Radiographic Response Research Articles

Using a Pre-Radiation Window to Identify Potentially Active Cytotoxic Agents in Adults with Newly Diagnosed Glioblastoma.

Therapies shown to improve outcomes in patients with recurrent cancers are commonly used in the neoadjuvant setting to optimize surgery, reduce radiation fields, and treat micro-metastatic disease. While pre-radiation chemotherapy (PRC) use has flourished in systemic cancers, it has not in glioblastomas. This review documents these trajectories and highlights the potential of PRC to rapidly and safely screen cytotoxic drugs for efficacy in patients with newly diagnosed glioblastoma. Prospective trials of adults with newly diagnosed systemic and brain cancers treated with PRC published between 1980 and 2023 were identified in PubMed. NCCN guidelines were used to document the standard use of PRC in patients with systemic and brain cancers. Over 5,000 prospective PRC trials in solid tumors were identified. These accrued >1 million patients and resulted in neoadjuvant therapies being standard-of-care in ~28 systemic cancers. Only 50 similar trials (2,206 patients) were identified in high grade gliomas. In 13 trials containing PRC temozolomide (n=846), radiographic responses ranged from 6-53% with a median survival of ~13 months. Glioblastoma PRC trials were not associated with unexpected toxicities or major negative impacts on survival. PRC in patients with glioblastoma appears safe and feasible. The pre-radiation window is ideally suited to rapidly screen cytotoxic agents for efficacy. It permits radiographic response as a primary outcome, small sample sizes, and initiation of standard therapies a few months after diagnosis. PRC may be most appropriate in patients with glioblastoma who are unlikely to benefit from temozolomide.

Voxel-Based Dosimetry Predicts Local Tumor Progression Post 90Y Radiation Segmentectomy of Colorectal Liver Metastases

Background Radiation segmentectomy (RS) is an alternative potential local curative treatment for selected colorectal liver metastases (CLMs) not amenable to ablation or limited resection. Purpose The aim of this study was to evaluate the dosimetric response of low volume CLMs to RS in heavily pretreated patients who are not candidates for resection or percutaneous ablation. Patients and Methods This single-center retrospective study evaluated CLMs patients treated with RS (prescribed tumor dose >190 Gy) from 2015 to 2023. RS doses to tumor(s) and margins were calculated from SPECT/CT and PET/CT images. Response and local tumor progression (LTP) were assessed using anatomic (RECIST 1.1) and metabolic (PERCIST) criteria. LTP-free survival (LTPFS) and overall survival were estimated with Kaplan-Meier methodology. Variables were assessed as predictors of LTPFS using the Cox proportional hazards model. Results Thirty-six patients underwent 38 RS procedures to treat 57 tumors. Median time from initial diagnosis to detection of liver metastases and RS were 16.4 (interquartile range: 6.5–32.2) and 26.8 (interquartile range: 12.5–40.0) months, respectively. Median overall survival after RS was 14.3 (95% confidence interval [CI]: 10.8–30.7) months. Predictors of LTPFS included tumor number(s), mean tumor dose (MTD), and margin mean absorbed dose (MMAD). Complete radiographic (hazards ratio [HR]: 1.29e-16, 95% CI: 4.06e–17-4.07e-16, P < 0.001) and metabolic response (HR: 0.38, 95% CI: 0.15–0.95, P = 0.038) correlated with prolonged LTPFS. One-year LTPFS rate was 83.3% for tumors receiving MTD ≥400 Gy and a 5-mm surrounding MMAD ≥350 Gy (P = 0.006). No instances of LTP were observed when tumors received stereotactic irradiation over 300 Gy (at least 95% of the tumor volume received ≥300 Gy). One-year LTPFS rate for tumors receiving MTD ≥400 Gy was 68.6% versus 14.3% for those that did not reach this threshold (P = 0.013). In multivariate analysis, MTD ≥400 Gy and 5-mm MMAD ≥350 Gy were independent predictors of LTPFS (HR: 0.11; 95% CI: 0.01–0.81; P = 0.03). Conclusions MTD ≥400 Gy, MMAD ≥350 Gy, and stereotactic tumor irradiation ≥300 Gy are associated with prolonged LTPFS after RS for CLMs.

