systematic search was conducted in PubMed, the Cochrane Library, Embase, and Web of Science databases for relevant studies up to January 15, 2024. Inclusion criteria encompassed single-arm or multi-arm studies of nonrandomized controlled trials, observational studies, and single-arm studies in English language, focusing on NSCLC patients treated with BACE. Data extraction, quality assessment, and statistical analysis were performed following predefined protocols. Results: In total, 172 articles were initially retrieved, with 11 studies meeting the inclusion criteria. The included studies comprised 510 patients. Meta-analysis revealed significant heterogeneity among studies for median progression-free survival (PFS), median overall survival (OS), objective response rate, and disease control rate. The combined median PFS was 6.87 months (95% confidence interval [CI] 5.30-8.44), and the combined median OS was 13.68 months (95% CI 10.69-16.67). Subgroup analysis based on intervention measures demonstrated varying efficacy outcomes. Adverse reactions associated with BACE were generally mild, with no reports of grade 3 or higher adverse events. Conclusion: BACE emerges as a promising treatment modality for advanced NSCLC, exhibiting favorable efficacy and safety profiles.

CTNI-28. IN VITRO GLIOMA STEMLIKE CELL-BASED SCREENING TO PREDICT DRUG SENSITIVITY IN RECURRENTGLIOBLASTOMA: A CLINICAL SERIES AND SYSTEMATIC LITERATURE REVIEW

Abstract INTRODUCTION There is no standard care for recurrent glioblastoma (GBM) after surgery and radiochemotherapy. Lomustine is commonly used in clinical trials, while regorafenib, a multikinase inhibitor, has shown a survival benefit in the randomized multicentric REGOMA trial, becoming the standard treatment in several countries, including Italy. However, due to nonnegligible toxicity, early identification of likely responders is crucial for personalized treatment. Various studies have explored putative molecular predictors of response with conflicting results. Glioma stem-like cells (GSCs), the most treatment-resistant subpopulation, are believed to drive GBM recurrence post-chemoradiotherapy. Thus, GSCs might provide valuable insights into the drug sensitivity of recurrent GBM. MATERIALS AND METHODS Between 2020 and 2022, nine patients enrolled in a prospective study to obtain GSC cultures from tumor tissue obtained at first surgery were treated with regorafenib upon tumor recurrence. Four patients underwent reoperation before starting regorafenib. GSC cultures were exposed to increasing regorafenib doses in vitro to determine sensitivity (IC50). RESULTS The median progression-free survival (PFS) was 3 months, consistent with REGOMA data. Only one patient achieved 6-month PFS (11.1%). GSCs from this patient were the only ones with an IC50 below the plasma range of regorafenib during treatment (IC50 4.6 μM, range 5.2-8.1 μM). Additionally, this patient had not undergone reoperation before starting regorafenib. Systematic literature review showed few but promising studies in which therapy personalization was based on in vitro drug screening. CONCLUSIONS Although preliminary, these findings suggest a potential paradigm shift in personalized treatment for recurrent GBM, utilizing a GSC-based approach rather than molecular profiling. Further evaluation of GSCs from recurrent tumor tissue is necessary to determine their utility.

RADT-50. CLINICAL OUTCOME OF DAILY 5-FRACTIONATED GAMMA KNIFE RADIOSURGERY FOR LARGE BRAIN METASTASES

Abstract INTRODUCTION With the introduction of the Gamma Knife Icon, hypo-fractionated Gamma Knife radiosurgery (GKRS) for large brain metastases (LBMs) is beginning to be performed. This study aimed to assess the clinical outcome and risk of the daily 5-fractionated GKRS for LBMs. METHODS A total of 100 patients who underwent 5-fractionated GKRS for LBMs (> 14cm3) were enrolled. Forty-six were male patients, and the median age was 60 years. Most common primary cancer sites were lung (41 non-small cell cancers), breast (24), and kidney (14). The median tumor volume was 22cm3 (14 – 69cm3) and marginal dose was 35Gy (50% isodose line) in 5 fractions. Median follow-up duration was 18 months (3 – 72 months). RESULTS The last follow-up showed local tumor control in 74 cases. The cumulative 1, 2, and 3-year local tumor control rates were 73, 65, and 60%, respectively. Eighty-six tumors showed best MRI response in a year, and median tumor volume decrease rate was 80% (22 – 100%). Thirty patients experienced dramatically tumor volume decrease (> 95%). Median progression free and overall survival were 7 and 16 months, respectively. Radiation necrosis occurred in 24 patients, of which only 9 had neurological symptoms and treated with steroid and bevacizumab. CONCLUSIONS The daily 5-fractionated GKRS for very LBMs showed favorable local tumor control and acceptable radiation necrosis, but questionable survival benefit. In the future, prospective multi-center study is needed.

