bluuebunny/crossref_metadata_2025 huggingface dataset:
RADT-16. CLINICAL OUTCOMES FOR HIGH RISK WHO GRADE II GLIOMA PATIENTS TREATED WITH UPFRONT TMZ-BASED CHEMORADIOTHERAPY
Authors: Zarabi Hosniya , Wicks Robert , Russel Gregory , Banderage Dineth , Strowd Roy , Mott Ryan , Laxton Adrian , Tatter Stephen , White Jaclyn , Lo Hui-Wen , Debinski Waldemar , Chan Michael , Lesser Glenn , Cramer Christina
Published: November 2022

OBJECTIVE

RTOG 9802 demonstrated improved survival using chemoradiotherapy (CRT) over radiotherapy (RT) alone for WHO Grade II gliomas (LGG) using PCV with RT. We analyze our retrospective dataset of predominantly temozolomide (TMZ)-based CRT in LGG patients who would have been eligible for RTOG 9802.

METHODS

Retrospective review of LGG patients (2000–2017) treated at a single institution (67 patients). Histologies included oligodendroglioma(OD), astrocytoma(AC) or astrocytoma (OA). Those who received upfront RT +/- chemotherapy were included. The CRT cohort (n=40) consisted primarily of TMZ (n=36) administered concurrently with RT. 27 patients received RT alone. RT for both cohorts consisted of a median dose of 54 Gy (range 50.4 - 54 Gy). 65/67 patients had “high risk” LGG as defined by RTOG 9802 criteria. Kaplan Meier analysis was used to assess overall survival (OS) and progression free survival (PFS).

RESULTS

5-year PFS for patients receiving CRT was 64% vs. 44% in those receiving RT alone (log rank p=0.009). Difference in PFS due to chemotherapy was driven by AC histology (57% vs. 21% PFS at 5 years, log rank p=0.002) while OD/OA PFS was not statistically altered (79% vs. 72% PFS at 5 years, p=0.21). 5-year OS for patients receiving CRT was 76% vs. 69% in those receiving RT alone (p=0.11). Cox Proportional Hazards analysis showed that use of upfront CRT (HR=0.4, p=0.009) was the only factor that decreased the risk of earlier progression.

CONCLUSION

Use of upfront, predominantly TMZ-based CRT, has a PFS benefit over RT alone in a population of WHO grade II gliomas. This benefit appears to be driven by AC histology and also appears to extend beyond the “very high risk” cohort from RTOG 0424 to include the “high risk” group from RTOG 9802.
RADT-18. PARTICLE BEAM RADIATION THERAPY PLUS TUMOR TREATING FIELDS IN THE TREATMENT OF NEWLY DIAGNOSED WHO GRADE 4 GLIOMAS: AN EARLY RESULT OF PHASE 2 SINGLE-ARM TRIAL
Authors: Qiu Xianxin , Gao Jing , Yang Jing , Hu Jiyi , Hu Weixu , Huang Qingting , Zhang Haojiong , Kong Lin , Lu Jiade
Published: November 2022

OBJECTIVES

Tumor Treating Fields (TTFields) is increasingly provided to patients with WHO grade 4 gliomas following radiotherapy. Particle beam radiotherapy (PBRT) represents a novel promising radiation approach with improved therapeutic ratio. This study was aimed to report an early result of TTFields in combination with PBRT for treating WHO grade 4 gliomas based on a prospective phase 2 trial from Shanghai Proton and Heavy Ion Center.

METHODS

This phase 2 trial was designed as a single-arm study to test the outcome of PBRT plus TTFields. Six patients with newly diagnosed WHO grade 4 gliomas receiving surgery, PBRT, temozolomide, and TTFields, from August 2021 to May 2022, were enrolled and analyzed. Tumor histologies based on the WHO CNS5 classification system were IDH-wild glioblastoma (n=4), IDH-mutant astrocytoma (n=1), and H3G34-mutant diffuse hemispheric glioma (n=1). For PBRT, all patients were irradiated with a baseline standard dose of 60GyE/30 utilizing proton. Carbon-ion boost of 15GyE/3 for tumor residual was performed for one patient prior to proton radiation. TTFields treatment was recommended to start soon after PBRT.

RESULTS

With a median follow-up of 5.5 months, all patients were alive at the time of this analysis; one patient with left thalamic glioblastoma had tumor progression of distant failure outside the radiation field at 4 months after partial tumor resection. The median interval between PBRT and TTFields was 2 days (range 1-22 days). No patient had dermatitis during PBRT. No severe TTField-related skin toxicity (Grade 3 or above) was observed. Five patients (83.3%, 5/6) developed mild skin toxicities (Grade 1) during TTField treatments.

CONCLUSIONS

Starting TTField early following PBRT is feasible for treating WHO grade 4 gliomas, the overall side effects are mild. Prospective studies with further follow-up are warranted to identify the outcomes of PBRT in combination with TTField in terms of survival and side effects.
RADT-21. PATTERNS OF CARE AND OUTCOMES IN PEDIATRIC HIGH-GRADE GLIOMA PATIENTS ENROLLED IN THE PEDIATRIC PROTON/PHOTON CONSORTIUM REGISTRY
Authors: Schramski Anna , Yock Torunn I , Hill-Kayser Christine , Indelicato Daniel J , Paulino Arnold C , Hartsell William , Ermoian Ralph , Mangona Victor , Kwok Young , MacEwan Iain , Wolden Suzanne , DeNunzio Nicholas , Shin Brion , Goyal Subir , Eaton Bree
Published: November 2022

BACKGROUND

Proton therapy (PRT) is increasingly utilized for pediatric brain tumors to reduce radiation associated treatment effects, but there is a lack of data evaluating PRT in pediatric high-grade glioma (pHGG). The purpose of this analysis is to report patterns of care and clinical outcomes for pHGG patients treated with PRT and enrolled in the prospective Pediatric Proton/Photon Consortium Registry (PPCR).

METHODS

Fifty-five pHGG participants treated with PRT were enrolled in the PPCR between Jan 2013 and Aug 2020. Progression free (PFS) and overall survival (OS) rates were calculated according to the Kaplan-Meier method. Univariate analyses were performed using Cox proportional hazards model with Firth’s penalization.