Abstract B023: Cell-free HPV-DNA dynamics during induction chemotherapy and response-stratified de-escalation in viral-mediated oropharyngeal cancer

Abstract Background: Cell-free HPV-DNA (cfHPV-DNA) in plasma represents a promising biomarker to grade treatment response and monitor for persistence/recurrence. We evaluated the dynamic changes of cfHPV-DNA during induction chemotherapy followed by response-stratified de-escalation in HPV associated (HPV+) oropharyngeal squamous cell cancer (OPSCC). Methods: A prospective biomarker clinical trial of response-stratified de-escalation therapy was conducted. Eligible patients had loco-regional HPV+ OPSCC and received induction chemotherapy with carboplatin and paclitaxel for three cycles followed by risk and response-stratified de-escalation with transoral robotic surgery (TORS), de-escalated radiation (RT) to 50Gy with or without cisplatin, or standard RT to 70Gy with cisplatin. Patients with deep response (>=50% tumor shrinkage per RECIST 1.1) qualified for de-escalated therapy. Cell-free HPV-DNA was measured using a CLIA-certified HPV-SEQ assay that utilizes NGS technology to detect and quantify HPV16 and HPV18 DNA in plasma at baseline, after each cycle of induction chemotherapy, during radiation, and post-treatment surveillance at 3, 6, 9, 12, 18, and 24 months following treatment. Results: Forty-six eligible patients were enrolled, with 464 cfHPV-DNA plasma samples analyzed (median 10 samples per patient). There were five recurrences (10.9%), all detected by HPV-SEQ. Baseline cfHPV-DNA was detected in 44/46 patients (96%). Patients with rapid early cfHPV-DNA clearance after one 3-week cycle of induction (>=95% clearance) predicted deep radiographic response following induction therapy (p=0.003). The detection of cfHPV-DNA at 3 months or later after treatment was associated with worse progression free survival (PFS), with 2-year PFS of 25% (95% CI 0.012-0.65) compared with patients without detectable cfHPV-DNA of 100% (95% CI 1.0-1.0); p<0.001). The longest lead-time from positive cfHPV-DNA to developing recurrent disease was 25 months. Conclusion: Rapid early clearance of cfHPV-DNA during induction has utility in predicting response to treatment. Detectable cfHPV-DNA following treatment is strongly associated with worse PFS. A subsequent trial using cfHPV-DNA to select patients for treatment de-escalation is ongoing. Clinicaltrials.gov ID: NCT04572100 Citation Format: Ari Rosenberg, Evgeny Izumchenko, John Cursio, Augustin Vannier, Aditya Juloori, Rohan Katipally, Rifat Hasina, Frederick Jones, Anna Starus, Elizabeth Blair, Daniel J. Haraf, Alexander T. Pearson, Everett E. Vokes, Nishant Agrawal. Cell-free HPV-DNA dynamics during induction chemotherapy and response-stratified de-escalation in viral-mediated oropharyngeal cancer [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B023.

CTNI-82. BELZUTIFAN TREATMENT OF VHL-ASSOCIATED CENTRAL NERVOUS SYSTEM HEMANGIOBLASTOMA

Abstract Von Hippel-Lindau (VHL) disease is caused by pathogenic variants in the VHL gene. Abnormal function of VHL protein leads to accumulation of HIF-α and the engagement of hypoxia-sensitive genes with oncogenic effects. VHL is associated with tumors in multiple organs. Belzutifan is an oral selective inhibitor of hypoxia-inducible factor 2 alpha. Belzutifan was approved in 2021 as a targeted therapy for VHL-associated CNS hemangioblastomas, renal cell carcinomas, and pancreatic neuroendocrine tumors. Here, we report on our institutional clinical experience with belzutifan for VHL-associated CNS hemangioblastomas. From October 2021 to May 2024, thirteen adults (9 female, 4 male, median age 40) were treated. Median duration of therapy was 24 months. Seven had a partial radiographic response after median of 3 months; one patient had a partial response; 1 patient had progressive disease on belzutifan. Four patients have been taking belzutifan for less than 3 months, and do not have follow-up imaging to assess response. The most common adverse effect was fatigue (7 patients). Four patients experienced anemia and 2 experienced hypoxia. Three patients discontinued belzutifan due to adverse effects. One patient had to take multiple medication pauses, due to seizure and kidney injury, but resumed treatment with dose reduction. Nine patients remain on therapy. Based on this data, belzutifan is often well-tolerated and associated with durable radiographic responses. Toxicity profile among our patients was similar to that encountered in the clinical trial leading to approval of the agent. These findings provide real-world data supporting continued use of belzutifan in this patient population, with an awareness of potential adverse reactions. Future studies should assess continued radiographic response, sex differences, and effects after long-term use.

CTIM-02. PIONEERING QUAD-TARGETING CAR T CELL THERAPY IN PEDIATRIC CNS TUMORS – ANALYSIS FROM THE INITIAL PATIENTS TREATED ON THE FIRST-IN-HUMAN PHASE 1 TRIAL BRAINCHILD-04

