Response Assessment In Neuro-Oncology Criteria Research Articles

RADT-43. RADIOSURGERY FOR BRAIN METASTASES FROM GYNECOLOGICAL PRIMARIES: AN INSTITUTIONAL PERSPECTIVE OF 58 METASTATIC LESIONS

Abstract Stereotactic radiosurgery (SRS) is being increasingly employed in the treatment of brain metastases. The evidence of radiological response of metastatic lesions from gynecological primary is lacking in literature. To assess the response rate of metastatic lesions to gamma knife SRS over a longitudinal follow-up period, a single centre prospectively maintained database was analysed retrospectively from 2014 to 2024. Lesion volumes were contoured at each follow up scan using Leksell Gammaplan software. Response assessment in neuro-oncology (RANO) criteria was used to assess radiological tumor response rates. Fifteen patients with 58 lesions were included. Average duration of radiological follow-up available was 16.7 months. The primary gynecological source of brain metastases in patients were cervical(n=4), ovarian(n=7), endometrial(n=3) and vulvar (n=1). Single fraction SRS was used for 49 lesions (range 16-20 Gy) and hypofractionated SRS for 9 lesions (8Gy x 3 to 9Gy x3). Average time to complete response was 9.01 months (range 1-25.7). The average follow-up for lesions with partial response was 12.2 months (range 1 -32) As per RANO criteria, complete response was seen in 33(56.9%) lesions and partial response in 25(43.1%). At 6month follow up, complete response was seen in 58.49% (n=31) of the lesions available(n=53) for assessment and partial response in 41.51%(n=22). At 18-months, complete response was seen in 66.67%(n=22) and partial response in 33.33%(n=11). Within pathological subgroups, endometrial (60%,n=3) primary showed higher rate of complete response at 6months than ovarian (52.7%,n=19), vulvar (50%, n=1) and cervical (40%,n=6) subgroups. Brain metastases from ovarian primary source were most encountered and endometrial metastases showed highest response rates to SRS. Six month and 18-month response rates were better than previously reported literature.

Non-secreting IL12 expressing oncolytic adenovirus Ad-TD-nsIL12 in recurrent high-grade glioma: a phase I trial

Malignant glioma is a highly fatal central nervous system malignancy with high recurrence rates. Oncolytic viruses offer potential treatment but need improvement in efficacy and safety. Here we describe a phase I, dose-escalating, single arm trial (ChiCTR2000032402) to study the safety of Ad-TD-nsIL12, an oncolytic adenovirus expressing non-secreting interleukin-12, in patients with recurrent high-grade glioma that connects with the ventricular system. Eight patients received intratumoral treatment via stereotaxis or an Ommaya reservoir, with doses ranging from 5 × 109 to 5 × 1010vp. The primary end point was to determine the maximal tolerated dose. Secondary endpoints included toxicity and anti-tumour ability. Minimal adverse events were observed at doses of 5 × 109 and 1 × 1010vp. Grade 3 seizure was observed in two patients from Cohort 3 (5 × 1010vp). Therefore, the maximum tolerated dose was determined to be 1 × 1010vp. Four patients developed hydrocephalus during follow-up. Among them, symptoms in two patients were relieved after placement of a ventriculo-peritoneal shunt, and the other two only showed ventriculomegaly on MRI scan without neurological deterioration. Complete response (according to Response Assessment in Neuro-Oncology Criteria) in one patient, a partial response in one patient and post-treatment infiltrations of CD4+ and CD8 + T cells into the tumour were documented during this trial. In conclusion, Ad-TD-nsIL12 has demonstrated safety and preliminary efficacy in patients with recurrent high-grade glioma.

Intraarterial Administration of Peptide Receptor Radionuclide Therapy in Patients with Advanced Meningioma: Initial Safety and Efficacy.

Peptide receptor radionuclide therapy (PRRT) is a treatment option for patients with advanced meningioma. Recently, intraarterial application of the radiolabeled somatostatin receptor agonists has been introduced as an alternative to standard intravenous administration. In this study, we assessed the safety and efficacy of intraarterial PRRT in patients with advanced, progressive meningioma. Methods: Patients with advanced, progressive meningioma underwent intraarterial PRRT with [177Lu]Lu-HA-DOTATATE. The safety of PRRT was evaluated according to the Common Terminology Criteria for Adverse Events version 5.0. Treatment response was assessed according to the proposed Response Assessment in Neuro-Oncology criteria for meningiomas and somatostatin receptor-directed PET/CT. Results: Thirteen patients (8 women, 5 men; mean age, 65 ± 13 y) with advanced meningioma underwent 1-4 cycles (median, 4 cycles) of intraarterial PRRT with [177Lu]Lu-HA-DOTATATE (mean activity per cycle, 7,428 ± 237 MBq; range, 6,000-7,700 MBq). Treatment was well tolerated with mainly grade 1-2 hematologic toxicity. Ten of 13 patients showed radiologic disease control at follow-up after therapy (1/10 complete remission, 1/10 partial remission, 8/10 stable disease), and 9 of 13 patients showed good control of clinical symptoms. Conclusion: Intraarterial PRRT in patients with advanced meningioma is feasible and safe. It may result in improved radiologic and clinical disease control compared with intravenous PRRT. Further research to validate these initial findings and to investigate long-term outcomes is highly warranted.