RESULTS

Among 49 patients with complete data, the median age was 12, the majority of patients were male (29), white (35), and non-Hispanic/Latino (41). Histology was grade IV (37), grade III (10) or HGG not specified (8). Resection was gross-total (24), near-total (4), or sub-total/biopsy (17). Six patients received prior RT. The median RT dose was 57.6 Gy (RBE) starting a median of 33.5 days after surgery. 39 patients received chemotherapy. The most common acute treatment toxicities were alopecia (36), fatigue (34), radiation dermatitis (22), nausea/vomiting (19), and headache (19). Median follow-up was 3.14 years (95% CI 1.62-3.97). At 3 years, PFS (95% CI) was 35.5% (20.8-50.6%) and OS was 55.6% (38-70%). Median PFS and OS are 1.6 (1.2-3.1) and 3.6 (1.6-NA) years, respectively. Higher radiation dose was associated with greater PFS (HR 0.97 (0.94-1.01), p=0.059) and OS (HR 0.95 (0.93-0.99), p=0.006). Patients ≤ 3 years at diagnosis (n=8) had 3-year PFS/OS of 72.9%/87.5% vs. 27.8%/49.4% for older patients (p=0.068/0.089, respectively).

CONCLUSION

These are the first published data with PRT for pHGG. Clinical outcomes are comparable to historical data with photon therapy. Additional analysis of treatment associated toxicity and patient quality-of-life are warranted.
RADT-27. FRACTIONATED RADIOTHERAPY AS FIRST-LINE TREATMENT FOR INTRACRANIAL MENINGIOMAS
Authors: Wang Justin , Landry Alexander , Nassiri Farshad , Lee Grace , Rogers Lauren , Zuccato Jeffrey , Voisin Mathew , Munoz David , Tsang Derek , Laperriere Normand , Zadeh Gelareh
Published: November 2022

BACKGROUND

Meningiomas are the most common primary brain tumour, and patients requiring intervention typically undergo surgical resection as first-line therapy. However, fractionated radiotherapy (fRT) as primary treatment remains an option for patients with larger tumours and surgical contraindications, although outcome prediction in this group remains uncertain. We aimed to assess the clinical factors that contribute to treatment failure in a cohort of meningiomas treated with fRT as first-line therapy.

METHODS

Patients treated with primary fRT for intracranial meningiomas at our institution from November 1, 1998 to December 30, 2017 were reviewed. Those who received upfront surgical resection, radiosurgery, or had less than 6 months of clinical follow up were excluded. We applied logistic regression and Cox regression analysis to ascertain key predictors of treatment failure, progression-free survival (PFS), and adverse events following radiotherapy.

RESULTS

Our cohort included 147 tumours, of which 25 progressed after fRT (median PFS of 3.45 years). Tumours that progressed following RT had a larger median gross tumour volume (GTV) than those that did not (32.3cm3 vs 20.2cm3,p = 0.03768). Pre-RT GTV greater than 11.27cm3 was independently predictive of treatment failure. Larger pre-RT GTV was also associated with significant (grade 3/4) adverse events following fRT. Finally, cerebellopontine angle meningiomas were more prevalent in the group that progressed (20% vs 3.3%, p = 0.0046), whereas cavernous sinus and optic nerve sheath meningiomas had longer PFS (p = 0.0067).

CONCLUSION

We present the largest known cohort of meningiomas treated with fRT as first line therapy and find pre-RT tumour GTV and location to be the critical predictors of outcome, adding to the discussion of treatment considerations in this heterogeneous disease.
RADT-28. MULTI-SESSION RADIOSURGERY FOLLOWING SURGERY FOR INTRACRANIAL MENINGIOMAS: 10-YEAR OUTCOMES FROM A SINGLE INSTITUTION PROTOCOL
Authors: Carrasquilla Michael , Cantalino Jonathan , Hay Kathryn , Chesney Kelsi , Sayah Anousheh , Sloan Emily , Watson Joseph , Anaizi Amjad , Jean Walter , McGrail Kevin , Collins Sean , Collins Brian
Published: November 2022

INTRODUCTION

Meningioma is the most common adult primary intracranial tumor. Surgical resection is the favored treatment with radiotherapy often utilized for residual or recurrent disease. Long-term outcomes are well-established for single-session radiosurgery but mature outcomes for multisession radiosurgery do not yet exist. We report our institution’s 10-year efficacy and toxicity outcomes for 5-fraction radiosurgery following surgical resection of intracranial meningiomas.

METHODS

All intracranial meningioma patients treated at our institution between 2002-2018 with 5-fraction radiosurgery following surgery were eligible for inclusion. Standard variables were analyzed to predict local failure and overall survival.

RESULTS

Forty-one consecutive patients with a female predominance (76%) and median age of 58 years (range: 27–84) were included. Thirty benign (73%) and 11 atypical meningiomas (27%) with a median gross tumor volume of 7.79cc (range: 0.38-52.63) were treated. All patients completed radiosurgery for residual tumor (41%) or recurrent disease (59%). A median dose of 3000cGy (range: 2500-3500cGy), was delivered to a median isodose line of 82% (range: 71%-90%). The median follow-up from the date of surgery was 10 years. Nine tumors (22.0%) progressed following radiosurgery. The local control rate at 10-years was significantly better for benign tumors than atypical tumors (93% vs 27%, p = 0.001). Factors found to be predictive of local failure on multivariate analysis were tumor grade (HR: 13.8, p = 0.002) and tumor volume (HR: 1.08, p = 0.031). For benign tumors all failures occurred at the margin of the unirradiated tumor bed, while atypical tumors failed predominately in-field (71%). Three patients with atypical meningioma developed radiation necrosis following aggressive treatment (3500cGy). Overall survival at 10-years was 93% for benign tumors and 60% for atypical tumors (p = 0.026).

CONCLUSION

Multisession radiosurgery following surgery for benign intracranial meningiomas provides excellent long-term tumor control with minimal toxicity. However, for atypical meningiomas this approach results in poor local control.
RADT-37. THE OUTCOMES OF INTRACRANIAL GERM CELL TUMOR PATIENTS WITH CHORIOCARCINOMA COMPONENT AND/OR Β-HCG HIGHER THAN 500IU/L UNDER RADIOTHERAPY-BASED TREATMENTS
Authors: Li Bo , Qiu Xiaoguang
Published: November 2022

BACKGROUND

In the previous studies, intracranial germ cell tumor (iGCTs) patients with pure choriocarcinoma or mixed germ cell tumors containing choriocarcinoma components showed similar dismal prognoses with median overall survival of 22 months and a one-year survival rate around 60%. However, those conclusions need update since radiotherapy, a milestone for this disease, was not applied to many patients in the published reports. Patients and

METHODS

Clinical data of iGCTs patients with histologically confirmed choriocarcinoma component and/or β-HCG > 500IU/L were collected from the archive of our institute and studied retrospectively.