Bevacizumab as a mitigating factor for the impact of high systemic immune-inflammation index on chemorefractory in advanced epithelial ovarian cancer.

Predicting chemorefractory disease in advanced epithelial ovarian cancer (EOC) remains challenging. This study aimed to identify clinicopathological factors and hemogram data as predictive markers for chemorefractory EOC and to explore potential therapeutic approaches that may mitigate these unfavorable conditions. We conducted a retrospective analysis of patients with advanced EOC treated with chemotherapy. Hemogram data and clinicopathological variables were collected. We employed logistic regression to assess factors associated with chemorefractory EOC and used the Kaplan-Meier method for survival analysis. Among the 191 patients analyzed, suboptimal surgery, lymphocyte count < 1440/mm3, systemic immune-inflammation index (SII) ≥ 2350, and lack of bevacizumab therapy were independently associated with chemorefractory EOC (OR 19.30, 95% CI 7.01-53.12; OR 9.07, 95% CI 2.76-29.82; OR 12.45, 95% CI 3.87-40.07; OR 6.61, 95% CI 2.01-21.78, respectively). Elevated SII was also identified as a risk factor for poor progression-free (PFS) and overall survival (OS). Specifically, patients with high SII who did not receive bevacizumab had a significantly higher probability of chemorefractory EOC and poorer survival outcomes compared to those who received bevacizumab. Our findings suggest that hemogram parameters and clinicopathological factors such as suboptimal surgery, lymphocyte count, SII, and bevacizumab therapy status are predictive markers for chemorefractory disease in advanced EOC. Elevated SII emerged as a predictor for poorer PFS and OS outcomes, particularly in the absence of bevacizumab therapy.

CNSC-15. DURATION AND TIMING ANALYSIS OF TUMOR TREATING FIELDS (TTFIELDS) THERAPY FOR NEWLY DIAGNOSED HIGH-GRADE GLIOMA PATIENTS: A REAL-WORLD RETROSPECTIVE STUDY IN TWO CENTERS

Abstract BACKGROUND In the EF-14 phase 3 trial, tumor treating fields (TTFields) plus temozolomide improved progression-free and overall survival versus temozolomide alone in newly diagnosed glioblastoma. However, the optimal duration and timing of TTFields treatment have not been reported yet. In this study, we aimed to analyze the relationship between the timing of TTFields use, the total duration of therapy, and daily compliance with overall survival in high-grade glioma (HGG) and, therefore, provided detailed suggestions for clinical use of TTFields. METHODS A total of 343 patients were screened retrospectively after resection or biopsy at two centers and received TTFields treatment from April 2019 to April 2023. All the patients were re-evaluated based on the 2021 WHO CNS5 Classification. We collected clinical data, including basic clinical information, pathology, surgery, radiotherapy, and TTFields. Follow-up for survival was performed for all patients in December 2023, and another follow-up is planned for June 2024. RESULTS After excluding non-HGG or lacking critical diagnostic information, 308 patients were included. Of these, 264 were Glioblastoma, IDH-wildtype, 27 were Astrocytoma, IDH-mutant, 3 were Oligodendroglioma, IDH-mutant, and 1p/19q-codeleted, and 14 were Diffuse midline glioma, H3 K27-altered, or Diffuse hemispheric glioma, H3 G34-mutant. Baseline characteristics were listed below: median age was 53 years; 56.82% male; median baseline KPS was 90; 75.97% underwent gross total resection; 51.30% received chemoradiation with concurrent TTFields. Only 26.30% of patients were still using TTFields by December 31, 2023. The median time difference between TTFields and surgery was 55.5 days. The overall TTFields median duration was 334 days, with a median compliance rate of 85%. By December 31, 2023, 59.09% of the patients were still alive. CONCLUSION The study group will continue to follow up on patients’ survival. Further analysis of the correlation between treatment duration, compliance or timing and survival will be performed.