A First-in-Human Phase I Study of BXQ-350, a First-in-Class Sphingolipid Metabolism Regulator, in Patients with Advanced/Recurrent Solid Tumors or High-Grade Gliomas.

BXQ-350, a nanovesicle formulation of saposin C, is an allosteric sphingolipid metabolism regulator that increases proapoptotic ceramide and decreases oncogenic sphingosine-1-phosphate levels. We conducted a first-in-human phase I study of BXQ-350. Adults (≥18 years old) with advanced/recurrent, treatment-refractory solid tumors or high-grade gliomas received BXQ-350 intravenously in five dose cohorts (0.7-2.4 mg/kg) in a 3+3 dose escalation and expansion design. The primary endpoints during dose escalation were dose-limiting toxicities and maximum tolerated dose; the primary objective in expansion parts was assessment of antitumor activity (RECIST v1.1/Response Assessment in Neuro-Oncology criteria). Eighty-six patients were enrolled. Dose-limiting toxicities were not observed during dose escalation (n = 18), and a maximum tolerated dose was not identified. An additional 68 patients received the 2.4 mg/kg dose. Nine patients (10%) discontinued due to adverse events. The most common treatment-related adverse events were nausea (24%) and fatigue (23%). Eight patients had a progression-free survival of ≥6 months. Two of these achieved a partial response, and six had stable disease, among whom three had a reduction in ≥1 target lesion. Of those with progression-free survival of ≥6 months, seven remained on study for >12 months, five for >24 months, and after 7 years, two remained on study without disease progression. BXQ-350 was well-tolerated as monotherapy at doses up to 2.4 mg/kg. It provided some lasting clinical benefit in patients with recurrent solid malignancies across several tumor types, consistent with a decreased systemic sphingosine-1-phosphate/ceramide metabolic rheostat. BXQ-350 warrants further clinical investigation alone and combined with standard of care for advanced solid tumors.

FLAIR MRI sequence synthesis using squeeze attention generative model for reliable brain tumor segmentation

Manual segmentation of brain tumors using structural magnetic resonance imaging (MRI) is an arduous and time-consuming task. Therefore, automatic and robust segmentation will considerably influence neuro-oncological clinical trials by reducing excessive manual annotation time. Herein, we propose a deep learning model that automatically segments brain tumors even in cases of missing MRI sequences, which are common in practical clinical settings. To address this issue, we enhance a generative adversarial network (GAN) by incorporating a squeeze-and-excitation (SE) attention module into its generator and a PatchGAN into its discriminator. The SE module recalibrates channel responses by explicitly modeling interdependencies, enabling the network to focus on critical regions such as tumor areas. Our proposed generative model is optimized using a combination of adversarial, structural similarity, and mean absolute error losses to synthesize missing MRI sequences more effectively. This enhancement allows our model to synthesize the missing MRI sequence (fluid attenuated inversion recovery [FLAIR]) by leveraging information from other available sequences (T1-weighted, T2-weighted, or contrast-enhanced T1-weighted [T1ce]). For the segmentation task, we employ an optimized nnU-Net model, which is trained using existing sequences and evaluated using both available and synthesized sequences (including missing ones), mimicking real-world scenarios where often only limited MRI sequences are available or usable. Our findings reveal a notable enhancement in brain tumor segmentation, as indicated by a significant increase in overall the Dice similarity coefficient (DSC) from 0.688% (when FLAIR is missing) to 0.873% (when using synthesized FLAIR derived from T2). This improvement brings the segmentation performance closer to what was achieved when real FLAIR was available, where the DSC reaches 0.901%. Moreover, our synthesizing model was also tested on two additional datasets: the BraTS 2020 validation set and BraTS Africa 2023 training set, which produces results comparable to those of BraTS 2021, thereby proving its robustness and generalizability. In addition, the resulting tumor segmentations are subsequently employed to assess the response to treatment in cases where all sequences were available and when synthesis was employed, according to response assessment in neuro-oncology criteria.

MRI and 18F-FET PET for Multimodal Treatment Monitoring in Patients with Brain Metastases: A Cost-Effectiveness Analysis.

