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Background The landscape of glioma research has evolved in the past 20 years to include numerous large, multi-institutional, database efforts compiling either clinical data on glioma patients, molecular data on glioma specimens, or a combination of both. While these strategies can provide a wealth of information for glioma research, obtaining information regarding data availability and access specifications can be challenging. Methods We reviewed the literature for ongoing clinical, molecular, and combined database efforts related to glioma research to provide researchers with a curated overview of the current state of glioma database resources. Results We identified and reviewed a total of 20 databases with data collection spanning from 1975 to 2022. Surveyed databases included both low- and high-grade gliomas, and data elements included over 100 clinical variables and 12 molecular data types. Select database strengths included large sample sizes and a wide variety of variables available, while limitations of some databases included complex data access requirements and a lack of glioma-specific variables. Conclusions This review highlights current databases and registries and their potential utility in clinical and genomic glioma research. While many high-quality resources exist, the fluid nature of glioma taxonomy makes it difficult to isolate a large cohort of patients with a pathologically confirmed diagnosis. Large, well-defined, and publicly available glioma datasets have the potential to expand the reach of glioma research and drive the field forward.

Background Veledimex (VDX)-regulatable interleukin-12 (IL-12) gene therapy in recurrent glioblastoma (rGBM) was reported to show tumor infiltration of CD8+ T cells, encouraging survival, but also up-regulation of immune checkpoint signaling, providing the rationale for a combination trial with immune checkpoint inhibition. Methods An open-label, multi-institutional, dose-escalation phase I trial in rGBM subjects (NCT03636477) accrued 21 subjects in 3 dose-escalating cohorts: (1) neoadjuvant then ongoing nivolumab (1mg/kg) and VDX (10 mg) (n = 3); (2) neoadjuvant then ongoing nivolumab (3 mg/kg) and VDX (10 mg) (n = 3); and (3) neoadjuvant then ongoing nivolumab (3 mg/kg) and VDX (20 mg) (n = 15). Nivolumab was administered 7 (±3) days before resection of the rGBM followed by peritumoral injection of IL-12 gene therapy. VDX was administered 3 hours before and then for 14 days after surgery. Nivolumab was administered every two weeks after surgery. Results Toxicities of the combination were comparable to IL-12 gene monotherapy and were predictable, dose-related, and reversible upon withholding doses of VDX and/or nivolumab. VDX plasma pharmacokinetics demonstrate a dose-response relationship with effective brain tumor tissue VDX penetration and production of IL-12. IL-12 levels in serum peaked in all subjects at about Day 3 after surgery. Tumor IFNγ increased in post-treatment biopsies. Median overall survival (mOS) for VDX 10 mg with nivolumab was 16.9 months and for all subjects was 9.8 months. Conclusion The safety of this combination immunotherapy was established and has led to an ongoing phase II clinical trial of immune checkpoint blockade with controlled IL-12 gene therapy (NCT04006119).

BACKGROUND Accurate response criteria are crucial for determining treatment efficacy. The response assessment in neuro-oncology (RANO) criteria was developed to standardize response assessment in neuro-oncology. Modified RANO (m-RANO) criteria were recently proposed to address some limitations of the initial criteria including the use of a post-radiation baseline and an additional scan to confirm progression. We sought to identify differences in the association of progression-free survival (PFS) and overall survival (OS) using RANO and m-RANO criteria. METHODS We conducted a retrospective review of newly diagnosed glioblastoma (GBM) patients treated at Dana-Farber Cancer Institute from January 2013 until December 2019. Patients with available clinical and imaging data obtained before initiation of treatment, after radiation completion and at intervals of 1 to 3 months were included. MRIs were evaluated by two independent readers, and PD dates determined using RANO and m-RANO criteria. RESULTS 552 patients were included. 97.1% of the tumors were IDH wild-type. MGMT promoter was unmethylated in 51.4%, methylated in 35.1% and undetermined in 8.5%. Median OS among patients was 18.1 months. 72 patients (13%) did not have PD at the end of the study. 83 patients had treatment change while being clinically stable and without a confirmation scan and were excluded from the final analysis. PFS was 8.2 months with RANO and 8.4 months with mRANO. Difference in PD dates between RANO and m-RANO was detected in 76 patients (14%), where PFS was 3.5 months with RANO and 5.1 months with m-RANO. These patients had a worse median OS than those with identical RANO and m-RANO PD dates (15.2 vs. 22.4 months, p< 0.0001). CONCLUSION RANO and m-RANO criteria resulted in identical PFS for most patients. 14% of patients had discordant PD dates and a worse prognosis. These patients progressed early, and their PD was identified sooner with RANO criteria.

BACKGROUND Approaches using anti-PD1 therapy alone in rGBM is of limited efficacy. 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 may be a promising approach in rGBM. 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 between two arms. RESULTS 90 patients (Median age 60.6 years ranged 27.4-86.4, 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 not significantly different 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 (At 1-year: 46.2% vs 23.8%; Median: 10.6 vs 5.9 months; P=0.046). OS was no different in the two arms for 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 to historical benchmarks of bevacizumab monotherapy. Nivolumab with standard bevacizumab seem to benefit patients older than 60 years old.

Background Patients with glioblastoma (GBM) have a dismal prognosis. Nearly all will relapse with no clear standard of care for recurrent disease (rGBM). Approximately 50% of patients have tumors harboring epidermal growth factor receptor (EGFR) amplification. The antibody–drug conjugate depatuxizumab mafodotin (depatux-m) binds cells with EGFR amplification, is internalized, and releases a microtubule toxin, killing the cell. Here we report efficacy, safety and pharmacokinetics (PK) of depatux-m + temozolomide (TMZ) in patients with EGFR-amplified rGBM. Methods M12-356 (NCT01800695) was an open-label study encompassing patients with newly diagnosed or rGBM across 3 treatment arms. Results are reported for adults with EGFR-amplified, measurable rGBM who received depatux-m (0.5–1.5 mg/kg) on days 1 and 15, and TMZ (150–200 mg/m2) on days 1–5 in a 28-day cycle. Patients were bevacizumab and nitrosourea naïve. Results There were 60 patients, median age 56 years (range, 20–79). Fifty-nine patients previously received TMZ. Common adverse events (AEs) were blurred vision (63%), fatigue (38%), and photophobia (35%). Grades 3/4 AEs were split between ocular and non-ocular AEs, occurring in 22% of patients each. Systemic PK exposure of depatux-m was dose proportional. The objective response rate was 14.3%, the 6-month progression-free survival rate was 25.2%, and the 6-month overall survival rate was 69.1%. Conclusions Depatux-m + TMZ displayed an AE profile similar to what was described previously. Antitumor activity in this TMZ-refractory population was encouraging. Continued study of depatux-m in patients with EGFR-amplified, newly diagnosed, or recurrent GBM is ongoing in 2 global, randomized trials (NCT02573324, NCT02343406).

BACKGROUND Novel T cell-enabling therapies, in combination with checkpoint inhibition, may improve OS in GBM. INO-5401 (synthetic DNA plasmids encoding hTERT, WT-1, PSMA) plus INO-9012 (synthetic DNA plasmid encoding IL-12), and the PD-1 immune checkpoint inhibitor cemiplimab, is given to patients with newly diagnosed GBM to evaluate tolerability, efficacy and immunogenicity. METHODS Phase I/II, single arm, 2 cohort study (A: MGMT unmethylated, B: MGMT methylated). Primary endpoint is safety; efficacy and immunogenicity are secondary. Nine mg INO-5401 plus 1 mg INO-9012 (every 3 weeks x 4 doses, then Q9W) is given IM with EP by CELLECTRA® 2000 with cemiplimab (350 mg IV Q3W). RT is given as 40 Gy over 3 weeks. TMZ is given with radiation (all patients), and adjuvantly (Cohort B only). RESULTS Fifty-two subjects enrolled: 32 in Cohort A; 20 in Cohort B. 35% women; median age 60 years (19–78 years). The adverse event profile is consistent with single-agent (INO-5401, INO-9012, EP and cemiplimab) reported events. OS at 12 months was 84.4% (Cohort A) and 85% (Cohort B). OS at 18 months in Cohort A is 50% (95% CI 31.9 - 68.1); median OS is 17.9 months (14.5 - NR); Cohort B OS18 and median OS will be presented. Tumor gene transcripts at diagnosis confirmed expression of INO-5401 antigens. Peripheral immune responses following INO-5401 revealed antigen-specific T cell responses by Interferon gamma ELISpot and flow cytometry, including cytokine production and expansion of antigen specific CD8+T cells with lytic potential. CONCLUSIONS INO-5401 + INO-9012, a novel DNA plasmid immunotherapy, demonstrates acceptable risk/benefit and generates robust systemic immune responses to encoded tumor antigens when administered with cemiplimab and RT/TMZ in newly diagnosed GBM patients. Overall survival is encouraging. Clinical trial information: NCT03491683.