Abstract BACKGROUND BrainChild-04 is a first-in-human clinical trial of quad-chimeric antigen receptor (CAR) T cell therapy for children and young adults with central nervous system (CNS) tumors. This trial administers repeated locoregional CAR T cells targeting B7-H3, EGFR, HER2, and IL-13Ralpha2 (“quad-CAR T cells”), leveraging multi-antigen targeting to address the tumor heterogeneity of high-grade CNS tumors. METHODS The primary endpoints are feasibility and safety, and secondary endpoints are disease response and correlative studies of CAR T cell activity. The trial utilized a Bayesian Optimal Interval (BOIN) statistical design with three planned dose regimens(DR). There are 2 arms with weekly delivery for 3 weeks of a 4-week cycle:(A) –diffuse intrinsic pontine glioma (DIPG), (B) –non-pontine diffuse midline glioma (DMG) or other relapsed CNS tumors. RESULTS Enrolled patients include DMG N=6, DIPG N=5, other CNS tumors N=4. Of the 15 enrolled patients, 7 have been infused with 8 awaiting infusions. A total of 33 intracranial CAR T doses have been delivered, including Arm A DR 1 (N=1), Arm B DR 1 (N=3), DR2 (N=3). The most common adverse events have been grade 1-2 fever (7/7 patients), grade 1-3 headache (6/7), and grade 1-2 nausea/vomiting (6/7). There have been no DLTs and no cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity (ICANS). CTCAE and tumor inflammation-associated neurotoxicity are both being captured. All treated patients are alive with median follow up time post-initial infusion of 93(14-198) days. CAR T cells were detected by flow cytometric analysis of CSF post-infusion in 14/24 CSF samples. Radiographic response, CSF circulating tumor DNA, targeted mass spectrometry, and cytokine analysis will be presented. CONCLUSIONS Our preliminary experience suggests tolerability of locoregional delivery of quad-CAR T cells at doses currently evaluated. The trial remains ongoing and these data support continued evaluation of this product to better assess anti-tumor activity in patients with CNS tumors, including DIPG/DMG.

CTNI-80. 177LU-DOTATATE IN PATIENTS WITH RECURRENT MENINGIOMA

Abstract BACKGROUND There are no effective medical therapies for patients with meningioma who progress after surgical and radiotherapeutic interventions. Somatostatin receptor type 2 (SSTR2) represents a promising treatment target in meningiomas. Here, we describe our experience with use of 177Lu-DOTATE in recurrent meningioma PATIENTS AND METHODS This is a retrospective study. All patients had progressive intracranial meningiomas and were heavily pre-treated. Patients underwent 68Ga-DOTATATE PET-MRI at baseline and received 177Lu-DOTATATE every eight weeks for up to four doses. We collected patient demographics, tumor grade, treatment history prior to starting 177Lu-DOTATATE, duration of treatment, toxicities, overall survival (OS) and progression-free survival (PFS). Descriptive statistics were used to summarize patient’s characteristics. RESULTS Seven patients (female = 2, male = 5) with progressive meningiomas (WHO 1 = 1, 2 = 1, 3 = 5) were enrolled. Median age was 56 (range 41-72) years. All patients previously underwent tumor resection and at least one course of radiation. Treatment with 177Lu-DOTATATE was well tolerated. Three patients achieved PFS-6. One patient with malignant meningioma remains progression free at 13 months. Three patients remain on active treatment. Best radiographic response was stable disease (SD) in six patients. CONCLUSIONS Treatment with 177Lu-DOTATATE was well tolerated and demonstrated encouraging efficacy. Updated survival data will be presented.

INNV-37. REAL-WORLD OUTCOMES AMONG HIGH GRADE IDH1-MUTANT GLIOMA PATIENTS TREATED WITH AN IDH INHIBITOR

Abstract BACKGROUND Isocitrate dehydrogenase (IDH) inhibitors are transforming the treatment of patients with non-enhancing grade 2 IDH-mutant gliomas. Uncertainty remains on the utility of IDH-inhibitors in high-grade IDH-mutant glioma patients that had prior therapies and have progressive disease. METHODS From October 2020 to December 2023, we identified high-grade IDH1-mutant patients treated with off-label ivosidenib, a mutant IDH1 inhibitor. We report their clinical and imaging characteristics. RESULTS In our cohort (n=18), the patient age range was 29-68 years with male predominance (n=11). Diagnoses included astrocytoma grades 3 (n=9) or 4 (n=2), and oligodendroglioma grade 3 (n=7). The median number of progressions prior to ivosidenib initiation was 2 (range 1-7). Fifteen patients had prior surgical resection, three had biopsy. Prior treatment exposures included radiation therapy (n=15), temozolomide (n=18), lomustine (n=5), bevacizumab (n=3), etoposide (n=1), optune (n=1) and a clinical trial (n=1). Mean time from diagnosis to ivosidenib treatment was 9.6 years (95% CI, 6.7 to 16.4 years). Karnofsky performance-status score upon initiation was 80 (n=6) or 90 (n=12). Thirteen patients had >1 cm enhancing disease, five had non-enhancing disease. Ivosidenib was initiated due to enhancing disease progression (n=11), non-enhancing disease progression (n=4), a combination of both (n=2) or temozolomide intolerance (n=1). Best radiographic responses per RANO criteria were partial response (n=2), minor response (n=3), stable disease (n=7), and progressive disease (n=6). Nine patients continue ivosidenib without disease progression, with a median treatment duration of 27.5 months (95% CI, 18.0 to 33.0 months). All had FLAIR stabilization/improvement and 45% (n=4) had improved enhancing disease. Nine patients discontinued ivosidenib due to progression, with a median treatment duration of 7 months (95% CI, 3 to 9 months). CONCLUSIONS These data suggest that treatment with an IDH inhibitor can provide disease control for some high-grade IDH-mutant glioma patients who had prior therapies and progressive disease. Future studies are needed to investigate this patients population.