PET using the radiolabeled amino acid O-(2-[18F]fluoroethyl)-l-tyrosine (18F-FET) has been shown to be of value for treatment monitoring in patients with brain metastases after multimodal therapy, especially in clinical situations with equivocal MRI findings. As medical procedures must be justified socioeconomically, we determined the effectiveness and cost-effectiveness of 18F-FET PET for treatment monitoring of multimodal therapy, including checkpoint inhibitors, targeted therapies, radiotherapy, and combinations thereof in patients with brain metastases secondary to melanoma or non-small cell lung cancer. Methods: We analyzed already-published clinical data and calculated the associated costs from the German statutory health insurance system perspective. Two clinical scenarios were considered: decision tree model 1 determined the effectiveness of 18F-FET PET alone for identifying treatment-related changes, that is, the probability of correctly identifying patients with treatment-related changes confirmed by neuropathology or clinicoradiographically using the Response Assessment in Neuro-Oncology criteria for immunotherapy. The resulting cost-effectiveness ratio showed the cost for each correctly identified patient with treatment-related changes in whom MRI findings remained inconclusive. Decision tree model 2 calculated the effectiveness of both 18F-FET PET and MRI, that is, the probability of correctly identifying nonresponders to treatment. The incremental cost-effectiveness ratio was calculated to determine cost-effectiveness, that is, the cost for each additionally identified nonresponder by 18F-FET PET who would have remained undetected by MRI. One-way deterministic and probabilistic sensitivity analyses tested the robustness of the results. Results: 18F-FET PET identified 94% of patients with treatment-related changes, resulting in €1,664.23 (€1.00 = $1.08 at time of writing) for each correctly identified patient. Nonresponders were correctly identified in 60% by MRI and in 80% by 18F-FET PET, resulting in €3,292.67 and €3,915.83 for each correctly identified nonresponder by MRI and 18F-FET PET, respectively. The cost to correctly identify 1 additional nonresponder by 18F-FET PET, who would have remained unidentified by MRI, was €5,785.30. Conclusion: Given the considerable annual cost of multimodal therapy, the integration of 18F-FET PET can potentially improve patient care while reducing costs.

Abstract CT104: Results from a phase 1 study of the anti-immunoglobulin-like transcript 4 (ILT4) monoclonal antibody MK-4830 plus pembrolizumab in patients with previously treated advanced solid tumors

Abstract Background: In the dose escalation phase of a first-in-human phase 1 study (NCT03564691), the anti-ILT4 IgG4 monoclonal antibody MK-4830 + pembrolizumab (pembro) had a manageable safety profile and demonstrated promising antitumor activity in patients (pts) with previously treated advanced solid tumors, including those with PD on immunotherapy. Here, we present safety, efficacy, and biomarker analyses for MK-4830 + pembro for the previously treated pancreatic adenocarcinoma, glioblastoma, head and neck squamous cell carcinoma (HNSCC), and gastric cancer cohorts of the expansion phase. Methods: Eligible pts were aged ≥18 y with metastatic pancreatic adenocarcinoma and 1-3 lines of prior therapy (cohort A), unresectable glioblastoma and 1 prior line of therapy (cohort B), recurrent or metastatic HNSCC that progressed on a platinum-based chemotherapy and PD-(L)1 inhibitor (cohort C), or recurrent or metastatic gastric or gastroesophageal junction adenocarcinoma that progressed on ≥2 prior chemotherapy regimens (cohort I). Pts in cohorts A, B, and I had not previously received a PD-(L)1 inhibitor. All pts received MK-4830 800 mg + pembro 200 mg Q3W for 35 cycles or until PD, unacceptable toxicity, or study withdrawal. Primary objectives were to evaluate safety and ORR per RECIST v1.1 (cohorts A, C, and I) or Response Assessment in Neuro-Oncology (RANO) criteria (cohort B) by investigator assessment. Exploratory objectives included evaluating DOR and PFS per RECIST v1.1 (cohorts A, C, and I) or RANO criteria (cohort B) by investigator assessment. Results: At data cut-off (September 27, 2023), 33 pts were enrolled and received treatment in cohort A, 20 pts in cohort B, 35 pts in cohort C, and 35 pts in cohort I. Median follow-up duration was 38.4 mo (range, 35.5-39.9) in cohort A, 34.1 mo (32.3-36.2) in cohort B, 37.5 mo (33.4-42.1) in cohort C, and 29.5 mo (22.3-36.4) in cohort I. Treatment-related adverse events (TRAEs) occurred in 15 pts (45%) in cohort A, 13 pts (65%) in cohort B, 19 pts (54%) in cohort C, and 16 pts (46%) in cohort I; grade 3 or 4 TRAEs occurred in 3 pts (9%), 0 pts, 2 pts (6%), and 4 pts (11%), respectively. No deaths due to TRAEs occurred. ORR was 6% (95% CI, 1-20) in cohort A, 5% (0-25) in cohort B, 0% (0-10) in cohort C, and 20% (8-37) in cohort I. Median DOR was 14.3 mo (range, 14.0-14.7) in cohort A, 7.4 mo (7.4-7.4) in cohort B, and 9.6 mo (3.0-27.6+) in cohort I. Median PFS was 1.9 mo (95% CI, 1.6-2.0) in cohort A, 1.2 mo (1.1-1.4) in cohort B, 2.2 mo (1.9-4.1) in cohort C, and 1.4 mo (1.3-3.0) in cohort I. Conclusions: In pts with select previously treated advanced or metastatic solid tumors, MK-4830 + pembro had a manageable AE profile but no significant antitumor activity beyond that historically observed with pembro monotherapy. Other treatment options must be explored for these difficult-to-treat tumors. Citation Format: Lillian L. Siu, Marta Gil-Martin, Byoung Chul Cho, Ruth Perets, John Hilton, Ravit Geva, Iwona Lugowska, Martin Gutierrez, Marcelo Bonomi, Rafal Dziadziuszko, Drew Rasco, Eytan Ben-Ami, Cristina P. Rodriguez, Shabana Siddiqi, Nicole Myer, Leah Suttner, Douglas Wilson, Ombololaji O. Akala, Maria de Miguel. Results from a phase 1 study of the anti-immunoglobulin-like transcript 4 (ILT4) monoclonal antibody MK-4830 plus pembrolizumab in patients with previously treated advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT104.