RESULTS

Totally, 76 patients were eligible for the study. 11 patients took surgery as initial treatment, followed by chemoradiotherapy in terms of treatments. Sixty-one patients initiated their treatments with chemotherapy. Among them, twelve patients received second-look surgery due to residue disease. Subsequently, all received radiotherapy except for two early deaths. Four patients received radiotherapy initially, followed by chemotherapy. The median follow-up time was 63 months. The 5-year EFS and OS were 81.5% and 84.1%, respectively. Among patients who did not suffer from early death or progressed disease after induction chemotherapy (n = 68), multivariate analysis found chemotherapy cycles ( > 4 vs ≤ 4) (Hazard ratio [HR] for EFS 0.156, p = 0.021; HR for OS 0.110, p = 0.032), β-HCG level ( > 3000IU/L vs ≤ 3000IU/L) (HR for EFS 4.512, p = 0.052; HR for OS 6.604, p=0.028), and intertumoral hemorrhage (Yes vs No) (HR for EFS 23.177, p = 0.006; HR for OS 12.173, p = 0.081) were independent factors for survival. While radiation field (CSI vs non-CSI) was not proved to be a prognostic factor, either for EFS or OS.

CONCLUSIONS

iGCTs patients with choriocarcinoma component or β-HCG > 500IU/L showed improved survival with radiotherapy-based treatments. Patients with higher β-HCG levels and hemorrhage had a poorer prognosis. More chemotherapy cycles could bring additional survival benefits.
RADT-39. STAGED GAMMA KNIFE STEREOTACTIC RADIOSURGERY FOR LARGE INTACT AND RESECTED BRAIN TUMORS; THE MUSC EXPERIENCE
Authors: Duffy Edward , Rivers Charlotte , Stroud Maggie , Hall Michael , DePaoli Bradley
Published: November 2022

Stereotactic radiosurgery (SRS) is a well-established treatment modality for management of both benign and malignant central nervous tumors. One limiting factor in the use of SRS is tumor size. Staged radiosurgery treatment is an option to utilize this treatment modality while still limiting associated toxicity. This involves treating each target in 2 separate sessions, spaced apart by approximately 30 days. We describe a series of 17 patients with 20 unique lesions treated using this technique in our department from January of 2019 through December of 2021. 18 treated lesions were malignant brain metastases and 2 were meningiomas. For 13 lesions, SRS was the primary treatment, and for 7 lesions, SRS was adjuvant treatment after surgery. The median target size for fraction 1 was 18.40 cm^3 with a median dose of 12.65 Gy. The median target size for fraction 2 was 14.50 cm^3 with a median dose of 12.08 Gy. All but one target was prescribed to the 50% isodose line. Median follow up was 7.12 months. Local control at the site of treated lesions was 90%. 3 patients with local control at the site of the fractionated treatment were noted to have additional progression within the CNS. There were 2 patient deaths within 30 days of treatment. One death was due to respiratory failure. The other cause of death was unknown. Treatment was well tolerated with no grade 3 or higher acute toxicity. 50% of patients went on to receive additional systemic therapy. 55% of patients are known to have died at the time of latest follow up. Overall, staged gamma knife radiosurgery appears to be an effective option for treating both intact and resected tumors with an acceptable toxicity profile.
RADT-42. EFFECTS OF RADIOTHERAPY FOR CNS NEOPLASMS IN PEOPLE WITH MULTIPLE SCLEROSIS
Authors: Phan Angela , Tseng Yolanda , Graber Jerome
Published: November 2022

INTRODUCTION

Patients with multiple sclerosis (MS) may be at higher risk of brain tumors (Khalil 2012, London 2020, etc.). However, MS patients have been reported to have adverse effects from radiotherapy, a mainstay of CNS treatment. In the last ten years, radiation techniques have improved. We submit a case report of an MS patient with demyelinating CNS lesions shortly after radiation therapy for an astrocytoma and review the literature. Case description: A 40-year-old woman with a history of MS treated with Siponimod underwent resection of a right frontotemporal grade 2 astrocytoma, IDH mutant. She received adjuvant proton radiotherapy (54 Gy(RBE) over 30 fractions) followed by temozolomide chemotherapy. She tolerated radiotherapy well and only experienced grade 1 dermatitis, fatigue, and hair loss within the field of treatment. 1-month post radiation MRI was stable. 4 months post radiation there was an asymptomatic new typical demyelinating lesion on FLAIR without T1 or contrast changes. This was outside the high dose radiation field (i.e. received ~30 Gy(RBE)). Her Siponimod had been held for concerns of interactions with radiation or chemotherapy.

DISCUSSION

Cases have been reported of people with MS experiencing adverse effects from radiotherapy. Murphy, et al., reported a 30-year-old woman with MS experiencing an attack of demyelination 2 months after radiotherapy (50 Gy over 25 fractions), and Borges, et al. presents a 28-year-old patient who experienced radiotherapy-induced inflammatory demyelination after receiving whole-ventricular irradiation (24 Gy over 15 fractions). Miller, et al., reported 6 patients without exacerbations of MS but had developed grade 4 neurotoxicity in a median of 1 year; most of those patients were treated with older radiation techniques, however. Radiotherapy effects in people with MS is a topic that should be revisited in the era of more conformal RT techniques, effective MS therapies, and cancer treatment including immunotherapy.
CTIM-02. TIP: PHASE I/II STUDY OF STEREOTACTIC RADIOSURGERY WITH CONCURRENT OLAPARIB FOLLOWED BY ADJUVANT DURVALUMAB AND PHYSICIAN’S CHOICE SYSTEMIC THERAPY IN SUBJECTS WITH BREAST CANCER BRAIN METASTASES
Authors: Shen Colette , Abdou Yara , Tan Xianming , Gupta Gaorav , Lynce Filipa , Stringer-Reasor Erica , Anders Carey
Published: November 2022