BACKGROUND Comprehensive next generation sequencing (NGS) is available through many academic institutions and commercial entities, and is incorporated in practice guidelines for glioblastoma (GBM). We retrospective evaluated the practice patterns and utility of incorporating NGS data into routine care of GBM patients at a clinical trials-focused academic center. METHODS We identified 1,011 consecutive adult patients with histologically confirmed GBM with OncoPanel testing, a targeted exome NGS platform of 447 cancer-associated genes at Dana Farber Cancer Institute (DFCI), from 2013-2019. We selected and retrospectively reviewed clinical records of all IDH-wildtype GBM patients treated at DFCI. RESULTS We identified 557 GBM IDH-wildtype patients, of which 227 were male (40.7%). OncoPanel testing revealed 833 single nucleotide variants and indels in 44 therapeutically relevant genes (Tier 1 or 2 mutations) including PIK3CA (n=51), BRAF (n=9), FGFR1 (n=8), MSH2 (n=4), MSH6 (n=2) and MLH1 (n=1). Copy number analysis revealed 509 alterations in 18 therapeutically relevant genes including EGFR amplification (n= 186), PDGFRA amplification (N=39) and CDKN2A/2B homozygous loss (N=223). Median overall survival was 17.5 months for the whole cohort. Seventy-four therapeutic clinical trials accrued 144 patients in the upfront setting (25.9%) and 203 patients (36.4%) at recurrence. Altogether, NGS data for 107 patients (19.2%) were utilized for clinical trial enrollment or targeted therapy indications. High mutational burden (>17mutations/Mb) was identified in 11/464 samples (2.4%); of whom 3/11 received immune checkpoint blockade. Four patients received compassionate use therapy targeting EGFRvIII (rindopepimut, n=2), CKD4/6 (abemaciclib, n=1) and BRAFV600E (dabrafenib/trametinib, n=1). CONCLUSION While NGS has greatly improved diagnosis and molecular classification, we highlight that NGS remains underutilized in selecting therapy in GBM, even in a setting where clinical trials and off-label therapies are relatively accessible. Continued efforts to develop better targeted therapies and efficient clinical trial design are required to maximize the potential benefits of genomically-stratified data.

Three-dimensional patient derived cultures hold great potential for use as personalized functional diagnostics, enabling more accurate preclinical evaluations of drug treatments compared to conventional cell lines. Optical imaging of live cells allows for continuous, time lapsed measurements, and can provide drug response data based on rich phenotypic changes of cell cultures. However, current imaging techniques based on 2D microscopy evaluation aren’t readily adaptable to evaluate the drug response of intact spheroids, which may better represent the in vivo environment and retain critical cellular interactions within the tumor microenvironment. Using the IncuCyte live cell imaging platform, we successfully imaged a large cohort (n = 77) of patient derived glioblastoma spheroid cultures and evaluated whether changes in sphere volume could be used as a direct measure of treatment response. Improving on the default Incucyte analysis software, we developed an R data processing pipeline better suited for spheroid measurements, which quantified the heterogeneity in GBM baseline spheroid growth, and calculated a drug response score based on spheroid changes in response to DNA damaging agents (TMZ as an example). Compared to conventional viability measurements, this novel 3D drug response score was found to accurately identify both drug sensitive and resistant spheroids and showed robust concordance with genomic biomarkers of response (NGS and MGMT promoter methylation) and patient outcomes. Additionally, we coupled the 3D drug score with known genetic data to explore other key pathways and genes involved in TMZ response. We provide here novel analysis methods and public code (Github) to advance the use of IncuCyte spheroid measurements, and deconvolute 3D spheroid drug response into a quantifiable statistic. These methods are adaptable to freshly isolated patient cells for rapid evaluation of treatment response in GBM patients while remaining widely applicable to other cancers such as pancreatic, colon, and non-cancer organoids/spheroids with 3D growth.

BACKGROUND The cyclin D-CDK4/6-Rb pathway is activated in most glioblastomas. Abemaciclib is a potent CDK4/6 inhibitor with good brain penetration approved for ER/PR/HER2- breast cancer. In order to efficiently evaluate the potential impact of abemaciclib on overall survival (OS) in newly diagnosed glioblastoma and to simultaneously develop information regarding potential genomic biomarker associations, abemaciclib was included as an arm on the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial. INSIGhT is a phase II platform trial using response adaptive randomization and deep genomic profiling to more efficiently test experimental agents in MGMT unmethylated glioblastoma and potentially accelerate identification of novel therapies for phase III testing. Initial randomization was equal between abemaciclib, control, and two other experimental arms but subsequent randomization was adapted based on efficacy as determined by progression-free survival (PFS). Ineffective arms were discontinued and new arms added by protocol amendment. We report preliminary results for the abemaciclib arm which has completed accrual. METHODS Patients with newly diagnosed MGMT-unmethylated glioblastoma were randomized to receive either radiotherapy with concomitant and adjuvant temozolomide at standard doses or standard radiochemotherapy followed by adjuvant abemaciclib (150–200 mg orally BID) without temozolomide. Treatment continued until progression or development of unacceptable toxicities. The primary endpoint was OS. Association between abemaciclib efficacy and cyclin D-CDK4/6-Rb pathway genomic alterations was also investigated. RESULTS There were 123 patients (50 control; 73 treated with abemaciclib). Abemaciclib was generally well-tolerated with no new toxicity signals identified. PFS was significantly longer (p=0.03, logrank test) with abemaciclib (median 6.31 months 95% CI [5.29, 8.18]) compared to the control arm (5.16 months 95% CI [4.37, 6.28]). 28/50 control and 36/73 abemaciclib patients remain alive. CONCLUSION Preliminary analysis suggests that abemaciclib increases PFS compared to control. Updated toxicity, PFS and survival data and potential genomic biomarker associations will be presented.

BACKGROUND CC-115 is an oral, CNS-penetrant, selective inhibitor of mammalian target of rapamycin kinase (mTOR) and deoxyribonucleic acid-dependent protein kinase (DNA-PK). Both targets are important in glioblastoma; PI3K/Akt/mTOR signaling is hyperactive in most glioblastomas, and DNA-PK is integral to repair of radiotherapy-mediated DNA damage. To investigate CC-115 in newly diagnosed glioblastoma and explore potential genomic biomarker associations, CC-115 was evaluated in the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial, an adaptive platform trial designed to efficiently test experimental agents. METHODS Adults with newly diagnosed MGMT-unmethylated glioblastoma, with genomic data available, are eligible for this ongoing trial. Patients are adaptively randomized to one of several experimental arms or the control arm: standard radiotherapy with concurrent and adjuvant temozolomide. The primary endpoint is overall survival (OS). Patients randomized to CC-115 (10mg po BID) received it concurrently with radiotherapy and as adjuvant monotherapy. As the first in-human use of CC-115 with radiation, a safety lead-in 3 + 3 design was used. RESULTS Twelve patients were randomized to CC-115; seven patients had possible treatment-related CTCAE grade > 3 toxicity, including four pre-specified dose-limiting toxicities: liver function abnormality (n=1), hyperlipidemia (n=1), lipase elevation (n=1) and cerebral edema (n=1). There was no significant difference in progression-free survival (PFS, median 4.2 months [CC-115] vs. 5.2 months, p=0.9) or OS (median 10.1 months [CC-115] vs. 14.5 months, p=0.9) compared to the 50 patients randomized to the control arm. Based on early PFS results, randomization probability to CC-115 decreased from 25% to < 10% at time of the trial arm closure. CONCLUSION Concurrent and adjuvant CC-115 was associated with toxicity and failed to improve PFS or OS. The INSIGhT trial design allowed for more efficient testing of CC-115, decreasing patients and resources allocated to a therapy that was discontinued due to concerns about toxicity and unfavorable risk-to-benefit ratio.