CCRG-04. RIBOCICLIB RESPONSIVE MENINGIOMA IN THE TREATMENT OF BREAST CANCER

Abstract BACKGROUND Meningiomas are the most common primary intracranial tumors, typically managed with surgical resection and/or radiation therapy. Systemic therapy options are limited and reserved for cases refractory to conventional interventions. Cyclin dependent kinase (CDK) proteins are key cell cycle regulators. CDK inhibitors are clinically available, approved for treatment of breast cancer and in clinical trials for meningioma. METHODS We present a case where a patient with incidentally-discovered intracranial meningioma undergoing CDK inhibitor therapy with ribociclib for breast cancer experienced a radiographic response. RESULTS A 73-year-old female was diagnosed with estrogen receptor (ER) positive, progesterone receptor (PR) positive, HER2 negative metastatic invasive ductal carcinoma of the breast. She was treated with estrogen receptor antagonist fulvestrant and CDK 4/6 inhibitor ribociclib. MRI of the brain performed for disease staging demonstrated an extraaxial, dural-based, homogenously enhancing mass along the left posterior petrous ridge consistent with a meningioma. Two-month interval scan demonstrated a marginal decrease in size of the mass (15.6x18.3 mm to 15.4x17.5 mm). Systemic disease related to breast cancer concurrently improved. Two years later, with ongoing fulvestrant and ribociclib therapy, a repeat MRI brain demonstrated further decrease in size of the meningioma (13.4x16.8 mm). CONCLUSIONS Hormonally-directed therapies previously demonstrated limited benefit for meningiomas despite PR/ER positivity reported for these tumors. However, CDK 4/6 inhibitors abemaciclib and ribociclib have demonstrated activity in treatment of recurrent grade 2/3 meningiomas. The radiographic response noted in our case suggests there may be a role for systemic therapy even in treatment-naive cases that may not be amenable to surgical resection or radiation therapy.

INNV-30. TOXICITIES AND OUTCOME AFTER CD19-DIRECTED CHIMERIC ANTIGEN RECEPTOR T-CELL THERAPY FOR NEUROLYMPHOMATOSIS

Abstract BACKGROUND Lymphomatous infiltration of the peripheral nervous system (PNS), termed neurolymphomatosis, represents a distinct extranodal non-Hodgkin lymphoma variant with dismal outcome. CD19-directed chimeric antigen receptor (CD19-CAR) T-cell therapy has emerged as a safe and effective treatment for B-cell lymphomas. We aimed to assess toxicity and efficacy of CD19-CAR T-cells in neurolymphomatosis. METHODS Neurolymphomatosis treated with CD19-CAR T-cells were retrospectively identified at Massachusetts General Hospital over a six-year period. Toxicities were graded according to the ASTCT classification. Management, and response rates were recorded. RESULTS Eleven neurolymphomatosis cases, who had received a median 2 prior PNS-directed treatments (range: 1-3) before CD19-CAR T-cell exposure, were identified. Neurolymphomatosis localized to the nerve roots (8/11, 73%), plexus (5/11, 45%), peripheral (4/11, 36%) and cranial nerves (5/11, 45%). Low grade cytokine release syndrome was detected in 8/11 (73%; grade 1: N = 7; grade 2: N =1) cases. Low- and high-grade immune cell-associated neurotoxicity syndrome were recorded in 5/11 (45%; grade 1: N = 4; grade 2: N = 1) and 1/11 (9%; grade 4) patients, respectively. Seven of eleven neurolymphomatosis patients (64%) responded to CD19-CAR T-cells. Complete remissions were achieved in three cases (27%), of which two are still sustained now 9 and 46 months after CD19-CAR T-cell infusion. All radiographic responses were associated with remission of neurological symptoms. CONCLUSIONS CD19-CAR T-cell treatment was well tolerated and yielded promising efficacy in recurrent neurolymphomatosis, a difficult to treat condition with unmet medical need. Findings suggest that CD19-CAR may sufficiently penetrate the blood-nerve barrier, and toxicity and outcomes were overall similar to CAR-T cell therapy in CNS lymphoma.