STEM-05. SHARED ONCOGENIC MUTATIONS IN THE SUBVENTRICULAR ZONE AND GLIOBLASTOMA: GENETIC AND CLINICAL IMPLICATIONS

Abstract The subventricular zone (SVZ), a neurogenic niche in the adult brain, is suspected to harbor neural stem cells (NSCs) that can acquire cancer-driving mutations and give rise to glioblastoma (GBM). Nevertheless, the corroborating genetic data are restricted to a small patient cohort. This study aimed to validate the presence of low-level oncogenic mutations in the SVZ of GBM patients and assess their clinical implications.. We performed deep hybrid capture sequencing of 15 GBM-associated genes and TERT promoter amplicon sequencing on triple-matched samples from the SVZ, primary tumor, and blood of 60 GBM patients. Approximately 62% of patients (40 of 61 patients) showed shared oncogenic mutations between the tumor and tumor-free SVZ, including TERT promoter, PTEN, and TP53. While shared mutations did not affect overall clinical profiles, TERT promoter mutations were significantly enriched in the shared group (94.9% of patients, p ≤ 0.001). RNA sequencing revealed upregulation of proliferation-related genes in tumors with shared SVZ mutations, and these patients had worse progression-free and overall survival (p = 0.038 and 0.031, respectively). This study provides the largest-scale genetic validation of the SVZ as a potential cellular origin of GBM, highlighting the distinct genetic and clinical features associated with shared oncogenic mutations. These findings warrant further investigation into the role of SVZ mutations in GBM genesis and their potential as therapeutic targets.

RADT-44. EARLY CLINICAL EXPERIENCE WITH PROTON CRANIOSPINAL IRRADIATION FOR THE TREATMENT OF LEPTOMENINGEAL DISEASE

Abstract BACKGROUND Leptomeningeal disease (LMD) is a uniformly terminal event of advanced cancer with limited therapeutic options, with survival ranging from weeks to a few months. Recently, proton craniospinal irradiation (pCSI) has been demonstrated to confer a progression-free and overall survival benefit in select patients with LMD as compared to more limited site radiotherapy. Early results from an institutional experience of pCSI for patients with LMD from solid tumor malignancies are reviewed. METHODS All patients with LMD and treated with pCSI at our institution were reviewed, specifically with regards to baseline patient characteristics, radiation dosimetry parameters and clinical outcomes. RESULTS Between February 2023-April 2024, nine patients were treated with pCSI for a range of primary tumor histologies, including two with triple-negative breast cancer and one each with ER+/PR+/HER2- breast cancer, non-small cell lung cancer, small cell lung cancer, gastric cancer, esophageal cancer, pancreatic cancer and ovarian cancer. All patients received 30Gy(RBE) in 10 fractions to the craniospinal axis, with one patient receiving an intracranial boost (6Gy(RBE)). Median age and performance status was 58 years and KPS 80, respectively. Five (56%) patients underwent CSF diversion prior to pCSI, 22% of patients had undergone prior CNS-directed radiotherapy, and all patients received at least one line of systemic therapy in the metastatic setting prior to pCSI. Median survival from the first day of pCSI was 4.3 months (range 1.3-10.7mo). Median survival among patients undergoing CSF diversion prior to pCSI (n=5) was 5.3 months (vs. 2.9mo with no CSF diversion). Median survival among patients who received systemic treatment after pCSI (n=5) was 9.1 months (vs. 2.9mo for patients who did not). CONCLUSIONS Careful patient selection is imperative to identify those who will best benefit from pCSI with suggestion of patients undergoing pre-pCSI CSF diversion and receiving post-pCSI systemic therapy achieving superior survival.