PURPOSE Vascular endothelial growth factor (VEGF) is upregulated in glioblastoma and may contribute to immunosuppression. We performed a phase 2 study of pembrolizumab, a programmed death-1 (PD-1) blocking antibody alone or with the anti-VEGF antibody bevacizumab in recurrent glioblastoma with detailed analyses of biomarkers and patient neurologic function. METHODS Eighty bevacizumab-naive, recurrent glioblastoma patients were randomized to receive pembrolizumab with bevacizumab (cohort A, n=50) or pembrolizumab monotherapy (cohort B, n=30). The primary endpoint was six-month progression-free survival (PFS-6). Exploratory endpoints included evaluation of tumor PD-L1 expression, TIL density, immune activation gene expression signature and plasma cytokines with outcome. Changes in neurologic function were prospectively assessed using the Neurologic Assessment in Neuro-Oncology (NANO) scale. RESULTS Pembrolizumab alone or with bevacizumab was well tolerated but of limited benefit. For cohort A, PFS-6 was 26.0% (95% CI: 16.3, 41.5), median OS was 8.8 months (95% CI: 7.7, 14.2), ORR was 20% and median duration of response was 48 weeks. For cohort B, PFS-6 was 6.7% (95% CI: 1.7, 25.4), median OS was 10.3 months (95% CI: 8.5, 12.5) and ORR was 0%. Factors associated with worsened OS included baseline dexamethasone use and increased post-therapy plasma VEGF (cohort A) and wild-type IDH1, unmethylated MGMT and increased baseline PlGF and sVEGFR1 levels (cohort B), but tumor immune markers were not informative. The NANO scale effectively predicted neurologic function. CONCLUSIONS Although well tolerated, pembrolizumab was ineffective both as monotherapy and with bevacizumab for recurrent glioblastoma. Nonetheless, radiographic responses to combinatorial therapy were durable. Baseline dexamethasone use and plasma cytokines but not tumor immunologic biomarkers were associated with outcome. Neurologic function evaluated by the NANO scale contributed to outcome assessment.

BACKGROUND Dexamethasone, a uniquely potent corticosteroid, is frequently administered to brain tumor patients to decrease tumor-associated edema, but limited data exist describing how dexamethasone affects the immune system systemically and intratumorally in glioblastoma patients – particularly in the context of immunotherapy. METHODS We evaluated the dose-dependent effects of dexamethasone when administered with anti-PD-1 and/or radiotherapy in immunocompetent C57BL/6 mice with syngeneic GL261 or CT-2A glioblastoma tumors, including analyses of intracranial tumors, draining lymph nodes, and spleen. Clinically, the effect of dexamethasone on survival was additionally evaluated in 181 consecutive IDH-wildtype glioblastoma patients treated with anti-PD-(L)1, with adjustment for relevant prognostic factors. RESULTS Despite the inherent responsiveness of GL261 to immune checkpoint blockade, concurrent dexamethasone administration with anti-PD-1 therapy decreased survival in a dose-dependent fashion and decreased survival following anti-PD-1 plus radiotherapy in both GL261 and immunoresistant CT-2A models. Dexamethasone quantitatively decreased T lymphocytes by reducing the proliferation while increasing apoptosis. Dexamethasone also decreased lymphocyte functional capacity. Myeloid and NK cell populations were also generally reduced. Thus, dexamethasone negatively affects both the adaptive and innate immune responses. As a clinical correlate, a retrospective analysis of 181 consecutive IDH-wildtype glioblastoma patients treated with PD-(L)1 blockade revealed worse survival among those on baseline dexamethasone. Upon multivariable adjustment with relevant prognostic factors, baseline dexamethasone use – regardless of dose – was the strongest predictor of poor survival (reference no dexamethasone; < 2mg HR 2.28, 95%CI=1.41–3.68, p=0.001; ≥2mg HR 1.97, 95%CI=1.27–3.07, p=0.003). CONCLUSIONS Our preclinical and clinical data indicate that concurrent dexamethasone therapy may be detrimental to immunotherapeutic approaches for glioblastoma patients. Our preclinical analyses also suggest that dexamethasone’s detrimental effects are dose-dependent, suggesting that the lowest possible dose should be used for patients when dexamethasone use is unavoidable. Careful evaluation of dexamethasone use is warranted for neuro-oncology patients undergoing immunotherapy clinical trials.

In oncology, “immunotherapy” is a broad term encompassing multiple means of utilizing the patient’s immune system to combat malignancy. Prominent among these are immune checkpoint inhibitors, cellular therapies including chimeric antigen receptor T-cell therapy, vaccines, and oncolytic viruses. Immunotherapy for glioblastoma (GBM) has had mixed results in early trials. In this context, the past, present, and future of immune oncology for the treatment of GBM was discussed by clinical, research, and thought leaders as well as patient advocates at the first annual Remission Summit in 2019. The goal was to use current knowledge (published and unpublished) to identify possible causes of treatment failures and the best strategies to advance immunotherapy as a treatment modality for patients with GBM. The discussion focuses on past failures, current limitations, failure analyses, and proposed best practices moving forward.

Glioblastomas are the most common form of malignant primary brain tumor and an important cause of morbidity and mortality. In recent years there have been important advances in understanding the molecular pathogenesis and biology of these tumors, but this has not translated into significantly improved outcomes for patients. In this consensus review from the Society for Neuro-Oncology (SNO) and the European Association of Neuro-Oncology (EANO), the current management of isocitrate dehydrogenase wildtype (IDHwt) glioblastomas will be discussed. In addition, novel therapies such as targeted molecular therapies, agents targeting DNA damage response and metabolism, immunotherapies, and viral therapies will be reviewed, as well as the current challenges and future directions for research.

BACKGROUND The neurologic assessment in neuro-oncology (NANO) scale was developed as a standardized metric to objectively measure neurologic function in patients with brain tumors and complement radiographic assessment in defining overall outcome. The scale has been incorporated in clinical trials. Early data is suggestive of feasibility and that NANO contributes to overall outcome assessment. However, real-world use of the NANO scale to drive clinical-decision making and the predictive value of the NANO scale to determine overall survival remains unclear in IDH-wt GBM. METHODS We report on an ongoing study using the NANO scale to evaluate neurologic function in patients with IDH-wt GBM, seen at Dana-Farber Cancer Institute (DFCI). Patient demographics, tumor histology and molecular status, treatment history and progression dates are being captured. NANO score, as collected by a built-in scale in our institutional electronic medical record (EMR), functional status (Karnofsky performance status) and corticosteroid dose are collected at prespecified time points (prior to start of therapy, and during each subsequent MRI visit). Changes in the NANO score will be correlated to overall survival. Statistical analyses including descriptive data analysis and generalized linear models will be performed using R (version 3.4.3). RESULTS Since June 2020, 50 patients have been enrolled in this study, including 42 (84%) with ≥2 follow up visits. Study accrual was initially impacted by the COVID-19 pandemic, but adaptation to a virtual platform for NANO allowed for improved recruitment and follow up of patients. Study results will be available for discussion at the 2021 SNO conference. CONCLUSIONS Evaluation of neurologic function by NANO is feasible in a virtual framework in a prospective study in patients with GBM, aided by integration of the scale in our institutional EMR. NANO is able to objectively track neurologic function throughout disease course in IDH-wt GBM.