BACKGROUND

Despite progress in the treatment of brain metastasis (BrM) for HER2+ breast cancer (BC), outcomes for patients with HER2-negative BC BrM remain poor. Current standard of care consists of local therapies, including surgery and radiotherapy, followed by systemic therapy. Preclinical studies show inhibitors of poly(ADP-ribose) polymerase (PARP) are effective with radiation therapy as a DNA damage response inhibitor. Triple negative BC (TNBC) has higher rates of homologous recombination deficiency compared to other BC subtypes, and together with HER2-negative, BRCA-mutated BC would be particularly sensitive to PARP inhibition. PARP inhibition also shows promising efficacy combined with immunotherapy in patients with germline BRCA-mutant and metastatic TNBC in clinical trials (MEDIOLA, TOPACIO). In addition, immunotherapy with stereotactic radiosurgery (SRS) is associated with favorable intracranial control and survival in patients with BrM. We hypothesize that this biologically-rational combination will enhance local control of SRS-treated BrM through synergy with PARP inhibition, while controlling micrometastatic disease in the brain and extracranial sites via potentiation of the immune response.

METHOD

We are conducting a multi-institution, Phase I/II trial of SRS plus olaparib, followed by durvalumab (with physician’s choice systemic therapy), for patients with TNBC (any BRCA status) or HER2-negative with BRCA-mutated (germline or somatic) BC BrM [NCT04711824]. The primary objectives are to evaluate safety and tolerability (Phase I) and determine intracranial disease control at 6 months (Phase II) of this treatment combination. Secondary objectives include determining clinical activity via intracranial and global progression-free survival, overall survival, and intracranial and extracranial response rate. Exploratory objectives will assess potential biomarkers of treatment response, including changes in circulating tumor cells and DNA in blood and cerebrospinal fluid, germline and tumor mutations in DNA repair pathway genes, and PD-L1 expression, as well as quality of life and patient-reported outcomes. A surgical sub-study will evaluate olaparib concentration/distribution in resected BrM.
CTIM-03. PEMBROLIZUMAB MONOTHERAPY FOR MICROSATELLITE INSTABILITY-HIGH (MSI-H) OR MISMATCH REPAIR DEFICIENT (DMMR) RECURRENT GLIOMAS: RESULTS FROM THE MULTICOHORT PHASE 2 KEYNOTE-158 STUDY
Authors: Baldini Capucine , Cassier Philippe A , Delord Jean-Pierre , Simonelli Matteo , Touat Mehdi , Yao Lili , Duic J Paul , Gozman Alexander , Marabelle Aurelien
Published: November 2022

BACKGROUND

Patients with recurrent glioma have limited treatment options. The anti‒ PD-1 monoclonal antibody pembrolizumab demonstrated antitumor activity as monotherapy in a subset of patients with PD-L1–positive recurrent glioblastoma (GBM) in the KEYNOTE-028 study; and durable clinical benefit in patients with previously treated unresectable/metastatic MSI-H/dMMR non-colorectal tumors in the multicohort KEYNOTE-158 (NCT02628067) study. We report outcomes with pembrolizumab in patients with MSI-H/dMMR recurrent glioma enrolled in KEYNOTE-158.

METHODS

Adults with MSI-H/dMMR recurrent glioma, measurable disease per RECIST v1.1, ECOG PS 0/1, and tumor sample for biomarker analysis were eligible for cohort K (any MSI-H/dMMR advanced solid tumor, except colorectal cancer; local, prospective determination of MSI-H/dMMR status by PCR and/or IHC). Patients received pembrolizumab 200 mg Q3W for up to 35 cycles or until PD/unacceptable AEs (clinically stable patients could continue treatment until PD confirmed after ≥ 4 weeks). Primary endpoint was ORR per RECIST v1.1 by independent central review.

RESULTS

Among 21 enrolled patients, all received prior temozolomide, 12 (57%) received prior bevacizumab, and 14 (67%) received ≥ 2 prior lines of therapy. 14 (67%) patients had GBM, 4 (19%) had oligodendroglioma/oligoastrocytoma, and 3 (14%) had glioma NOS. Median time from first dose to data cutoff (January 12, 2022): 50.0 months; 19 (90%) patients discontinued treatment. 1 patient with GBM had PR (ORR, 4.8% [95%CI, 0.1%‒23.8%]); duration of response was 18.9 months, PFS 29.2 months, and OS 32.7 months. 3 (14%) patients had SD; PFS was 23.2, 14.5, and 3.3 months; OS was 23.2, 15.1, and 9.1 months. Overall, median PFS and OS (95%CI) were 1.4 (1.0‒2.1) months and 5.6 (2.6‒16.2) months. Treatment-related AEs occurred in 7 (33%) patients (grade 3/4, n = 1; no grade 5) and led to discontinuation in 1 (5%) patient.

CONCLUSIONS

Pembrolizumab demonstrated antitumor activity with manageable toxicity in a small subset of patients with relapsing/refractory MSI-H/dMMR glioma.
CTIM-10. A PHASE II STUDY OF RETIFANLIMAB (PD-1 INHIBITOR) IN COMBINATION WITH BEVACIZUMAB AND HYPOFRACTIONATED RADIOTHERAPY FOR RECURRENT GLIOBLASTOMA: NCT03532295
Authors: Butt Omar , Huang Jiayi , Luo Jingqin , Tao Yu , Strowd Roy , Hissim Deanna , Kizilbash Sani , Abraham Christopher , Anstass George , Johanns Tanner , Kim Albert , Ciorba Matthew , Chheda Milan G , Campian Jian
Published: November 2022

INTRODUCTION

Immunotherapies targeting PD-1 in recurrent glioblastoma (rGBM) have shown limited activity. We hypothesize combining therapies targeting immunosuppressive pathways with cytotoxic and antiangiogenic therapies will improve survival. This nonrandomized, noncomparative Phase II study examines safety and efficacy of an anti-PD-1 monoclonal antibody (retifanlimab), hypofractionated radiotherapy (HFRT), and bevacizumab, with or without an IDO1 inhibitor (epacadostat), in patients with rGBM.