INNV-31. THE USE OF IVOSIDENIB IN PATIENTS WITH ENHANCING IDH1 MUTANT GLIOMAS

Abstract Ivosidenib offers a novel targeted therapy for non-enhancing IDH1 mutated gliomas following initial resection. Potential effects of IDH inhibitors on enhancing disease in clinical settings are not well established. This study characterizes a cohort of patients with IDH1 mutated gliomas with enhancing disease, who were initiated on monotherapy, off-label ivosidenib between October, 2020 to August, 2023. The cohort included 21 patients ages 29 to 73 years, 11 female and 10 male. Diagnoses represented were astrocytoma IDH1 mutant, grade 2-4 (N=9) and oligodendrogliomas IDH1 mutant, grade 2-3 (N=12). Prior treatment exposures included radiation therapy (N=11), temozolomide (N=15), bevacizumab (N=3), and treatment naïve (N=6). Time from diagnosis to ivosidenib initiation was 9.1±2.7 years. Although all patients had enhancing disease, ivosidenib was initiated due to non-enhancing disease progression (N=7), enhancing disease progression (N=13), and temozolomide intolerance (N=1). Size of enhancement by cross-section measured >1cm (N=15) and <1cm (N=6). Best radiographic responses per RANO criteria were partial response (N=3), stable disease (N=11), and progressive disease (N=7). At last contact, eleven patients were maintained on ivosidenib with no evidence of disease progression since initiation with an average treatment duration of 25.5±6.4 months and overall survival of 11.7±3.1 years. Ten patients had disease progression at median 5.2±3.1 months following ivosidenib initiation, three of whom died 16.7 (range 6.8-34.4) months after treatment initiation with an overall survival of 9.4 years (range 4.6-13.6). Adverse events from therapy included diarrhea (N=2), CK elevation (N=4), and QTc prolongation (N=2). No patients discontinued ivosidenib due to adverse events. No significant difference was detected between patients with and without disease progression due to size of enhancement (p=0.4) or prior treatment exposure (p=0.3). Future studies should include biopsies to understand the role of enhancing lesions in treatment response of IDH inhibitors.

CSIG-29. BRAF INHIBITOR THERAPY IN BRAF-MUTATED PRIMARY BRAIN TUMORS: A SINGLE-CENTER EXPERIENCE

Abstract BACKGROUND BRAF pathway alterations are frequent in glial/neuroepithelial tumors. BRAF-targeted therapy with BRAF inhibitors (BRAFi) and/or MEK inhibitors (MEKi) has proven efficacy in clinical trials, though mainly enrolling pediatric patients. We sought to investigate real-world data for adult patients with BRAF-pathway mutant glial/neuroepithelial neoplasms treated with BRAFi/MEKi. METHODS Adults with BRAF-pathway mutated glial/neuroepithelial neoplasms treated with BRAFi/MEKi were retrospectively reviewed. RESULTS Five patients (n=4 female, median age at diagnosis 36) were identified (tumor types: glioblastoma n=1, high-grade astrocytoma with epithelioid features n=1, low-grade neuroepithelial tumor n=1, pilocytic astrocytoma n=1, pleomorphic xanthoastrocytoma n=1). Four had BRAF V600E and one had NF1 p.S2687Cfs*5 mutant tumors. Prior to targeted therapy initiation, patients underwent a median 2.4 treatments including surgery (n=4), radiation therapy (n=4), chemotherapy (temozolomide n=4; carboplatin/vincristine n=1). BRAF-targeted therapies included dabrafenib/trametinib (n=4), binimetinib/encorafenib (n=2), binimetinib (n=2). One NF1-mutant glioblastoma received binimetinib followed by binimetinib/bevacizumab. Median BRAFi/MEKi treatment was 15.2 months (range: 6-36 months). Toxicities included leukopenia (n=3), peripheral edema (n=1), reduced ejection fraction (n=1), skin rash (n=5), transaminitis (n=1) with all patients requiring dose reductions and 3 cases requiring discontinuation. Among patients where BRAFi/MEKi was discontinued due to toxicity, 2 received other treatments at progression, then switched to a different BRAFi/MEKi combination, which they tolerated (duration 6-10months). Best radiographic response was partial response, noted in 3 patients treated with dabrafenib/trametinib. Four patients remain alive and continue BRAFi/MEKi. CONCLUSIONS In this cohort of heavily-pretreated patients with glial/neuroepithelial neoplasms, BRAF-targeted therapy was associated with durable responses. Interestingly, two patients who were unable to tolerate one combination of BRAFi/MEKi were able to tolerate a different combination with sustained response. Our findings support ongoing use of BRAF targeted therapy for CNS tumors. Optimal timing and duration of treatment requires further prospective evaluation in adult patients.