BACKGROUND Hypermutation is an emerging biomarker for predicting response to immunotherapy in cancer patients, however its clinical value in gliomas is not established. We sought to assess the determinants of hypermutation in gliomas, and its value for predicting response to standard of care and immune checkpoint blockade (ICB). METHODS We performed comprehensive genomic characterization of 2,420 clinically annotated gliomas. We assessed the clinical and molecular characteristics associated with hypermutation and relationships between hypermutation and response to cancer treatments. RESULTS Hypermutation occurred predominantly as an adaptive resistance mechanism to temozolomide in gliomas and was most prevalent in recurrent gliomas with MGMTpromoter methylation (33.8%), IDH1/2mutation (41.0%) or 1p/19q co-deletion (59.5%). Hypermutation was almost always associated with molecular defects in DNA mismatch repair (MMR), and was associated with shorter survival after its appearance based on multivariate analysis (hazard ratio 1.91; 95% CI 1.24–2.94; P=0.004). The molecular mechanisms whereby gliomas undergo hypermutation during therapy with alkylating agents were dissected using patient-derived glioma models in vitro and in vivo. Outcomes of hypermutated gliomas treated with immune checkpoint blockade or with standard of care agents will be presented at the conference. CONCLUSIONS Using the largest set of hypermutated gliomas described to date, this study establishes that mutational burden and mutation signatures are clinically and biologically significant biomarkers that can be used to predict therapy response and guide treatment decisions in gliomas

INTRODUCTION Herein we examine the epidemiology across all pediatric intracranial tumors in the U.S. METHODS Pediatric patients (< 20yo) presenting between 2010–2015 with an intracranial tumor as the first evidence of cancer were queried from the National Cancer Database, which comprises >70% of cancers newly-diagnosed in the U.S. Tumor types were classified by WHO2016 ICD-O3. RESULTS 14,952 pediatric patients without a history of cancer presented with intracranial tumors between 2010–2015. Across all ages, these were comprised of 1) 22% diffuse astrocytic and oligodendroglial (n=3,328), 2) 17% sellar region (n=2,530), 3) 16% other astrocytic (n=2,378, 2,131 were pilocytic and pilomyxoid), 4) 13% embryonal (n=1,896; 1,092 were classic histology medulloblastomas), 5) 7% neuronal and mixed neuronal-glial (n=981), 6) 5% ependymal (n=752), 7) 4% GCTs (n=615), 8) 3% mesenchymal non-meningothelial (n=492), 9) 3% nerve sheath (n=428), and 10) ≤2% each of meningioma, choroid plexus, brain metastatic (44% from neuroblastoma), pineal region, hematologic, and other glioma tumors. Embryonal tumors predominated in neonates and infants (0-2yo), diffuse gliomas in childhood (3-11yo), and sellar tumors in adolescents (12-19yo). Females represented 49% of the cases, but sellar tumors predominated (23%, vs. only 11% in males); whereas in males diffuse gliomas predominated (23%; vs. 22% in females) overall and in pediatric patients older than 2yo. CONCLUSIONS In U.S. pediatric patients that present with a new intracranial tumor, embryonal tumors and diffuse gliomas predominate in infants ≤2yo, and continue to predominate in male children 3-11yo, whereas female children 3-11yo shifted towards a predominance by diffuse gliomas and other astrocytic tumors (e.g. pilocytic and pilomyxoid). In female adolescents 12-19yo, sellar tumors predominated, followed by diffuse gliomas; whereas in male adolescents diffuse gliomas predominated, followed by other astrocytic tumors and sellar tumors. Our findings demonstrate that newly-diagnosed intracranial masses in pediatric patients significantly vary by both age and sex.

BACKGROUND Among patients with glioma, little is known about the clinical significance of hypermutation. We sought to define the determinants of hypermutation in gliomas, and to assess the value of this biomarker for predicting response to standard of care and immune checkpoint blockade. MATERIAL AND METHODS We performed comprehensive molecular characterization of 2420 pediatric and adult gliomas with clinical annotation. We determined the clinical and molecular characteristics associated with hypermutation, and assessed the relationship between hypermutation and clinical response to cancer therapies. RESULTS Overall, 114 hypermutated gliomas were identified. Hypermutation occurred predominantly in therapy-responsive subtypes characterized by methylated MGMT promoter, IDH1/2mutation or 1p/19q co-deletion. Hypermutation was almost always associated with prior treatment with temozolomide and molecular defects in DNA mismatch repair (MMR), which were identified in one-third of IDH1/2-mutated recurrent gliomas and was associated with shorter survival in multivariate analyses (hazard ratio 2.11 [95% CI 1.24–3.6], P=0.006). The molecular mechanisms whereby gliomas undergo hypermutation during therapy with alkylating agents were dissected using patient-derived glioma models in vitro and in vivo. Outcomes of hypermutated gliomas treated with immune checkpoint blockade or with standard of care agents will be presented at the conference. CONCLUSION This study establishes that mutation burden and mutation signatures are clinically and biologically significant biomarkers that can be used to predict therapy response and guide treatment decisions in gliomas.

BACKGROUND: TGF- signaling promotes tumor immunosuppression; TGF- inhibition in the tumor microenvironment may enhance the response to antiPD-L1 treatment. M7824 is an innovative, first-in-class, bifunctional fusion protein composed of a human antiPD-L1 IgG1 monoclonal antibody fused with two extracellular domains of TGF RII to function as a TGF- trap. We report safety and efficacy of M7824 in patients with rGBM. METHODS: In this efficacy expansion cohort of the ongoing, phase 1 trial NCT02517398, patients with rGBM who progressed after chemoradiation received M7824 1200 mg q2w until disease progression, unacceptable toxicity, or trial withdrawal. The primary objective was disease control rate (DCR) per RANO; secondary objectives included safety/tolerability. RESULTS: Among 35 patients, median age was 57 years, 68.6% were male, and 91.4% were at first recurrence. At 15 months minimum follow-up, median treatment duration was 8.1 (range, 2.0–72.1) weeks; four patients remained on treatment at >1 year, and one additional patient decided to stop treatment per protocol at 12 months. Two patients had a partial response, and nine had stable disease (DCR, 31.4% [95% CI, 16.9–49.3]), of which two exhibited early progressive disease and subsequent durable stable disease ongoing for >12 months per investigators assessment. The most common treatment-related adverse events (TRAEs) were gingival bleeding (17.1%), asthenia (14.3%), pruritus, and rash (each 11.4%). Grade 3 TRAEs (6 patients, 17.1%) included diarrhea, eczema, increased liver/pancreatic enzymes, papular rash, papules, one grade 4 asymptomatic increased lipase, and one grade 5 intratumoral hemorrhage (investigator-assessed) coterminous with disease progression. CONCLUSIONS: M7824 demonstrated a manageable safety profile and encouraging efficacy in rGBM, including two durable partial responses and a DCR of 31.4%. Further investigation of M7824 in GBM is warranted; future development aims to define molecular characteristics of responders.

BACKGROUND: MMR deficiency (MMRd) is found in a subset of gliomas. Emerging evidence indicates that MMRd could serve as predictive biomarker for both response to immunotherapy and resistance to alkylating agents. However, the molecular epidemiology, outcome, and the optimal diagnostic method of MMRd are poorly defined in gliomas. METHODS: A cohort of 350 adult gliomas was characterized as to WHO 2016 diagnosis, IDH1/2 sequencing, MGMT promoter methylation, prior treatment and outcome. Immunohistochemistry of MMR proteins (MSH2, MSH6, MLH1, PMS2) was performed in 260 tumors with available tissue. 100 tumors were analyzed with next generation targeted exome sequencing (NGS, Oncopanel) of 447 cancer genes, including full exon coverage of MMR genes. Comparisons between results from IHC, NGS and microsatellite instability (MSI) testing using pentaplex PCR amplification testing were incorporated to inform best practices. RESULTS: 53/260 tumors showed immunohistochemical (ie MMR protein staining loss) and/or molecular (ie presence of MMR pathogenic mutation with hypermutation) evidence of MMRd. No MSI was found by pentaplex PCR. 38/260 tumors harbored loss of protein expression of one or two MMR proteins: 15 showed loss of MSH6 protein (with/without concomitant MSH2 loss) and 23 had loss of PMS2 (with/without MLH1 loss). Analysis of 201 consecutive recurrent tumors from alkylator pre-treated patients showed significant association between MMRd and the presence of IDH1/2 mutation: MMRd in 20/90 (22.2%) of IDH1/2-mutant tumors vs 2/111 (1.8%) of IDH1/2-wild-type tumors (p

Glioblastoma is the most common malignant brain tumor in adults and is associated with poor survival. It is often resistant to standard-of-care chemotherapy and radiation, necessitating the development of more effective treatments. The Ivy Foundation Early Phase Clinical Trials’ Consortium conducted a randomized, multi-institution clinical trial to evaluate the immune response and survival following neoadjuvant and adjuvant therapy with pembrolizumab, a PD-1 monoclonal antibody, in thirty patients with recurrent, surgically resectable glioblastoma. Patients who received neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that received adjuvant, post-surgical PD-1 blockade alone (HR=0.33, p