NIMG-42. ANALYSIS OF TUMOR RELAPSE PROBABILITY AND OVERALL SURVIVAL PREDICTION FOLLOWING TEMOZOLOMIDE CHEMORADIATION USING FET PET INCLUDING RADIOMICS IN PATIENTS WITH GLIOBLASTOMA

Abstract BACKGROUND Early after surgery and completion of first-line concomitant chemoradiation with temozolomide, the evaluation of tumor relapse probability and overall survival prediction is of considerable interest for the management of patients with glioblastoma METHODS Sixty-three newly diagnosed patients with glioblastoma (age range, 19-82) who received static and dynamic PET imaging using the radiolabeled amino acid O-(2-[18F]fluoroethyl)-L-tyrosine (FET) after surgery or biopsy and completion of concomitant chemoradiation with temozolomide were evaluated. Static FET PET parameters such as maximum and mean tumor-to-brain ratios (TBRmax, TBRmean) and metabolic tumor volumes (MTV), and the dynamic FET PET parameter time-to-peak (TTP) were obtained. Additionally, FET PET radiomics features (n=1,303) were extracted for each patient and a test-retest analysis was performed to identify robust features prior to feature selection. The prognostic value of FET PET parameters and radiomics features was evaluated using receiver-operating-characteristic (ROC) analyses with regard to a significantly prolonged progression-free and overall survival (PFS, OS). Subsequently, univariate and multivariate survival estimates were performed to assess the prognostic value of these parameters to predict a significantly longer PFS and OS RESULTS ROC analyses revealed that the parameter TBRmax was a powerful parameter to predict both a significantly longer PFS (20.3 vs. 8.9 months; P=0.002; threshold, 2.75) and OS (34.9 vs. 18.7 months; P=0.005; threshold, 2.75). MTV had a similar prognostic value for both PFS (16.7 vs. 7.2 months; P=0.002; threshold, 34.0 mL) and OS (30.6 vs. 14.8 months; P=0.002; threshold, 32.6 mL). After feature selection, 3 of 15 selected radiomics features predicted a significantly longer PFS and OS in univariate analyses. TBRmax, MTV, and one of 15 radiomics features remained significant in multivariate survival analysis (all P≤0.03) CONCLUSION Our results suggest that FET PET and radiomics parameters were highly prognostic in this group of patients at an early stage of first-line therapy.

EPCO-43. DECONVOLUTION OF GLIOBLASTOMA RNA-SEQ REVEALS IMMUNE SUBPOPULATIONS PREDICTING THERAPEUTIC RESPONSE

Abstract Bulk RNA-seq is now among the standard of care for patients with newly diagnosed glioblastoma (GBM), but whether this data can predict therapeutic response is unclear. In silico deconvolution of bulk RNA-seq data allows for quantification of cell types comprising the tumor and its microenvironment. Our study tests whether cell type proportions predict therapeutic response in patients with GBM and high-grade glioma (HGG) enrolled in trials of investigational agents. 127 patients with GBM/HGG underwent post-resection/biopsy whole exome RNA-seq and reads were post-processed using standard computational pipelines. In silico deconvolution was performed using GBMDeconvoluteR, which generates cellular proportions comprising the RNA-seq reads. Multivariate Cox regression models were used to examine each cell proportion as a predictor of progression-free (PFS) and overall (OS) survival. Statistical significance was ascertained using Bonferroni correction for multiple comparisons. Among 54 patients treated with a PD-L1 inhibitor (nivolumab) and VEGF inhibitor (bevacizumab), the proportions of NK cells (p=0.0024), radial glial cells (p=0.0010), and mural cells (p=0.0025), was associated with increased PFS, while proportion of endothelial cells (p=0.0008) was associated with decreased PFS. Astrocyte (p=0.0022), macrophage (p=0.0015), NK cell (p&amp;lt;0.0001), and mural cell (p=0.0004) proportions were associated with longer OS, while endothelial cell proportion (p=0.0001) was associated with shorter OS. Among 21 patients treated with a tyrosine kinase inhibitor (ibrutinib) combined with radiation and temozolomide (RT/TMZ), cell proportions assessed at the time of diagnosis did not predict PFS or OS. In 52 patients with HGG treated with a JAK inhibitor (ruxolitinib) with RT/TMZ, only mural cell proportion was associated with a longer OS (p=0.0017). Our results highlight how bulk RNA-seq data can be used to predict therapeutic response. In GBM patients treated with immunotherapies, the proportion of NK cells may predict response. Further work will examine which gene programs are predictive of therapeutic response.