Ga68] DOTATATE PET/MRI-guided radiosurgical treatment planning and response assessment in meningiomas.

Our purpose was to determine the utility of [68Ga]-DOTATATE PET/MRI in meningioma response assessment following radiosurgery. Patients with meningioma prospectively underwent postoperative DOTATATE PET/MRI. Co-registered PET and gadolinium-enhanced T1-weighted MRI were employed for radiosurgery planning. Follow-up DOTATATE PET/MRI was performed at 6-12 months post-radiosurgery. Maximum absolute standardized uptake value (SUV) and SUV ratio (SUVRSSS) referencing superior sagittal sinus (SSS) blood pool were obtained. Size change was determined by Response Assessment in Neuro-Oncology (RANO) criteria. Association of SUVRSSS change magnitude and progression-free survival (PFS) was evaluated using Cox regression. Twenty-seven patients with 64 tumors (26% World Health Organization [WHO]-1, 41% WHO-2, 26% WHO-3, and 7% WHO-unknown) were prospectively followed post stereotactic radiosurgery (SRS) or stereotactic body radiotherapy (SBRT; mean dose: 30 Gy, modal dose 35 Gy, mean of 5 fractions). Post-irradiation SUV and SUVRSSS decreased by 37.4% and 44.4%, respectively (P < .0001). Size product decreased by 8.9%, thus failing to reach the 25% significance threshold as determined by RANO guidelines. Mean follow-up time was 26 months (range: 6-44). Overall mean PFS was 83% and 100%/100%/54% in WHO-1/-2/-3 subcohorts, respectively, at 34 months. At maximum follow-up (42-44 months), PFS was 100%/83%/54% in WHO-1/-2/-3 subcohorts, respectively. Cox regression analyses revealed a hazard ratio of 0.48 for 10-unit reduction in SUVRSSS in the SRS cohort. DOTATATE PET SUV and SUVRSSS demonstrated marked, significant decrease post-radiosurgery. Lesion size decrease was statistically significant; however, it was not clinically significant by RANO criteria. DOTATATE PET/MR thus represents a promising imaging biomarker for response assessment in meningiomas treated with radiosurgery. NCT04081701.

Abstract 6199: Defining and capturing progression in glioma by harnessing NLP in unstructured electronic health records