DDDR-24. REAL WORLD EXPERIENCE USING THE IDH INHIBITOR IVOSIDENIB IN IDH MUTANT GLIOMA: TOLERABILITY AND OUTCOMES

Abstract BACKGROUND Mutant isocitrate dehydrogenase (IDHm) inhibitors represent a novel therapeutic strategy for treating IDHm glioma, though their optimal use outside of clinical trials remains undefined. This study describes real world utilization of the IDH1 inhibitor, ivosidenib, in patients with IDHm glioma. METHODS We retrospectively reviewed clinical and radiographic data from IDHm glioma patients treated with ivosidenib monotherapy at Dana-Farber Cancer Institute and Massachusetts General Hospital from 2020-2024. Patients with a baseline MRI at ivosidenib initiation and at least 2 subsequent scans while on ivosidenib were included in radiographic response analysis (452 scans). RESULTS This cohort included 77 patients (39 males) age 17-75 years (median 41). Thirty-eight patients (49%) had astrocytomas and 39 (51%) had oligodendrogliomas; 48 (62%) had grade 2, 26 (34%) grade 3, and 3 (4%) grade 4 gliomas. Twenty-four patients (31%) received ivosidenib as first-line therapy and 53 (69%) received ivosidenib after failing prior treatments. Among those in the radiographic analysis, 4 (6%) demonstrated partial response, 4 (6%) minor response, 44 (62%) stable disease, and 19 (27%) progressive disease (PD). Significantly higher PD rates were seen in those with enhancing disease (p<0.001) or received ivosidenib as subsequent-line therapy (p=0.002); PD rate was similar between grades 2 and 3 in the first-line group (p=0.64). One-year progression free survival was 100% in the first-line group and 66% in the subsequent-line group. At the time of our analyses, 4 patients (5%) had died (all in the subsequent-line group). Infrequent side effects included CK elevation, QTc prolongation, transaminitis, and diarrhea. One patient (1%) was dose reduced and 3 (4%) discontinued drug due to side effects. CONCLUSIONS In this real world IDHm glioma cohort, ivosidenib was well-tolerated. Better response rates were seen in patients without enhancing disease at ivosidenib initiation and those who received the drug as first-line therapy.

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.

NIMG-54. AUTOMATED IMAGING RESPONSE EVALUATION SYSTEM (AIRES) FOR NEURO-ONCOLOGY: PROTOTYPE SOFTWARE TOOL FOR DETERMINING STANDARDIZED RADIOGRAPHIC RESPONSE ASSESSMENT FOR GLIOBLASTOMA CLINICAL TRIALS

Abstract Standardized radiographic response assessment criteria like Modified Response Assessment in Neuro-Oncology (mRANO) and now the RANO 2.0 are utilized for evaluating progression-free survival and objective response rate during glioblastoma clinical trials. After measuring tumor size with either bidimensional diameters or volumetric segmentations, the crucial and final time-consuming step of categorizing progression, stable disease, and response based on multiple criteria and numerical thresholds (e.g. ≥40% volumetric growth = progressive disease) is currently done manually. We developed an application prototype, Automated Imaging Response Evaluation System (AIRES) for Neuro-Oncology, that uses the mRANO criteria to label each timepoint as treatment response, stable disease, or disease progression based on either bidimensional or volumetric measurements as well as optional inputs of clinical status and corticosteroid dosage. These inputs may be uploaded via CSV files, which can integrate with automated tumor segmentation volumetry workflows, or entered in the AIRES graphical user interface (GUI). The AIRES GUI displays a patient report consisting of a table and graph that contain the lesion size, percent change from baseline, percent change from nadir, and the mRANO response category for each timepoint. To test AIRES in a real-world application, tumor size measurements from 367 scans across 41 patients from NUTMEG, a phase II multicenter clinical trial, were used to perform mRANO reads and calculate progression-free survival and time to response. AIRES-assisted reads performed by reader 1 were significantly quicker than fully manual reads performed by reader 2 (37.1±8.6 vs 107.7±58.6 seconds, P<0.0001). These results show that the AIRES app can make the reads quicker and potentially feasible for non-trained personnel, while reducing the amount of error-prone manual steps. Additionally, the underlying logic of AIRES is easily adaptable to integrate other response criteria including but not limited to RANO 2.0 and other future response assessment updates.