METHODS

This is an open-label Phase II study of two regimens. Regimen A examines retifanlimab (500mg IV Q4W) + bevacizumab (10mg/kg IV Q2W) + HFRT (3.5Gy/day x 10) in patients with IDH1/2-WT rGBM. Regimen B adds epacadostat. Key inclusions include dexamethasone ≤ 4 mg/day and reirradiation candidacy. The primary endpoint is overall survival (OS) probability at 9 months (OS-9). An increase of OS-9 from 38% (bevacizumab alone) to 60% was considered clinically relevant and required 24 efficacy evaluable patients.

RESULTS

Regimen A accrual is complete; interim results are as follows: 26 rGBM enrolled, with 24 evaluable [median age 64.2 years (42.1-81.8); 29% female; 29% MGMT promotor methylated; 33.3% with multi-focal disease; median KPS 90 (70-100); median baseline dexamethasone 0 mg (0-4) and ALC 1,000 cells/µl (300-3,700)]. Patients received a median of 6 cycles as of May 2022 (2-24). Median follow-up is 16.0 months. Interim median PFS is 7.0 months (95%CI: 4.5~11.1) and median OS is 12.2 months (95%CI 7.1~18.0). Regimen A met primary endpoint with OS-9 of 67% (95%CI: 44~82%). Overall response rate is currently 58% (95%CI: 36.94~77.2%). There were five possible immune-related grade 3+ toxicities to date (n = 1 each colitis, vomiting, and seizure; n = 2 diarrhea). Regimen B is enrolling.

CONCLUSIONS

Interim analysis suggests combination retifanlimab, HFRT, and bevacizumab in rGBM is generally well-tolerated, with encouraging OS and PFS at the time of submission. Correlative analysis is ongoing and will be presented at the meeting.
CTIM-11. SINGLE-CENTER, OFF-LABEL NEOADJUVANT PEMBROLIZUMAB FOR TREATMENT OF RECURRENT GBM AT UCLA
Authors: Baisiwala Shivani , Sun Lu , Ellingson Benjamin , Prins Robert , Nghiemphu Phioanh L , Cloughesy Timothy , Everson Richard G
Published: November 2022

Neoadjuvant drug administration provides a window of opportunity for developing novel therapies. Specifically, neoadjuvant pembrolizumab (PD1 checkpoint inhibitor) has the potential for improving understanding of immunomodulatory effects on the tumor microenvironment and for treating recurrent GBM. It is known that a functional immune deficit exists within the tumor T-lymphocyte compartment. As pembrolizumab promotes lymphocyte infiltration, it may contribute to antitumor effects in the neoadjuvant setting. Our previous randomized clinical trial (RCT) suggested that neoadjuvant pembrolizumab improved survival for recurrent GBM patients with 1-2 relapses. Here, we sought to extend our original findings and analyze the role of off-label neoadjuvant pembrolizumab in patients with multiple recurrences. We identified a retrospective 22-patient cohort at UCLA. Every patient had a GBM tissue diagnosis, received standard treatment, and had one to five recurrences. Each received off-label neoadjuvant pembrolizumab and surgical resection within 7-21 days. Progression-free (PFS) and overall survival (OS) for our cohort of neoadjuvant-treated patients were calculated as days from surgical resection and compared to historical control data from the original RCT (n = 15 neoadjuvant, 15 adjuvant). Results show that administration of neoadjuvant pembrolizumab in our cohort significantly increased median PFS compared to our historical adjuvant control (114 vs 75 days, p = 0.03). The OS of our neoadjuvant cohort was 294 days as compared to 192 days in the historical control. Both PFS and OS in our neoadjuvant cohort were not statistically different than the historical neoadjuvant cohort (PFSp = 0.08, OSp = 0.13). Since our cohort was not limited to initial recurrences, this data suggests that patients with more advanced recurrences could also benefit from neo-adjuvant therapy. Ongoing work will evaluate the microenvironmental genetic signature induced by pembrolizumab and assess pre-surgical tumor volume so that adequate comparisons can be made with other trials. We believe this promising finding offers novel therapeutic options for those patients with multiple recurrences.
CTIM-17. EO2401 THERAPEUTIC VACCINE FOR PATIENTS WITH RECURRENT GLIOBLASTOMA: PHASE 1/2 ROSALIE STUDY (NCT04116658)
Authors: Reardon David A , Idbaih Ahmed , Vieito Maria , Tabatabai Ghazaleh , Stradella Agostina , Ghiringhelli François , Burger Michael C , Mildenberger Iris , González Macarena , Hervieu Alice , Martin Marta Gil , Renovanz Mirjam , Touat Mehdi , Wen Patrick Y , Wick Antje , Gouttefangeas Cécile , Maia Ana , Bonny Christophe , Fagerberg Jan , Wick Wolfgang
Published: November 2022

EO2401 includes microbial-derived, synthetically produced HLA-A2 restricted peptides with molecular mimicry to antigens (IL13Rα2, BIRC5 and FOXM1) upregulated in glioblastoma, and the CD4 helper peptide UCP2. Patients with glioblastoma at first progression received EO2401 (300µg/peptide, q2weeks x4 then q4weeks), EO2401+nivolumab (3mg/kg q2weeks), or E02401+nivolumab+bevacizumab (10mg/kg q2weeks). Cohort-1 included EO2401x2 then EO2401+nivolumab. EO2401+nivolumab was evaluated in Cohort-2a, as adjuvant treatment in Cohort-2b, and as neoadjuvant/adjuvant treatment in Cohort-2c. Cohort-3 assessed EO2401+nivolumab+bevacizumab. Part 1 included 40 patients (Cohort-1/3, Cohort-2a/23, Cohort-2b/3, Cohort-3/11). Part 2 allowed low-dose-bevacizumab (5mg/kg q2weeks) for symptomatic edema and enrolled 38 patients (Cohort-1/18, Cohort-2a/15, Cohort-2b/3; and recruiting Cohort-2c/2 target 6, Cohort-3/0 target 15).Safety assessment of part 1 showed EO2401+nivolumab+/-bevacizumab to be well tolerated with EO2401 associated toxicity limited to local administration site reactions (48%; all grade 1-2). The nivolumab-/bevacizumab-toxicity was consistent with historical single-agent data. Strong CD8 T cell ELISPOT responses against the 3 vaccine peptides and cross-reactivity against targeted antigens was demonstrated in the majority of evaluable patients. Immune response was confirmed with tetramer staining of specific CD8 either ex vivo or after in vitro stimulation. For part 1, median progression-free survival (mPFS), and median survival (mOS) for EO2401+nivolumab (Cohorts-1/2/2b, n=29 median follow-up [mFU] 14.0 months) were 1.8 and 10.6 months. Patients on EO2401+nivolumab+bevacizumab (n = 11 mFU 9.6 m) had mPFS 5.5 months and 9 patients alive 7-12.4 months. Objective Response Rate/Disease Control Rate for EO2401+nivolumab and EO2401+nivolumab+bevacizumab was 10%/34% and 55%/82%.Median treatment duration for Cohort-2a part 1 was 6.1 weeks (1/23 on treatment), while it was 10.0 weeks (8/15 on treatment) for Cohort-2a part 2. Overall, in part 2, 36% received low-dose-bevacizumab.EO2401 generated strong immune responses and was well tolerated. Addition of standard bevacizumab to EO2401+nivolumab improved PFS and tumor response. Symptom driven low-dose-bevacizumab supported longer treatment durations. Outcome of study part 2 will be presented.
CTIM-18. PHASE 2 STUDY OF PD-1 BLOCKADE WITH PEMBROLIZUMAB PLUS RE-IRRADIATION FOR RECURRENT GLIOBLASTOMA (RGBM) (NCT03661723)
Authors: Iwamoto Fabio , Tanguturi Shyam , Desai Arati , Nayak Lakshmi , Uhlmann Erik , Wang Tony , Lustig Robert , Hertan Lauren , Bagley Stephen , Hayden Julia , Laforest-Roys Corey , Muzikansky Alona , McCluskey Christine , Chukwueke Ugonma , McFaline-Figueroa J Ricardo , Lee Eudocia , Wen Patrick Y , Reardon David
Published: November 2022