Abstract Gliomas exhibit nearly uniform recurrence and poor prognosis. Management of high-grade tumors is surgery followed by chemoirradiation (CRT). Radiographic progression is assessed using contrast-enhanced MRI with reporting captured in Electronic Health Records (EHR). The ability to harness large scale EHR data is limited by the Response Assessment in Neuro-Oncology (RANO) tumor progression criteria, which defines progression as an aggregate of clinical and/or radiographic parameters requiring clinician judgement. As a result, glioma progression is not captured systematically in large data sets, limiting Progression Free Survival (PFS) as an outcome endpoint in data analysis. We developed an AI-based method using natural language processing to capture PFS parameters for analysis of MRI radiology reports. 1088 available brain MRI radiology reports for 81 patients with a pathologically confirmed diagnosis of glioblastoma (GBM) were aggregated in the NIH Integrated Data Analysis Platform. MRI reports were systematically analyzed and PFS manually captured using RANO criteria as ground truth. Common report terms indicating progression were compiled and included in task prompts applied to Large Language Model (LLM) Extraction Tools. The words progression (n=1047) and stable (n=1133) did not necessarily indicate either overall progression or stability in a report. Yet, in the 24 (30%) patients who progressed within 3 months of CRT, recurrence and mass effect occurred in 3.7% and 53% of reports, respectively, which was comparable to the term frequencies of 5.8% and 54% in patients with stable disease. Thus, mass effect and recurrence could not necessarily be used alone as terms to signal overall progression. The analysis identified other commonly employed radiology report terms relevant to determining tumor progression including enhancement (n=2445), perfusion (n=2085), enhancing (n=1785), resection (n=1576), and increased (n=1331), which allowed for experimentation with more detailed LLM extraction task prompts. Our method flagged radiographic progression prior to clinician-coded progression in 43 (53%) patients. Future directions include handling further clinical context such as surgical features, radiation therapy dates, progress notes, and the coadministration of agents such as bevacizumab and steroids. These results indicate the feasibility of LLMs to identify tumor progression dates using EHR text with potential transferability to large glioma data sets pending further optimization and validation. Citation Format: Shreya Chappidi, Hawon Lee, Sarisha Jagasia, Casey Syal, George Zaki, Dylan Junkin, Nathan Golightly, Patrick Chitwood, Kevin Camphausen, Andra Krauze. Defining and capturing progression in glioma by harnessing NLP in unstructured electronic health records [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6199.

Intrathecal bivalent CAR T cells targeting EGFR and IL13Rα2 in recurrent glioblastoma: phase 1 trial interim results.

Recurrent glioblastoma (rGBM) remains a major unmet medical need, with a median overall survival of less than 1 year. Here we report the first six patients with rGBM treated in a phase 1 trial of intrathecally delivered bivalent chimeric antigen receptor (CAR) T cells targeting epidermal growth factor receptor (EGFR) and interleukin-13 receptor alpha 2 (IL13Rα2). The study's primary endpoints were safety and determination of the maximum tolerated dose. Secondary endpoints reported in this interim analysis include the frequency of manufacturing failures and objective radiographic response (ORR) according to modified Response Assessment in Neuro-Oncology criteria. All six patients had progressive, multifocal disease at the time of treatment. In both dose level 1 (1 ×107 cells; n = 3) and dose level 2 (2.5 × 107 cells; n = 3), administration of CART-EGFR-IL13Rα2 cells was associated with early-onset neurotoxicity, most consistent with immune effector cell-associated neurotoxicity syndrome (ICANS), and managed with high-dose dexamethasone and anakinra (anti-IL1R). One patient in dose level 2 experienced a dose-limiting toxicity (grade 3 anorexia, generalized muscle weakness and fatigue). Reductions in enhancement and tumor size at early magnetic resonance imaging timepoints were observed in all six patients; however, none met criteria for ORR. In exploratory endpoint analyses, substantial CAR T cell abundance and cytokine release in the cerebrospinal fluid were detected in all six patients. Taken together, these first-in-human data demonstrate the preliminary safety and bioactivity of CART-EGFR-IL13Rα2 cells in rGBM. An encouraging early efficacy signal was also detected and requires confirmation with additional patients and longer follow-up time. ClinicalTrials.gov identifier: NCT05168423 .

Selective DRD2 antagonist and ClpP agonist ONC201 in a recurrent non-midline H3 K27M-mutant glioma cohort.

Diffuse midline glioma, H3 K27-altered (H3 K27M-altered DMG) are invariably lethal, disproportionately affecting the young and without effective treatment besides radiotherapy. The 2016 World Health Organization (WHO) Central Nervous System (CNS) Tumors Classification defined H3 K27M mutations as pathognomonic but restricted diagnosis to diffuse gliomas involving midline structures by 2018. Dordaviprone (ONC201) is an oral investigational small molecule, DRD2 antagonist, and ClpP agonist associated with durable responses in recurrent H3 K27M-mutant DMG. Activity of ONC201 in non-midline H3 K27M-mutant diffuse gliomas has not been reported. Patients with recurrent non-midline H3 K27M-mutant diffuse gliomas treated with ONC201 were enrolled in 5 trials. Eligibility included measurable disease by Response Assessment in Neuro-Oncology (RANO) high-grade glioma, Karnofsky/Lansky performance score ≥60, and ≥90 days from radiation. The primary endpoint was overall response rate (ORR). Five patients with cerebral gliomas (3 frontal, 1 temporal, and 1 parietal) met inclusion. One complete and one partial response were reported by investigators. Blinded independent central review confirmed ORR by RANO criteria for 2, however, 1 deemed nonmeasurable and another stable. A responding patient also noted improved mobility and alertness. H3 K27M-mutant diffuse gliomas occasionally occur in non-midline cerebrum. ONC201 exhibits activity in H3 K27M-mutant gliomas irrespective of CNS location.