EPCO-09. DICER1-MUTANT PRIMARY INTRACRANIAL SARCOMA: ASSESSING THE ONCOGENIC ROLE OF MIRNA DYSREGULATION

Abstract Cross-cancer profiling has shown that mutations in human DICER1 are recurrent in diverse cancers including intracranial sarcoma. Due to the rarity of these tumors, treatment options for these patients remain poorly defined. DICER1 encodes an endoribonuclease that processes the hairpin precursor microRNAs (miRNAs) into functionally mature miRNAs. In particular, hotspot mutations in the RNase IIIb domain of DICER1 are predicted to confer an oncogenic role although the precise mechanism is unknown. In a case of a 28-year-old male who presented with multicentric right frontal dural and parenchymal enhancing masses and underwent partial resection, pathology showed a DICER1-mutant primary intracranial sarcoma with a hotspot E1813G mutation in the RNase IIIb domain. Additionally, due to a family history of an unknown fatal brain tumor in his mother, the patient had additional molecular testing which revealed a germline BRCA2 mutation. After surgery, the patient received intensity-modulated radiation therapy followed by 6 cycles of ICE (ifosfamide, carboplatin, etoposide) chemotherapy with significant radiographic response and clinical improvement. He remains progression-free on radiological surveillance for 13 months since diagnosis. The treatment was well tolerated with clinically manageable myelosuppression (including grade 3 thrombocytopenia). This is the first reported case of an adult DICER1-mutant primary intracranial sarcoma patient with a germline BRCA2 mutation although the interaction between these oncogenic mechanisms is unclear. Based on the role of DICER1 in miRNA processing and to test the hypothesize that DICER1 mutations drive primary intracranial sarcoma through dysregulation of miRNA function, we have established a multi-institutional collaboration that is collecting and profiling DICER 1 mutant primary intracranial sarcoma cases from across the United States preliminary results of which will be presented. Identification of a miRNA-driven oncogenic mechanism in these tumors may yield novel targeted approaches beyond intensive chemotherapy for these patients.

DDEL-05. IMPRESSIVE RESPONSE TO IDH-INHIBITOR THERAPY IN IDH-MUTANT, H3K27M INTACT BRAINSTEM GLIOMAS

Abstract IDH-mutated brainstem gliomas in adults are a rare entity, with only a handful of cases reported in the literature. Diagnosis and treatment of these gliomas remain challenging. There is significant morbidity associated with a surgical biopsy, thus biopsies are often deferred, and tumors of the brainstem are treated presumptively with radiation and temozolomide. However, in the presence of new targeted therapies, confirming pathology for these patients is becoming increasingly important. We present two cases of IDH-mutant grade 2 astrocytomas of the brainstem that revealed both clinical and radiographic responses to IDH-inhibitor therapy. Interestingly, both patients had the same non-canonical IDH mutation, IDH-R132C, towards which ivosedinib is known to have activity. One patient had tumor progression following radiation therapy and 8 cycles of temozolomide and had subsequently exhibited a dramatic radiographic improvement, including resolution of enhancing disease following initiation of ivosidenib therapy. Clinically, this patient improved from a KPS 50 to KPS 100 after 2.5 years of ivosedinib. The other patient also had an impressive clinical improvement after only 3 months of ivosedinib treatment, with radiographic stability, improvement in balance, and resolution of his previous refractory nausea. These case reports suggest that consideration should be given to brainstem biopsy in adults specifically to evaluate for the presence of a targetable IDH mutation.

Real-life effectiveness on overall survival of continued immune checkpoint inhibition following progression in advanced melanoma: estimation from the Melbase cohort.

The link between palliative care and oncology must continue to develop, taking into account advances in treatment.Immune checkpoint inhibition (ICI) for metastatic melanoma is associated with different types of response, making it difficult to assess the benefits to the patient. Some clinical trials suggest a survival advantage of ICI even in the absence of an objective radiographic response. The aim of this study is to assess the impact of continuing ICI after progression of the disease on the overall survival (OS) in a cohort of final-line metastatic melanoma patients. Clinical data from 120 patients with metastatic melanoma were collected via Melbase, a French multicentric biobank, prospectively enrolling unresectable melanoma. Two groups were defined: patients continuing final-line ICI at progression (treated) and patients stopping ICI at progression (controls). The primary end-point is the OS from progression. Propensity score weighting was used to correct for indication bias. From the 120 patients, 72 (60%) continued ICI. Median OS from progression was 4.2 months [95% confidence interval (CI) 2.6-6.27] in the treated group and median OS was 1.3 months (95% CI 0.95-1.74) in the control group (P < 0.0001). The calculated hazard ratio was 0.20 (0.13-0.33). Continued ICI was discovered to have an association with a higher rate of hospitalization at the end of life; more treatments received in the last 15 days of life and less utilization of specialist palliative care. This study discovered that patients with metastatic melanoma show a significant decrease in the instantaneous probability of mortality when they continue with finale-line ICI after progression.

Outcomes After Palliative Radiotherapy in Patients with Symptomatic Locoregionally Advanced Breast Cancer.