Blockade of immune cell co-inhibitory receptor PD-1 using monoclonal antibodies (mAbs) allows the development of anti-tumor immunity in various solid tumors and lymphoid malignancies. We recently demonstrated that PD-1 blockade elicits an anti-tumor immune response resulting in tumor rejection and long-term survival in approximately 50% of mice with intra-cranial GL-261 glioblastoma, despite the absence of accumulating CD8+ cytotoxic T cells in the tumor or draining lymph nodes. In this investigation, we provide evidence for the role of conventional CD4+ T cells and the innate immune response in PD-1 mediated anti-glioma immunity in this model. In response to anti-PD-1 monotherapy, intratumoral CD4+ T cells, but not CD8+ T cells, expressed significantly elevated levels of IFN-γ and TNF-α pro-inflammatory cytokines and the cytotoxic enzyme, granzyme B. Tbet, GATA3, and EOMES, transcription factors required for T cell proliferation, activation, and effector function, were also up-regulated in CD4+, but not CD8+ T cells in the brains of mice treated with PD-1 mAbs when compared to controls. We demonstrated that depletion of CD4+ or CD8+ T cells, but not NK, was sufficient to completely ablate anti-PD-1-mediated tumor eradication and long-term survival. CD4+ T cell activation was accompanied by the classical activation and M1 polarization of resident microglia and tumor-infiltrating macrophages. Together, these studies demonstrate for the first time a role for CD4+ T cells and the innate immune response in the eradication of glioblastoma by PD-1 blockade.

BACKGROUND: Durva is a human IgG1 mAb against PD-L1. Blockade of PD-1/PD-L1 has shown benefit among solid tumors; data implicate PD-1/PD-L1 signaling as a significant contributor to immunosuppression in GBM. BEV is an approved angiogenesis inhibitor for recurrent GBM; angiogenesis inhibition may promote antitumor benefit of immunotherapies. A review showed that lower dose BEV resulted in longer PFS/OS than the standard. METHODS: Ongoing Phase 2 open-label study (NCT02336165) evaluates safety and efficacy of durva (10mg/kg Q2W) in 5 GBM cohorts. Results are presented for Cohorts B2 (durva + BEV 10mg/kg Q2W) and B3 (durva +BEV 3mg/kg Q2W) in BEV-naïve recurrent GBM. Primary efficacy endpoint for Cohorts B2/B3 is 6-month progression-free survival (PFS6), by modified RANO per investigator assessment; secondary endpoints include safety/tolerability. Comparative benchmark for BEV in recurrent GBM is PFS6 of 42%. The null hypothesis (PFS6 ≤42%) was tested in Intent-to-Treat (ITT) population against the alternative hypothesis (PFS6 ≥62%). ITT includes patients receiving any dose of durva and having at least baseline and 1 post-baseline tumor assessment. Durva alone in Cohort B of this study demonstrated PFS6 of 20% (90% CI: 9.7, 33.0). RESULTS: As of 02Apr2018, 33 patients were treated in each cohort (B2, male: 54.5%, median age: 57.0 [40–74] years; B3, male: 60.6%, median age: 54.0 [23–73] years). Most common treatment-related adverse events (TRAEs, in ≥4 [12.1%] patients in either cohort): fatigue, dysphonia, increased ALT, AST, amylase, or lipase, diarrhea, hypertension, arthralgia, headache, and proteinuria. Incidences of TRAEs by maximum CTCAE grade (Gr) ≥3 for Cohorts B2/B3 were Gr3: 24.2/6.1%; Gr4: 0/6.1%; and Gr5: 0/0%. Kaplan-Meier estimate for PFS6 (n=33 each): B2, 15.2% (80% CI: 8.2, 24.0); B3, 21.1% (80% CI: 12.4, 31.4); 3 patients in each cohort showed partial response. CONCLUSIONS: The addition of durva to BEV did not improve on the outcome of durva alone.

BACKGROUND: Advances in genomic profiling, together with a better understanding of cancer genetic drivers have generated opportunities for precision medicine trials in newly diagnosed glioblastoma (GBM). ALLELE is a consortium to create independent infrastructure for prospective genomics and functional diagnostics to support biomarker-driven trials in GBM. METHODS: Multi-center prospective study of molecular profiling in newly diagnosed GBM. Clinical (CLIA) tumor/normal whole exome sequencing (WES) and genome-wide copy number array (CNA) were performed. Primary objective: to evaluate the feasibility of genotyping tumors with a turnaround time allowing prospective data use in prospective trials. Secondary objectives included developing infrastructure for novel functional biomarker assays and investigating the clinical yield of tumor/normal WES and CNA in GBM. RESULTS: As of 5/1/18, 65 patients with GBM enrolled among 7 sites. Median age was 59. WES and CMA were completed in 60 patients, with a median time between tissue submission and reporting of 22 days (range 15–35). 33 patients were enrolled in INSIGhT, a randomized platform adaptive trial comparing standard of care versus adjuvant CC-115, neratinib or abemaciclib in MGMT unmethylated newly diagnosed GBM (NCT02977780). In each arm, pre-defined biomarkers (EGFR, PI3K and CDK) will be evaluated for their ability to predict outcome. Potentially actionable findings were identified in 30 patients, and included EGFR amplification, mutations of BRAF, FGFR1, IDH1/2 or FGFR3 or MET fusion. Four tumors were reclassified based on genomics. Functional biomarker assays were developed for real-time evaluation of pharmacodynamic responses in ex vivo models. Updated results of exploratory biomarker analyses will be presented at the conference. CONCLUSIONS: Real-time WES, copy number arrays and functional diagnostics are feasible in newly diagnosed glioblastoma, and can support a variety of biomarker-driven trials. Genomic analyses conducted in a prospective manner can inform subsequent clinical trial analysis aiming at matching outcome with tumor genotyping.

INTRODUCTION: Evophosphamide is a hypoxia-activated prodrug that, when activated in hypoxic conditions, (

BACKGROUND: To test the hypothesis that, despite bleeding risk, anticoagulants improve outcome in glioblastoma because of reduced incidence of venous thromboembolic events and modulation of angiogenesis, infiltration and invasion. MATERIAL AND METHODS: We assessed survival associations of anticoagulant use from baseline up to start of temozolomide chemoradiotherapy (TMZ/RT) (period I) and from there to the start of maintenance TMZ chemotherapy (period II) by pooling data of three randomized clinical trials in newly diagnosed glioblastoma including 1,273 patients. Progression-free survival (PFS) and overall survival (OS) were compared between patients with: anticoagulant use versus no use; therapeutic versus prophylactic versus no use; different durations of anticoagulant use versus no use; anticoagulant use versus use of anti-platelet agents, versus neither nor. Cox regression models were stratified by trial and adjusted for baseline prognostic factors. RESULTS: Anticoagulant use was documented in 75 patients (5.9%) in period I and in 104 patients (10.2%) in period II. Anticoagulant use during period II, but not period I, was associated with inferior OS compared to no use on multivariate analysis (p=0.001, HR=1.52, 95% CI: 1.18–1.95). No decrease in OS became apparent when only patients with prophylactic anticoagulant use were considered. No survival association was established for anti-platelet agent use. CONCLUSION: Anticoagulant use was not associated with improved OS. Anticoagulants may not exert relevant anti-tumor properties in glioblastoma.

Blockade of immune cell co-inhibitory receptor PD-1 using monoclonal antibodies (mAbs) allows the development of anti-tumor immunity in various solid tumors and lymphoid malignancies. We recently demonstrated that PD-1 blockade elicits an anti-tumor immune response resulting in tumor rejection and long-term survival in approximately 50% of mice with intra-cranial GL-261 glioblastoma, despite the absence of accumulating CD8+ cytotoxic T cells in the tumor or draining lymph nodes. In this investigation, we provide evidence for the role of conventional CD4+ T cells and the innate immune response in PD-1 mediated anti-glioma immunity in this model. In response to anti-PD-1 monotherapy, intratumoral CD4+ T cells, but not CD8+ T cells, expressed significantly elevated levels of IFN-γ and TNF-α pro-inflammatory cytokines and the cytotoxic enzyme, granzyme B. Tbet, GATA3, and EOMES, transcription factors required for T cell proliferation, activation, and effector function, were also up-regulated in CD4+, but not CD8+ T cells in the brains of mice treated with PD-1 mAbs when compared to controls. We demonstrated that depletion of CD4+ or CD8+ T cells, but not NK, was sufficient to completely ablate anti-PD-1-mediated tumor eradication and long-term survival. CD4+ T cell activation was accompanied by the classical activation and M1 polarization of resident microglia and tumor-infiltrating macrophages. Moreover, CSF-1 inhibition with PLX3397 to deplete microglia and macrophages did not affect tumor growth, but did lead to a significant survival advantage when combined with anti-PD-1 mAb. Together, these studies demonstrate for the first time a role for CD4+ T cells and the innate immune response in the eradication of glioblastoma by PD-1 blockade.