Evolution of RANO in Assessing Brain Tumour Outcomes.

Assessing treatment response is extremely important in management of brain tumours. Response assessment in neuro-oncology (RANO) was introduced in 2008 for the purpose of making recommendations for it by addressing and countering the limitations in previously reported response criteriae. Subsequently, multiple RANO working groups have been formed to cater to different tumour types and to update their previous recommendations to counter the limitations in their criteria. Herein we have a summarized list of RANO criteria for adult brain tumours.

Olaparib in recurrent isocitrate dehydrogenase mutant high-grade glioma: A phase 2 multicenter study of the POLA Network

Abstract Background Based on preclinical studies showing that IDH-mutant (IDHm) gliomas could be vulnerable to PARP inhibition we launched a multicenter phase 2 study to test the efficacy of olaparib monotherapy in this population. Methods Adults with recurrent IDHm high-grade gliomas (HGGs) after radiotherapy and at least one line of alkylating chemotherapy were enrolled. The primary endpoint was a 6-month progression-free survival rate (PFS-6) according to response assessment in neuro-oncology criteria. Pre-defined threshold for study success was a PFS-6 of at least 50%. Results Thirty-five patients with recurrent IDHm HGGs were enrolled, 77% at ≥ 2nd recurrence. Median time since diagnosis and radiotherapy were 7.5 years and 33 months, respectively. PFS-6 was 31.4% (95% CI [16.9; 49.3%]). Two patients (6%) had an objective response and 14 patients (40%) had a stable disease as their best response. Median PFS and median overall survival were 2.05 and 15.9 months, respectively. Oligodendrogliomas (1p/19q codeleted) had a higher PFS-6 (53.4% vs. 15.7%, P = .05) than astrocytomas while an initial diagnosis of grade 4 astrocytoma tended to be associated with a lower PFS-6 compared to grade 2/3 gliomas (0% vs 31.4%, P = .16). A grade 2 or 3 treatment-related adverse event was observed in 15 patients (43%) and 5 patients (14%), respectively. No patient definitively discontinued treatment due to side effects. Conclusions Although it did not meet its primary endpoint, the present study shows that in this heavily pretreated population, olaparib monotherapy was well tolerated and resulted in some activity, supporting further PARP inhibitors evaluation in IDHm HGGs, especially in oligodendrogliomas.

A phase 1 dose escalation of pritumumab in patients with refractory or recurrent gliomas or brain metastases.

This phase 1 (NCT04396717) open-label, multicenter study, evaluated Pritumumab, a IgG1 monoclonal antibody, in patients with gliomas and brain metastases. The primary objective was to evaluate the safety and/or tolerability and to identify a recommended phase 2 dose (RP2D) of Pritumumab. Adult patients with recurrent gliomas or brain metastases were enrolled in the dose cohort that was open at the time of their consent. Study treatment consisted of pritumumab administered intravenously weekly on days 1, 8, 15, and 22 in 28-day cycles. Safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity were evaluated. Fifteen patients received Pritumumab in the recurrent setting. Pritumumab was well tolerated, with no serious adverse events related to Pritumumab reported. The most common drug-related toxicities were constipation and fatigue. There were no dose-limiting toxicities observed, and a maximum tolerable dose was not reached. Thus, the maximum feasible dose and recommended phase 2 dose of Pritumumab was established at 16.2 mg/kg weekly. Out of eleven patients evaluated for efficacy, one patient (9.1%) demonstrated partial response based on response assessment in neuro-oncology criteria, and disease stabilization was seen in 3 patients (27.3%). Pritumumab was well tolerated with no DLTs observed up to 16.2 mg/kg weekly. Further studies are warranted to determine clinical benefit in patients.

A phase I dose-escalation study of pulsatile afatinib in patients with recurrent or progressive brain cancer.

Afatinib (BIBW2992; Gilotrif®) is a selective and irreversible inhibitor of the epidermal growth factor receptor (ErbB; EGFR) family. It inhibits EGFR, HER2, and HER4 phosphorylation, resulting in tumor growth inhibition and regression. This phase I dose-escalation trial of pulsatile afatinib examined the safety, drug penetration into the central nervous system, preliminary antitumor activity, and recommended phase II dose in patients with progressive or recurrent brain cancers. Afatinib was taken orally once every 4 days or once every 7 days depending on dose cohort, until disease progression or unacceptable toxicity. A total of 24 patients received the investigational agent and were evaluable for safety analyses, and 21 patients were evaluable for efficacy. Dosing was administered at 80mg every 4 days, 120mg every 4 days, 180mg every 4 days, or 280mg every 7 days. A recommended phase II dose of pulsatile afatinib was established at 280mg every 7 days as there were no dose-limiting toxicities in any of the dosing cohorts and all toxicities were deemed manageable. The most common drug-related toxicities were diarrhea, rash, nausea, vomiting, fatigue, stomatitis, pruritus, and limb edema. Out of the 21 patients evaluable for efficacy, 2 patients (9.5%) exhibited partial response based on Response Assessment in Neuro-Oncology criteria and disease stabilization was seen in 3 patients (14.3%). Afatinib taken orally was safe and well-tolerated up to 280mg every 7 days in brain cancer patients.