Re-irradiation is therapeutically considered for select rGBM patients and may induce immunogenic cell death to stimulate anti-tumor immune responses. Our phase 2 study of re-irradiation with pembrolizumab among rGBM patients evaluated the efficacy and safety of this regimen.

METHODS

Adult rGBM patients with KPS ≥ 70, a maximum supratentorial tumor diameter of 6 cm who were on ≤ 2mg dexamethasone/day and were ≥ 6 months from initial conventional radiation therapy were eligible. Cohort A (bevacizumab [BEV]-naïve) had ≤ 2 prior progressions while cohort B (BEV-refractory) allowed unlimited progressions but only one on prior BEV. Re-irradiation included 35 Gy over 10 fractions to residual enhancing (cohort A) as well as enhancing + non-enhancing (cohort B) disease. Pembrolizumab was administered at 200 mg every three weeks beginning within one week of re-irradiation start. BEV was administered at 15 mg/kg every three weeks for cohort B only.

RESULTS

Sixty patients enrolled (n = 30 per cohort) with a median age of 61 years (range 20-76), 47% were female and 53% enrolled after 2 or more progressions. Grade 3 events deemed at least possibly related to study therapy in > one patient for cohort A included headache (n = 2) and for cohort B included elevated ALT (n = 2) and hypertension (n = 5). No grade 4 events occurred in more than single patients per cohort and no grade 5 events occurred. Median PFS and PFS-6 were 4.9 months (95% CI: 3.5, 5.6) and 26.0% (95% CI: 12.3%, 43.0%) for cohort A and 4.14 months (95% CI: 3.45, 5.42) and 16.9% (95% CI: 5.4, 33.7) for cohort B. Median survival for cohorts A and B were 11.5 months (95% CI: 9.6, 14.1) and 7.6 months (95% CI 5.5, 9.3), respectively.

CONCLUSIONS

Re-irradiation with pembrolizumab was overall well tolerated and achieved comparable efficacy to historical salvage therapy established with lomustine.
CTIM-19. RANDOMIZED PHASE II OPEN-LABEL STUDY OF NIVOLUMAB PLUS STANDARD-DOSE BEVACIZUMAB VS NIVOLUMAB PLUS LOW-DOSE BEVACIZUMAB IN RECURRENT GLIOBLASTOMA (RGBM): FINAL REPORT
Authors: Ahluwalia Manmeet , Khosla Atulya , Rauf Yasmeen , Peereboom David , Wen Patrick Y , Reardon David A
Published: November 2022

BACKGROUND

Anti-PD1 therapy alone in rGBM is of limited efficacy seen in three randomized trials. VEGF is upregulated proangiogenic growth-factor in GBM that contributes to tumor-associated immunosuppression. Preclinical data suggests a potential dose effect of anti-VEGF therapy on immunomodulation. Hence, a combination of anti-PD1 and anti-VEGF is promising approach.

METHODS

90 patients with GBM at first recurrence were randomized (1:1) to nivolumab (240 mg IV Q2 weeks) with bevacizumab at standard (10 mg/kg; Arm A) or at low dose (3 mg/kg; Arm B) IV Q2 weeks. Stratification included extent of resection, age, performance-status, and MGMT methylation status. Progression-free survival (PFS) and overall survival (OS) were compared.

RESULTS

90 patients (Median age 60.6 years, 67.8% male, median KPS 80) were enrolled between May 2018 and Jan 2020. Patients were followed in median 7.7 months (Range 0.7, 28.2). 35 patients were MGMT methylated and 53 patients were MGMT not hypermethylated and 2 were indeterminate. Overall survival was similar between arm A and arm B (1 year: 41.1 vs 37.7%, p = 0.14), while OS was better for arm A in age > 60 compared to arm B (At 1-year: 46.2% vs 23.8%; Median: 10.6 vs 5.9 months; P = 0.046). OS was not statistically different in the two arms for patients with age ≤ 60 years (At 1-year: 35.6% vs 56.4; Median 8.0 vs 12.4 months; P = 0.90). Most frequent toxicities ( >20%) included fatigue (45.6%), proteinuria (34.4 %), diarrhea (28.9%), hypertension (23.3%) and lipase increase (21.1%). Toxicities in grade 3-4 were hypertension (7.8%), fatigue (5.6) and other non-neurological toxicities including DVT, PE, infection, and abnormal liver function.