Background Combined immunotherapy approaches are promising cancer treatments. We evaluated anti-programmed cell death protein 1 (PD-1) treatment combined with gene-mediated cytotoxic immunotherapy (GMCI) performed by intratumoral injection of a prodrug metabolizing nonreplicating adenovirus (AdV-tk), providing in situ chemotherapy and immune stimulation. Methods The effects of GMCI on PD ligand 1 (PD-L1) expression in glioblastoma were investigated in vitro and in vivo. The efficacy of the combination was investigated in 2 syngeneic mouse glioblastoma models (GL261 and CT-2A). Immune infiltrates were analyzed by flow cytometry. Results GMCI upregulated PD-L1 expression in vitro and in vivo. Both GMCI and anti-PD-1 increased intratumoral T-cell infiltration. A higher percentage of long-term survivors was observed in mice treated with combined GMCI/anti-PD-1 relative to single treatments. Long-term survivors were protected from tumor rechallenge, demonstrating durable memory antitumor immunity. GMCI led to elevated interferon gamma positive T cells and a lower proportion of exhausted double positive PD1+TIM+CD8+ T cells. GMCI also increased PD-L1 levels on tumor cells and infiltrating macrophages/microglia. Our data suggest that anti-PD-1 treatment improves the effectiveness of GMCI by overcoming interferon-induced PD-L1-mediated inhibitory signals, and GMCI improves anti-PD-1 efficacy by increasing tumor-infiltrating T-cell activation. Conclusions Our data show that the GMCI/anti-PD-1 combination is well tolerated and effective in glioblastoma mouse models. These results support evaluation of this combination in glioblastoma patients.

Background Anti-angiogenic therapy with bevacizumab is the most widely used treatment option for recurrent glioblastoma, but therapeutic response varies substantially and effective biomarkers for patient selection are not available. To this end, we determine whether novel quantitative radiomic strategies on the basis of MRI have the potential to noninvasively stratify survival and progression in this patient population. Methods In an initial cohort of 126 patients, we identified a distinct set of features representative of the radiographic phenotype on baseline (pretreatment) MRI. These selected features were evaluated on a second cohort of 165 patients from the multicenter BRAIN trial with prospectively acquired clinical and imaging data. Features were evaluated in terms of prognostic value for overall survival (OS), progression-free survival (PFS), and progression within 3, 6, and 9 months using baseline imaging and first follow-up imaging at 6 weeks posttreatment initiation. Results Multivariable analysis of features derived at baseline imaging resulted in significant stratification of OS (hazard ratio [HR] = 2.5; log-rank P = 0.001) and PFS (HR = 4.5; log-rank P = 2.1 × 10-5) in validation data. These stratifications were stronger compared with clinical or volumetric covariates (permutation test false discovery rate [FDR]

Background The aim of this study was to determine correlations between progression-free survival (PFS) and the objective response rate (ORR) with overall survival (OS) in glioblastoma and to evaluate their potential use as surrogates for OS. Method Published glioblastoma trials reporting OS and ORR and/or PFS with sufficient detail were included in correlative analyses using weighted linear regression. Results Of 274 published unique glioblastoma trials, 91 were included. PFS and OS hazard ratios were strongly correlated; R2 = 0.92 (95% confidence interval [CI], 0.71–0.99). Linear regression determined that a 10% PFS risk reduction would yield an 8.1% ± 0.8% OS risk reduction. R2 between median PFS and median OS was 0.70 (95% CI, 0.59–0.79), with a higher value in trials using Response Assessment in Neuro-Oncology (RANO; R2 = 0.96, n = 8) versus Macdonald criteria (R2 = 0.70; n = 83). No significant differences were demonstrated between temozolomide- and bevacizumab-containing regimens (P = .10) or between trials using RANO and Macdonald criteria (P = .49). The regression line slope between median PFS and OS was significantly higher in newly diagnosed versus recurrent disease (0.58 vs 0.35, P = .04). R2 for 6-month PFS with 1-year OS and median OS were 0.60 (95% CI, 0.37–0.77) and 0.64 (95% CI, 0.42–0.77), respectively. Objective response rate and OS were poorly correlated (R2 = 0.22). Conclusion In glioblastoma, PFS and OS are strongly correlated, indicating that PFS may be an appropriate surrogate for OS. Compared with OS, PFS offers earlier assessment and higher statistical power at the time of analysis.

Background. High-grade gliomas with mutations in the isocitrate dehydrogenase (IDH) gene family confer longer overall survival relative to their IDH-wild-type counterparts. Accurate determination of the IDH genotype preoperatively may have both prognostic and diagnostic value. The current study used a machine-learning algorithm to generate a model predictive of IDH genotype in high-grade gliomas based on clinical variables and multimodal features extracted from conventional MRI. Methods. Preoperative MRIs were obtained for 120 patients with primary grades III (n = 35) and IV (n = 85) glioma in this retrospective study. IDH genotype was confirmed for grade III (32/35, 91%) and IV (22/85, 26%) tumors by immunohistochemistry, spectrometry-based mutation genotyping (OncoMap), or multiplex exome sequencing (OncoPanel). IDH1 and IDH2 mutations were mutually exclusive, and all mutated tumors were collapsed into one IDH-mutated cohort. Cases were randomly assigned to either the training (n = 90) or validation cohort (n = 30). A total of 2970 imaging features were extracted from pre- and postcontrast T1-weighted, T2-weighted, and apparent diffusion coefficient map. Using a random forest algorithm, nonredundant features were integrated with clinical data to generate a model predictive of IDH genotype. Results. Our model achieved accuracies of 86% (area under the curve [AUC] = 0.8830) in the training cohort and 89% (AUC = 0.9231) in the validation cohort. Features with the highest predictive value included patient age as well as parametric intensity, texture, and shape features. Conclusion. Using a machine-learning algorithm, we achieved accurate prediction of IDH genotype in high-grade gliomas with preoperative clinical and MRI features.

Background Bevacizumab is a humanized antibody against vascular endothelial growth factor approved for treatment of recurrent glioblastoma. There is a need to discover imaging biomarkers that can aid in the selection of patients who will likely derive the most survival benefit from bevacizumab. Methods The aim of the study was to examine if pre- and posttherapy multimodal MRI features could predict progression-free survival and overall survival (OS) for patients with recurrent glioblastoma treated with bevacizumab. The patient population included 84 patients in a training cohort and 42 patients in a testing cohort, separated based on pretherapy imaging date. Tumor volumes of interest were segmented from contrast-enhanced T1-weighted and fluid attenuated inversion recovery images and were used to derive volumetric, shape, texture, parametric, and histogram features. A total of 2293 pretherapy and 9811 posttherapy features were used to generate the model. Results Using standard radiographic assessment criteria, the hazard ratio for predicting OS was 3.38 (P < .001). The hazard ratios for pre- and posttherapy features predicting OS were 5.10 (P < .001) and 3.64 (P < .005) for the training and testing cohorts, respectively. Conclusion With the use of machine learning techniques to analyze imaging features derived from pre- and posttherapy multimodal MRI, we were able to develop a predictive model for patient OS that could potentially assist clinical decision making.