Symptomatic locoregionally advanced breast cancer (SLABC) can cause troublesome pain or wound complications that negatively impact quality of life. Although palliative radiotherapy (RT) can minimize tumor-related symptoms, how best to tailor RT to achieve the most meaningful and durable response is not well defined. This is a single-institution, multi-site retrospective review of patients with SLABC treated between 2016 and 2023 with palliative RT to symptomatic disease in the breast, chest wall, and/or regional lymph node basins. Overall survival (OS), locoregional control (LC), clinical and radiographic treatment response, overall pain scores, and treatment-related toxicities were analyzed. 164 patients with a median age of 57 years were analyzed with a median follow-up time of 4.97 months. 86% had distant metastases. The most common presenting symptom was pain (87%), followed by ulcerating or fungating lesion (76%) and discharge (45%). The median cumulative biologically effective dose to the gross tumor volume (BEDGTV) was 69 Gy. The 1-year OS and LC rates were 37% and 63%, respectively. Eighty-one percent experienced improvement in symptoms within 3 months after RT, the odds of which increased per Gy BEDGTV (OR 1.029, p=0.003). Acute toxicities were associated with number of fractions and BEDGTV (both p<.001), but not with concurrent systemic therapy nor reirradiation (both p>.05). Trends in pain scores showed a significant change in pain trajectory that was sustained during the first year after RT. OS and LC were not different among patients who received 1 vs 2-10 vs >10 fractions, and between ≤70 vs >70 Gy BEDGTV. In this large series of patients with SLABC, palliative RT was effective at relieving locoregional symptoms with acceptable toxicity, with the likelihood of symptom improvement associated with radiation dose. Survival of these patients remains poor, highlighting the importance of palliative care strategies that minimize overall symptom burden while maximizing quality of life.

Targeting ZNF638 activates antiviral immune responses and potentiates immune checkpoint inhibition in glioblastoma.

Viral mimicry refers to the activation of innate anti-viral immune responses due to the induction of endogenous retroelement (RE) expression. Viral mimicry has been previously described to augment anti-tumor immune responses and sensitize solid tumors to immunotherapy including colorectal cancer, melanoma, and clear renal cell carcinoma. Here, we found that targeting a novel, master epigenetic regulator, Zinc Finger Protein 638 (ZNF638), induces viral mimicry in glioblastoma (GBM) preclinical models and potentiates immune checkpoint inhibition (ICI). ZNF638 recruits the HUSH complex, which precipitates repressive H3K9me3 marks on endogenous REs. In GBM, ZNF638 is associated with marked locoregional immunosuppressive transcriptional signatures, reduced endogenous RE expression and poor immune cell infiltration (CD8 + T-cells, dendritic cells). ZNF638 knockdown decreased H3K9-trimethylation, increased cytosolic dsRNA and activated intracellular dsRNA-signaling cascades (RIG-I, MDA5 and IRF3). Furthermore, ZNF638 knockdown upregulated antiviral immune programs and significantly increased PD-L1 immune checkpoint expression in patient-derived GBM neurospheres and diverse murine models. Importantly, targeting ZNF638 sensitized mice to ICI in syngeneic murine orthotopic models through innate interferon signaling. This response was recapitulated in recurrent GBM (rGBM) samples with radiographic responses to checkpoint inhibition with widely increased expression of dsRNA, PD-L1 and perivascular CD8 cell infiltration, suggesting dsRNA-signaling may mediate response to immunotherapy. Finally, we showed that low ZNF638 expression was a biomarker of clinical response to ICI and improved survival in rGBM patients and melanoma patients. Our findings suggest that ZNF638 could serve as a target to potentiate immunotherapy in gliomas.

Afatinib plus bevacizumab combination after osimertinib resistance in advanced EGFR-mutant non-small cell lung cancer: Phase II ABCD-study

IntroductionMany clinical studies showed a synergy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) and vascular endothelial growth factor inhibitors. We hypothesized afatinib plus bevacizumab exerts clinical potency after developing various osimertinib resistant mechanisms. MethodsEGFR-mutant non-small cell lung cancer patients were enrolled after osimertinib resistance. Afatinib at 30–40 mg/day and bevacizumab at 15 mg/kg tri-weekly were administered until progression. Plasma/histologic rebiopsied samples after osimertinib failure were analyzed to examine resistant mechanisms: gene alterations/copy-number gain using cancer personalized profiling by deep sequencing. ResultsBetween January 2018 and October 2020, 28 patients were enrolled. Response and disease control rates were 17.9 % and 78.6 %, respectively. Median duration of response was 9.0 (range, 4.2–22.3) months. Median progression-free and overall survivals were 2.7 and 9.3 months, respectively. Twenty-eight (100 %) plasma and/or 21 (75 %) histologic rebiopsies identified: 17 (61 %) TP53; 15 (54 %) T790M; 9 (32 %) uncommon EGFR; 9 (32 %) MET; 6 (21 %) C797S; 3 (11 %) BRAF; 2 (7 %) HER2; 2 (7 %) KRAS; and 2 (7 %) PI3K mutations. One (17 %) of 6 C797S patients showed complete response. Three (33 %) of 9 uncommon EGFR-mutated patients achieved radiographic response. Neither 15 T790M-positive nor 6 EGFR downstream signaling mutations: BRAF; KRAS; or PI3K-positive patients responded, but 5 (38 %) of 13 T790M-negative patients responded. Adverse events ≥ grade 3 and incidence ≥ 5 % were: hypertension (29 %); proteinuria (7 %); and diarrhea (7 %). There were neither treatment-related death nor interstitial lung disease. ConclusionsSelected population could obtain clinical benefit from afatinib plus bevacizumab, based on rebiopsy results after osimertinib resistance.