Assessment of the clinical effectiveness and safety of immune checkpoint inhibitors for glioblastoma: A systematic review

Glioblastoma (GBM) is a malignant primary brain tumor which is commonly found in humans. Conventional therapeutic approaches for GBM offer only a short median overall survival (MOS), thereby accentuating its poor clinical outcome. Despite the promising potential shown by use of immune checkpoint inhibitor (ICI) in animal models to treat GBM, human trials result remains inconclusive. This systematic review evaluated the safety and clinical efficacy of ICIs in GBM patients. A literature search from Embase and MEDLINE (Ovid) was completed in October 2023. A total of 10 suitable articles, which encompass 168 patients (164 recurrent and 4 newly-diagnosed GBM), are taken into account. 3 studies assessed the OS, 7 studies assessed the PFS and/or response assessment in neuro-oncology (RANO) criteria and 8 studies assessed the safety, tolerability and/or adverse events. These studies show that the range of MOS of ICI treatments was between 2.6-10.4 months (MOS using current standard treatment for recurrent GBM = 3.5-12.5 months). The median PFS and the median period until patients reach partial response score based on RANO criteria are ranging from 1.5 months to 4.6 months (PFS using current standard treatment is 5.5 months). In conclusion, ICIs are safe in patients with GBM. Reported adverse effects only include mild fatigue, headache, hyperglycemia, and diarrhea. However, ICIs display suboptimal clinical efficacy compared to conventional GBM treatments. Therefore, further research is needed in order to improve the clinical efficacy of ICIs.

NIMG-74. COMPARING VOLUMETRIC GROWTH-RATE AND RANO CRITERIA IN DETERMINING THE RESPONSE OF MENINGIOMA TO BEVACIZUMAB THERAPY

Abstract Meningioma is the most prevalent primary tumor in the central nervous system (CNS). Although mostly benign, 15- 20% are aggressive and tend to recur and progress despite surgery and adjuvant radiation. Recent publications show that bevacizumab, a vascular endothelial growth factor inhibitor, effectively treats these refractory meningiomas. The standard method to monitor treatment’s effect on imaging is Response Assessment in Neuro-Oncology criteria (RANO). Recently, an alternative tool called 3D volumetric growth rate (3DVGR) has emerged. Our aim is to compare the effectiveness of conventional RANO criteria and the 3DVGR measure in evaluating the response to bevacizumab treatment in patients with refractory meningiomas. We will also assess their correlation with clinical outcomes over a period of up to 9 months. 68 MRI scans of 20 patients with aggressive meningiomas treated with bevacizumab were evaluated. For each tumor both RANO and 3DVGR were conducted in two subsequent head MRI studies acquired prior to the initiation of bevacizumab treatment and then in at least one exam within 6 months post-treatment. Measurements were obtained using PACS and BRAIN LAB software by two radiologists. A total of 43 lesions derived from 20 patients were included in the analysis. The mean age was 65.5; mean number of radiation treatments was 2.66; mean number of pre-surgical treatments was 2.7 and mean number of bevacizumab cycles was 22.7. All lesions showed a decrease or stabilization in growth rate compared to baseline. More specifically, 34 out of 43 lesions (79%) showed a negative growth rate value indicating decrease in tumor size. Comparison of treatment response using RANO criteria was not always in concordance with the 3DVGR measurement and showed inaccurate correlation with clinical outcome. 3DVGR measure seems to be more precise compared to RANO criteria. Furthermore, our results show great promise for treatment of refractory meningiomas with bevacizumab.

Incidence and outcome of pseudoprogression after radiation therapy in glioblastoma patients: A cohort study.