Advances in therapy for glioblastoma (GBM) have provided limited survival and health-related quality of life (HRQoL) benefit. Symptom management and maintaining HRQoL are important metrics for assessing treatment benefit. To inform on these metrics, both clinician- and patient-reported outcome measures to evaluate HRQoL and neurocognitive impairment were included as exploratory endpoints in the randomized cohort 2 of CHECKMATE-143, evaluating nivolumab monotherapy versus bevacizumab in adult patients with recurrent GBM. Clinician assessment of neurologic function will be done using the Neurologic Assessment in Neuro-Oncology (NANO) scale, which includes nine major domains (gait, strength, ataxia, sensation, visual field, facial strength, language, level of consciousness, and behaviour). The Cogstate assessment, consisting of a computerized battery of neurocognitive tests of approximately 15 minutes in duration, was used to evaluate neurocognitive functioning, cognitive deficits and/or executive functioning at baseline, and on day 1 of weeks 13, 21, 45, and 69, and at the time of treatment discontinuation. Patient-reported HRQoL was determined using the EORTC QLQ-C30, an assessment commonly used in oncology studies and comprising six functional scales (physical functioning, cognitive functioning, emotional functioning, social functioning, role functioning, and global QoL) as well as nine symptom scales (fatigue, pain, nausea/vomiting, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties), and the QLQ-BN20, a brain tumor-specific instrument evaluating four domains (future uncertainty, visual disorder, communication deficit, and motor dysfunction). The standardized EuroQoL-5D will be used for self-assessment of general health status across five dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety) and includes a visual analog rating scale. Scoring by using the NANO scale and assessment with the EORTC QLQ-C30, QLQ-BN20 and EQ5D will be done at baseline, weeks 7, 13, and every 8 weeks thereafter until treatment discontinuation. Methodology and baseline information regarding the use of these patient and clinician scales will be reported.

Immunotherapy represents a promising area of therapy among neuro-oncology patients. However, early phase studies reveal unique challenges associated with assessment of radiological changes reflecting delayed responses or therapy-induced inflammation. Clinical benefit, including long-term survival and tumor regression, can still occur following initial apparent progression or appearance of new lesions. Refinement of response assessment criteria for neuro-oncology patients undergoing immunotherapy is therefore warranted. A multinational and multidisciplinary panel of neuro-oncology immunotherapy experts describes immunotherapy response assessment for neuro-oncology (iRANO) criteria that are based on guidance for determination of tumor progression outlined by the immune-related response criteria (irRC) and the response assessment in neuro-oncology (RANO) working group. Among patients who demonstrate imaging findings meeting RANO criteria for progressive disease (PD) within six months of initiating immunotherapy including the development of new lesions, confirmation of radiographic progression on follow-up imaging is recommended provided that the patient is not significantly worse clinically. The proposed criteria also include guidelines for use of corticosteroids. The role of advanced imaging techniques and measurement of clinical benefit endpoints including neurologic and immunologic functions are reviewed. The iRANO guidelines put forth herein will evolve successively to improve their utility as further experience from immunotherapy trials in neuro-oncology accumulate.

BACKGROUND: Clinical outcomes were associated with immune response of HLA-A2+ patients enrolled in a randomized phase 2 trial of ICT-107. METHODS: 124 patients (77 HLA-A2+), randomized 2:1, received ICT-107 (autologous DCs incubated with 6 synthetic peptide CTL epitopes targeting GBM tumor/stem cell-associated antigens MAGE-1, HER-2, AIM-2, TRP-2, gp100, and IL-13Rα2) or matching control (un-incubated DC). Immune response was determined by a functional ELISPOT assay pre- and post-treatment (ICT-107 30.5% vs. 15.5% in controls). Determination of p-values and significance between dependent variables and overall survival (OS) or progression-free survival (PFS) was performed using log-rank test. Fisher's exact tests were performed for association between extended overall survival (EOS: OS > 22.2 months) and extended progression-free survival (EPFS: PFS > 16.5 months) and the same variables. RESULTS: HLA-A2+ patients showed evidence of immune response being associated with both OS and PFS. After determining HLA-A2 ELISPOT responders (responders) using a comprehensive scoring system, responders had a median OS of 23.1 months versus 13.7 for non-responders (p = 0.0673). Similarly, responders had an EOS percentage of 52% versus 29% non-responders (p = 0.0615). Further, responders had a significantly higher percentage of EPFS (41% versus 15%, p = 0.0259). When censored to 7.5 months post-treatment, immune response was found to significantly improve OS (median 17.6 months versus 13.7, p = 0.0018). Level of IL-12 production can be linked to survival. High IL-12 producers had a median OS of 20.6 compared to 15.4 for low producers (p = 0.0515). Within the treatment group, the difference was larger, with medians of 23.3 months versus 15.2 (p = 0.0654), and high producers had a significantly higher percentage of EOS (54% versus 31%, p = 0.0426) and EPFS (43% versus 19%, p = 0.0293). CONCLUSIONS: The associations identified between clinical outcomes of OS and PFS with immunologic response provide support for the efficacy of ICT-107 in HLA-A2+ patients due to a biologic T cell response.

The appropriate use of adjuvant therapy in patients with gross totally resected atypical meningioma requires an accurate assessment of recurrence risk. We sought to determine whether cytogenetic/genetic characterization may facilitate better estimation of the probability of recurrence.We first analyzed our clinical database, including high-resolution DNA copy number data, to identify 11 common copy number aberrations in a pilot cohort of meningiomas of all grades. We summed these aberrations to devise a cytogenetic abnormality score (CAS) and determined the CAS from archived tissue of a separate cohort of 32 patients with gross totally resected atypical meningioma managed with surgery alone. Propensity score adjusted Cox regression was used to determine whether the CAS was predictive of recurrence.An association between higher CAS and higher grade was noted in our pilot cohort with heterogeneity among atypical tumors. Among the 32 patients who underwent gross total resection of an atypical meningioma, the CAS was not significantly associated with age, gender, performance status, or tumor size/location but was associated with the risk of recurrence on univariable analysis (hazard ratio per aberration = 1.52; 95% CI = 1.08-2.14; P = .02). After adjustment, the impact of the dichotomized number of copy aberrations remained significantly associated with recurrence risk (hazard ratio = 4.47; 95% CI = 1.01-19.87; P = .05).The number of copy number aberrations is strongly associated with recurrence risk in patients with atypical meningioma following gross total resection and may inform the appropriate use of adjuvant radiation therapy in these patients or be useful for stratification in clinical trials.

High-grade gliomas, which include glioblastomas (GBMs) and anaplastic gliomas (AGs), are the most common malignant primary brain tumors in adults1 and are associated with poor survival despite maximal surgery, radiation, and chemotherapy.2–4 Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), is frequently used to treat recurrent high-grade glioma (HGG). Bevacizumab monotherapy received accelerated approval for recurrent GBM by the United States Food and Drug Administration in 2009 on the basis of phase II clinical trials demonstrating response rates of 20%–26%, 6-month progression-free survival (PFS6) rates of 29%–42.6%, and median overall survival (OS) of 7.1–9.2 months.5,6 Phase II studies in recurrent AG suggest that bevacizumab plus irinotecan also has activity in this patient population with response rates of 55%–66% and PFS6 rates of 56%–61%.7,8 However, responses to bevacizumab are not durable, and some patients fail to benefit.9 Panobinostat is a potent, small-molecule inhibitor of classes I, II, and IV histone deacetylases (HDACs) with greater potency than vorinostat.10 HDAC inhibitors, including panobinostat, may inhibit angiogenesis by reducing VEGF secretion and modulating the expression of other VEGF family members via inhibition of HIF-1α.11–14 In addition, the SDF-1α/CXCR4 pathway has been implicated in bevacizumab resistance,15–17 and panobinostat depletes CXCR4 levels and signaling.18 A phase I study of panobinostat in combination with bevacizumab for recurrent HGG suggested that oral panobinostat 30 mg 3 times per week, every other week, can be safely combined with bevacizumab 10 mg/kg every other week.19 We conducted a multicenter, phase II trial of panobinostat in combination with bevacizumab in patients with recurrent GBM. We also examined the same combination of agents in patients with recurrent AG as an exploratory arm.