CONCLUSIONS

Overall PFS and OS rates appear similar for nivolumab with either standard or low-dose bevacizumab compared bevacizumab monotherapy. Nivolumab with standard bevacizumab benefits patients older than 60 years old. Biomarkers of response data will be presented.
CTIM-21. NRG-BN010: A SAFETY RUN-IN AND PHASE II STUDY EVALUATING THE COMBINATION OF TOCILIZUMAB, ATEZOLIZUMAB, AND FRACTIONATED STEREOTACTIC RADIOTHERAPY IN RECURRENT GLIOBLASTOMA – TRIAL IN PROGRESS
Authors: Bagley Stephen , Polley Mei-Yin , Kotecha Rupesh , Brem Steven , Tolakanahalli Ranjini , Iwamoto Fabio , Gilbert Mark , Won Minhee , Mehta Minesh
Published: November 2022

BACKGROUND

The glioblastoma (GBM) tumor microenvironment (TME) is characterized by a paucity of effector T cells and massive infiltration of immunosuppressive tumor-associated macrophages (TAMs). Inhibition of the interleukin-6 receptor (IL6R) has been demonstrated in preclinical models to repolarize TAMs toward an immunostimulatory phenotype, rendering GBM more susceptible to PD-1/PD-L1 inhibition. Additional preclinical data suggest that fractionated stereotactic radiotherapy (FSRT) can stimulate the release and presentation of tumor-specific antigens, acting as an in-situ vaccine and potentially converting a “cold” TME to a T cell-inflamed state. We designed a safety run-in and phase II study to evaluate the efficacy, safety, and impact on the TME of the combination of IL6R inhibition (tocilizumab), PD-L1 inhibition (atezolizumab), and FSRT in patients with recurrent GBM (rGBM).

METHODS

NRG-BN010 (NCT04729959) is open to enrollment for adults with rGBM following prior radiotherapy and has 3 components: a safety run-in to determine the recommended phase II dose (RP2D) of the treatment regimen, a phase II single-arm nonsurgical cohort to assess efficacy of the treatment regimen at the RP2D, and a window-of-opportunity surgical cohort. Once the safety run-in (n=12, 3 + 3 design) has determined the RP2D, the phase II and surgical cohorts will open. Phase II patients (n=25, Simon 2-stage design, primary endpoint objective radiographic response) receive an initial pre-FSRT cycle of tocilizumab (plus atezolizumab if included in the RP2D). Within 3-7 days later, the patient receives FSRT (8 Gy x 3 fx), followed by resumption of systemic therapy. Surgical cohort patients (n=16, 1:1 randomization) receive a neoadjuvant cycle of atezolizumab with (n=8) vs. without (n=8) tocilizumab, then FSRT 3-7 days later, then surgical resection 7-14 days after FSRT. Post-operatively, all patients resume systemic therapy at the RP2D. Fresh tumor tissues will be subjected to deep immune profiling to understand the impact of tocilizumab on TAMs in the GBM TME.
CTIM-23. DOSE ESCALATION TRIAL OF FC-ENGINEERED ANTI-CD40 MONOCLONAL ANTIBODY (2141-V11) ADMINISTERED INTRATUMORALLY WITH D2C7-IT VIA CONVECTION-ENHANCED DELIVERY (CED) FOR RECURRENT MALIGNANT GLIOMAS (RMGS)
Authors: Desjardins Annick , Chandramohan Vidya , Landi Daniel , Peters Katherine B , Johnson Margaret , Khasraw Mustafa , Low Justin , Threatt Stevie , Bullock Chevelle , II James E Herndon , Lipp Eric S , Sampson John , Friedman Allan , Friedman Henry S , Ashley David , Knorr David , Ravetch Jeffrey , Bigner Darell
Published: November 2022

BACKGROUND

D2C7-IT, a novel immunotoxin-based cytotoxic therapy, targets epidermal growth factor receptor (EGFR) and mutant EGFR variant III. In preclinical studies, D2C7-IT kills tumor cells and prolongs survival, but is unable to generate cures in all animals. We hypothesized that immunosuppression in glioblastoma limits D2C7-IT efficacy. Eliminating glioblastoma immunosuppression via CD40 co-stimulation is anticipated to enhance D2C7-IT-induced antitumor responses. In murine glioma models, CED of D2C7-IT+αCD40 generated cures and long-term tumor-specific adaptive immunity. Hence, we are conducting a phase 1 trial of D2C7-IT+2141-V11 (αhuman-CD40) administered via CED in rMG patients.

METHODS

Eligibility includes adult patients with solitary supratentorial rMG (WHO grade 3/4); ≥ 4 weeks after chemotherapy, bevacizumab, or study drug; adequate organ function; and KPS ≥ 70%. Cohorts of 3 patients are treated with increasing doses of 2141-V11 to determine the maximum tolerated dose when administered sequentially following D2C7-IT (166,075 ng) via CED at 0.5 mL/hr. Five dose levels (DLs) are evaluated (2141-V11 at: #1: 0.70 mg; #2: 2.0 mg; #2**: 3.0 mg #2*: 4.0 mg; #3: 7.0 mg).

RESULTS

As of May 29, 2022, 13 patients were treated (3 patients on DL1, DL2, and DL2**; 2 patients on DL3 and DL2*). No dose-limiting toxicities were observed; however, lower DLs were added due to higher frequency of adverse events (AEs) expected with D2C7-IT+2141-V11 with DL3 and DL2* (fever, neurologic symptoms). All patients remain alive 0.7-10.6 months after therapy. Grade ≥ 2 AEs due to D2C7-IT+2141-V11 include: headache (grade 3, n = 1; grade 2, n = 4); pyramidal tract disorder (grade 3, n = 1; grade 2, n = 2); paresthesia (grade 3, n = 1); dysphasia (grade 3, n = 1); seizures (grade 2; n = 2); fever (grade 2; n = 2); and one each of grade 2 depressed level of consciousness, fatigue, and concentration impairment. Enrollment is ongoing.

CONCLUSIONS

Intratumoral administration of D2C7-IT+2141-V11 via CED is safe, encouraging efficacy results are observed.
CTIM-26. PHASE II TRIAL OF SURVAXM PLUS TEMOZOLOMIDE FOR NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Ahluwalia Manmeet , Ciesielski Michael J , Reardon David A , Abad Ajay , Curry William , Wong Eric , Peereboom David , Figel Sheila , Hutson Alan , Groman Adrienne , Withers Henry , Liu Song , Belal Ahmed , Qiu Jingxin , Mogensen Kathleen , Schilero Cathy , Khosla Atulya , Casucci Danielle , Mechtler Laszlo , Fenstermaker Robert
Published: November 2022

BACKGROUND

Newly diagnosed glioblastoma (nGBM) has dismal outcomes with survival of 15-18 months. Tumor associated “survivin” is expressed in > 95% of nGBM and targetable by SurVaxM immunotherapy.