Differentiating post-radiation MRI changes from progressive disease (PD) in glioblastoma (GBM) patients represents a major challenge. The clinical problem is two-sided; avoid termination of effective therapy in case of pseudoprogression (PsP) and continuation of ineffective therapy in case of PD. We retrospectively assessed the incidence, management, and prognostic impact of PsP and analyzed factors associated with PsP in a GBM patient cohort. Consecutive GBM patients diagnosed in the South-Eastern Norway Health Region from 2015 to 2018 who had received RT and follow-up MRI were included. Tumor, patient, and treatment characteristics were analyzed in relationship to re-evaluated MRI examinations at 3 and 6 months post-radiation using Response Assessment in Neuro-Oncology criteria. A total of 284 patients were included in the study. PsP incidence 3 and 6 months post-radiation was 19.4% and 7.0%, respectively. In adjusted analyses, methylated O6-methylguanine-DNA methyltransferase (MGMT) promoter and the absence of neurological deterioration were associated with PsP at both 3 (p < .001 and p = .029, respectively) and 6 months (p = .045 and p = .034, respectively) post-radiation. For patients retrospectively assessed as PD 3 months post-radiation, there was no survival benefit of treatment change (p = .838). PsP incidence was similar to previous reports. In addition to the previously described correlation of methylated MGMT promoter with PsP, we also found that absence of neurological deterioration significantly correlated with PsP. Continuation of temozolomide courses did not seem to compromise survival for patients with PD at 3 months post-radiation; therefore, we recommend continuing adjuvant temozolomide courses in case of inconclusive MRI findings.

RANO 2.0: Update to the Response Assessment in Neuro-Oncology Criteria for High- and Low-Grade Gliomas in Adults.

The Response Assessment in Neuro-Oncology (RANO) criteria for high-grade gliomas (RANO-HGG) and low-grade gliomas (RANO-LGG) were developed to improve reliability of response assessment in glioma trials. Over time, some limitations of these criteria were identified, and challenges emerged regarding integrating features of the modified RANO (mRANO) or the immunotherapy RANO (iRANO) criteria. Informed by data from studies evaluating the different criteria, updates to the RANO criteria are proposed (RANO 2.0). We recommend a standard set of criteria for both high- and low-grade gliomas, to be used for all trials regardless of the treatment modalities being evaluated. In the newly diagnosed setting, the postradiotherapy magnetic resonance imaging (MRI), rather than the postsurgical MRI, will be used as the baseline for comparison with subsequent scans. Since the incidence of pseudoprogression is high in the 12 weeks after radiotherapy, continuation of treatment and confirmation of progression during this period with a repeat MRI, or histopathologic evidence of unequivocal recurrent tumor, are required to define tumor progression. However, confirmation scans are not mandatory after this period nor for the evaluation of treatment for recurrent tumors. For treatments with a high likelihood of pseudoprogression, mandatory confirmation of progression with a repeat MRI is highly recommended. The primary measurement remains the maximum cross-sectional area of tumor (two-dimensional) but volumetric measurements are an option. For IDH wild-type glioblastoma, the nonenhancing disease will no longer be evaluated except when assessing response to antiangiogenic agents. In IDH-mutated tumors with a significant nonenhancing component, clinical trials may require evaluating both the enhancing and nonenhancing tumor components for response assessment. The revised RANO 2.0 criteria refine response assessment in gliomas.

Dabrafenib plus Trametinib in Pediatric Glioma with BRAF V600 Mutations

BackgroundDetection of the BRAF V600E mutation in pediatric low-grade glioma has been associated with a lower response to standard chemotherapy. In previous trials, dabrafenib (both as monotherapy and in combination with trametinib) has shown efficacy in recurrent pediatric low-grade glioma with BRAF V600 mutations, findings that warrant further evaluation of this combination as first-line therapy.MethodsIn this phase 2 trial, patients with pediatric low-grade glioma with BRAF V600 mutations who were scheduled to receive first-line therapy were randomly assigned in a 2:1 ratio to receive dabrafenib plus trametinib or standard chemotherapy (carboplatin plus vincristine). The primary outcome was the independently assessed overall response (complete or partial response) according to the Response Assessment in Neuro-Oncology criteria. Also assessed were the clinical benefit (complete or partial response or stable disease for ≥24 weeks) and progression-free survival.ResultsA total of 110 patients underwent randomization (73 to receive dabrafenib plus trametinib and 37 to receive standard chemotherapy). At a median follow-up of 18.9 months, an overall response occurred in 47% of the patients treated with dabrafenib plus trametinib and in 11% of those treated with chemotherapy (risk ratio, 4.31; 95% confidence interval [CI], 1.7 to 11.2; P<0.001). Clinical benefit was observed in 86% of the patients receiving dabrafenib plus trametinib and in 46% receiving chemotherapy (risk ratio, 1.88; 95% CI, 1.3 to 2.7). The median progression-free survival was significantly longer with dabrafenib plus trametinib than with chemotherapy (20.1 months vs. 7.4 months; hazard ratio, 0.31; 95% CI, 0.17 to 0.55; P<0.001). Grade 3 or higher adverse events occurred in 47% of the patients receiving dabrafenib plus trametinib and in 94% of those receiving chemotherapy.ConclusionsAmong pediatric patients with low-grade glioma with BRAF V600 mutations, dabrafenib plus trametinib resulted in significantly more responses, longer progression-free survival, and a better safety profile than standard chemotherapy as first-line therapy. (Funded by Novartis; ClinicalTrials.gov number, NCT02684058.)