METHODS

nGBM patients (pts) were enrolled in this Phase 2 study, age ≥ 18, KPS ≥ 70, IHC confirmed surviving-expression, expression of HLA-A*02, A*03, A*11 or A*24 MHC-I alleles and residual contrast enhancement of ≤1 cm3 by MRI. Pts were treated with standard TMZ chemoradiation followed by initiation of 4 priming doses of SurVaxM (500 mcg in emulsion with Montanide ISA 51, every 2 weeks) with 100 mcg sargramostim. Maintenance doses of SurVaxM-Montanide plus sargramostim given every 12 weeks with Adjuvant TMZ for at least 6 cycles. The primary endpoint was 70% progression free survival (PFS) at 6 mos. Primary analyses of median PFS (mPFS) and median overall survival (OS) were measured from the first immunization. Safety, tolerability, and immune responsiveness were also determined.

RESULTS

63 pts (38 males), median age, 60 years were treated at 5 sites. SurVaxM was well tolerated, with no serious adverse events. A strong positive correlation, accounting for censoring, was observed between PFS and OS of all pts (r = 0.79; 95% CI (0.66,0.87)). SurVaxM was immunogenic and produced survivin-specific CD8+ T-cells and antibody (IgG) titers in both methylated and unmethylated MGMT pts. Both groups showed clinical benefit with PFS of 11.4 months for the for the whole group, 7.0 months for unmethylated and 17.9 months for methylated group. OS of 25.9 months for the whole group, 16.5 months for unmethylated and 41.4 months for methylated group.

CONCLUSIONS

SurVaxM appeared to be safe and well-tolerated in pts with nGBM. SurVaxM was effective at stimulating survivin-specific immune responses and the primary endpoint was met. SurVaxM represents a promising therapy for nGBM, randomized trial is ongoing. Clinical trial information: NCT02455557.
CTIM-30. THE PRIVATE AND RECURRING ANTIGENIC PROFILE OF HUMAN MEDULLOBLASTOMA
Authors: Yang Changlin , Trivedi Vrunda , Mitchell Duane
Published: November 2022

BACKGROUND

Identifying tumor rejection antigens remains a major barrier to developing effective immunotherapeutics and their application to pediatric brain tumors. We performed a multi-faceted computer algorithm, the Open Reading Frame Antigen Network (O.R.A.N.), on medulloblastoma transcription profiles and predicted antigens across a broad array of antigen classes.

METHODS

Patient-specific HLA haplotypes were called via customized Optitype and Phlat algorithms. Only expressed mutations such as single nucleotide variations, small indels, gene fusions, and Tumor Associated Antigens (TAAs) were used for antigenic epitope predictions. TAAs were selected only if expressed > 1 transcript per million (TPM) in tumor and the standardized expression across a human tissue database. Immunogenic TAA epitopes were screened against a customized human proteomic library to guarantee that epitopes were not shared by other expressed isoforms or genes. Immune deconvolution with single cell RNASeq integration was leveraged for teasing out medulloblastoma immunologic landscape.

RESULTS

We hypothesized that medulloblastomas are immunologically heterogeneous and express genes with limited normal tissue expression that may serve as targets for immunotherapy. In this study, most neoantigens from medulloblastoma patients were found private suggesting a personalized neoantigen based therapy was on demand. In addition, recurring neoantigens were common in SHH but composed only a small proportion of putative antigens in WNT, Group 3 and Group 4 patients. However, recurring TAAs were found to be more commonly expressed in the latter three molecular subgroups but not in SHH. Together, combining personalized neoantigen vaccine and taking advantage of recurring TAAs approach may maximize anti medulloblastoma effect.

CONCULSION

Medulloblastoma is a heterogeneous disease, and the current standard of care treatments don’t take that into account. Newer, and safer, patient-specific treatment approaches are required to treat high-risk patients who are not cured by the standard therapies .Cellular immunotherapy might be key to improving survival and avoiding morbidity.
CTIM-31. IMMUNOLOGIC MONITORING AFTER ADOPTIVE CELL THERAPY IN PEDIATRIC PATIENTS WITH RECURRENT MEDULLOBLASTOMA USING IMMUNOGENOMICS APPROACH
Authors: Yegorov Oleg , Yang Changlin , Mitchell Duane
Published: November 2022

BACKGROUND

Adoptive cellular therapy (ACT) using transfer of tumor-specific lymphocytes has emerged as a potent strategy for treatment of advanced and refractory malignancies. We have employed the use of total tumor RNA (TTRNA)-pulsed DCs in the ex vivo expansion of tumor-specific lymphocytes for use in adoptive cellular therapy targeting pediatric malignant brain tumors.

METHODS

Total RNA was isolated from patient PBMC samples collected prior to adoptive cellular therapy and after 2-weeks and 4-weeks following immunotherapy treatment from 18 patients (Re-MATCH protocol, FDA IND BB-14058). We applied bulk RNA-Seq and high-throughput T cell receptor sequencing to monitor changes in blood draws after ACT.

RESULTS

We observed an increase of expression level of genes responsible for T cell activation in PBMC after adoptive cell therapy. We found that these genes were involved in T cell signaling pathways, proliferative signals, and cytokine production. The data revealed that certain T-cells were clonally expanded after ACT, with an increasing number of “hyper-expanded” TCR clones (comprising > 1% of all TCR beta or alpha sequences) after adoptive cellular therapy. These TCR clones established a new balance in the peripheral blood that was stable over the month following the completion of cellular immunotherapy. Hyper-expanded TCR clones and increased TCR diversity following ACT was associated with radiographic response to ACT and prolonged progression-free and overall survival. Limited TCR expansion and diversity following ACT was observed in patients with short overall and progression-free survival.

CONCLUSIONS

These results emphasize the importance of gene expression profiling to achieve higher resolution in monitoring immune responses in patients receiving immunotherapeutic treatment. Also, these findings support further study of the use of TCR sequencing to monitor responses to adoptive cellular therapy and suggest that TCR clonal expansion and increasing TCR diversity following treatment may be associated with positive clinical responses.