The tumor-specific epidermal growth factor receptor variant III mutation (EGFRvIII) is widely expressed in glioblastoma and thus represents an attractive target for immunotherapeutic approaches. The investigational vaccine rindopepimut is an EGFRvIII peptide sequence conjugated to keyhole limpet hemocyanin and is administered intradermally with GM-CSF. Previous single-arm studies of rindopepimut in newly diagnosed, resected, EGFRvIII+ glioblastoma have shown encouraging PFS and OS. This compassionate use program provided rindopepimut to 61 EGFRvIII+ glioblastoma patients who were ineligible for ongoing clinical trials. Data are currently available on 42 patients, 12 (29%) with newly diagnosed glioblastoma (resected or inoperable) and 30 (71%) with recurrent disease. MGMT methylation was seen in 9/17, while all tested patients were negative for IDH1 (12/12) and IDH2 (7/7). Median age was 53 years (15-70) and median time from diagnosis was 14.5 months (2.7-58.7). Rindopepimut, administered in combination with temozolomide (57%), bevacizumab (57%), and/or other (17%), was well tolerated, with frequent mild injection site reactions and one potentially treatment-related, serious event of cerebral edema. Median peak rindopepimut-induced anti-EGFRvIII titer was 1:1,200 (50% shrinkage in measurable disease) was observed in six patients receiving rindopepimut with other agents. One inoperable glioblastoma patient experienced a CR during treatment with rindopepimut, erlotinib, temozolomide, and bevacizumab, and has continued rindopepimut for >5 years without significant toxicity or disease recurrence. Biopsy at recurrence showed EGFRvIII was eliminated in a patient who received rindopepimut and temozolomide for ∼9 months. In patients with newly diagnosed and recurrent glioblastoma, respectively, median PFS was 9.1 and 2.5 months, and median OS was 15.7 and 8.7 months from first vaccination. In conclusion, rindopepimut in combination with various anticancer therapies resulted in robust anti-EGFRvIII humoral response with minimal toxicity. PFS and OS appear promising in this heterogeneous, poor prognosis population.

Although anti-angiogenic therapy for high-grade glioma is promising, responses are not durable. The SDF-1/CXCR4 axis may help mediate resistance to VEGFR inhibition. Plerixafor is a reversible CXCR4 inhibitor that has demonstrated growth inhibition in glioblastoma xenografts. We conducted a Phase I study to determine the safety and tolerability of plerixafor in combination with bevacizumab in patients with recurrent HGG. A 3 x 3 dose escalation design to a maximum planned dose level of plerixafor 320 µg/kg on Days 1-21 and bevacizumab 10 mg/kg on Days 1 and 15 of each 28 day cycle was used. DLTs were determined during the initial 4 weeks of therapy and included drug-related Grade ≥ 3 non-hematologic toxicities and Grade ≥ 4 hematologic toxicities. Part 1 of the study has been completed with a total of 23 patients enrolled with the following characteristics: median age 58 (23-72), median KPS 90 (70-100), 11 women (47.8%). One DLT (grade 3 rectal fistula) was seen at a dose level of plerixafor 240 µg/kg + bevacizumab and the cohort was expanded. Because no further DLTs were seen at the 240 µg/kg dose level, the maximum planned dose level of plerixafor 320 µg/kg + bevacizumb opened and a total of 12 patients were treated with no DLTs. Treatment was well tolerated with one grade 3 hypophosphatemia and one grade 3 rectal fistula. Preliminary pharmacokinetic data on plerixafor from the first two cohorts compares well with historical PK data. Combination treatment with bevacizumab and plerixafor was well tolerated in the studied HGG patients. No DLTs were encountered at the maximum planned dose level. The study will now expand to a surgical cohort to examine tumor tissue penetration as well as a separate non-surgical cohort with patients treated with continuous daily dosing of plerixafor 320 µg/kg and bevacizumab. Updated results will be presented.

Bevacizumab is frequently used to treat recurrent high-grade gliomas, but responses are generally not durable. Panobinostat is a histone deacetylase inhibitor with anti-neoplastic and anti-angiogenic effects in glioma models and may work synergistically with bevacizumab. We conducted a multicenter phase II trial of panobinostat in combination with bevacizumab. Two cohorts were enrolled: one with recurrent glioblastoma (GBM) as the primary study and one with recurrent anaplastic glioma (AG) as the exploratory study. Patients received oral panobinostat 30 mg 3 x per week, every other week, in combination with bevacizumab 10 mg/kg every other week. The primary endpoint was PFS6 in the GBM cohort and the study was powered to discriminate between a 35% and 55% PFS6 rate (85% power at an alpha level of 0.07). At planned interim analysis, 13 of the first 21 patients accrued to the GBM cohort had progressed within 6 months of initiating study treatment. The GBM cohort did not meet criteria for continued accrual and was closed early. In the GBM cohort, PFS6 rate was 30.4%, median PFS 5 months, median OS 9 months. Accrual in the AG cohort continued to completion and a total of 15 patients were enrolled. In the AG cohort, PFS6 rate was 46.7%, median PFS 7 months, median OS 17 months. The most common grade 3 or 4 toxicities in the GBM arm were hypophosphatemia (12.5%), thrombocytopenia (12.5%), lymphopenia (8.3%), neutropenia (8.3%), and ALT elevation (8.3%). In the AG arm, the most common toxicities were thrombocytopenia (20.0%) and hypophosphatemia (13.3%). Although reasonably well-tolerated, this phase II study of panobinostat and bevacizumab in recurrent GBM did not meet criteria for continued accrual and the GBM cohort of the study was closed. In the recurrent AG cohort, the PFS6 rate was similar to historical controls. Updated data will be presented.

BACKGROUND: EGFRvIII, a constitutively active tumorigenic EGFR deletion mutation, is linked to poor long-term survival. The investigational vaccine rindopepimut consists of the unique EGFRvIII peptide sequence conjugated to keyhole limpet hemocyanin (KLH), delivered intradermally with GM-CSF. Three phase II studies of rindopepimut in newly diagnosed, resected, EGFRvIII+ glioblastoma have shown encouraging PFS and OS. Bevacizumab (BV), an agent with activity in glioblastoma, may augment EGFRvIII-specific immune response and antitumor activity through inhibition of VEGF and its immunosuppressive properties. METHODS: “ReACT” is a Phase II study of rindopepimut plus BV in patients with 1st or 2nd relapse of EGFRvIII+ glioblastoma. BV-naive pts (Group 1; n = 70) are randomized 1:1 to BV plus double-blinded injection of either rindopepimut or control (KLH). BV-refractory patients (progression within 2 months of BV; Group 2/2C, n = 98) receive BV plus open-label rindopepimut. RESULTS: 234/700 (33%) screened patients are EGFRvIII+. 115 patients (Group 1 = 72, Group 2/2C = 43) are enrolled. Primary toxicity is Grade 1-2 injection site reaction. In group 1, for rindopepimut + BV vs. KLH + BV, objective response rate (ORR; investigator-assessed, RANO criteria) is 23% (6/26) vs 12% (3/25) [35% vs. 20% including responses observed at a single time point (“unconfirmed”)]. In Group 2/2C (evaluable n = 30), one unconfirmed PR and one sustained PR (patient continues treatment at 15 months) occurred. Two additional patients had pre-study progression >2 months after BV; one maintained a CR for 11.1 months (peak anti-EGFRvIII titer = 1:3,276,800), while the second experienced an unconfirmed CR. Median peak rindopepimut-induced anti-EGFRvIII humoral response is 1:25,600 [range

Patients with malignant brain tumors are prone to complications that negatively impact their quality of life and sometimes their overall survival as well. Tumors may directly provoke seizures, hypercoagulable states with resultant venous thromboembolism, and mood and cognitive disorders. Antitumor treatments and supportive therapies also produce side effects. In this review, we discuss major aspects of supportive care for patients with malignant brain tumors, with particular attention to management of seizures, venous thromboembolism, corticosteroids and their complications, chemotherapy including bevacizumab, and fatigue, mood, and cognitive dysfunction.

Alexander et al1 recently introduced a different interpretation involving our paper,2 in which we systematically evaluated glioblastoma clinical trials published from 1991 to the present and demonstrated that progression-free survival (PFS) may be an appropriate surrogate endpoint for overall survival (OS). Although the authors did not raise any methodological and clinical questions directly to us, we wish to comment on the authors' interpretation of our results and provide our insights. Since the introduction of temozolomide 10 years ago,3 there has been little success in developing an effective drug against glioblastoma. The prognosis remains poor, with median OS of approximately 15 months4 and 8 months2 for newly diagnosed and recurrent disease, respectively. To date, the increasing number of clinical trials and drug candidates has not expedited the progress but has instead created new challenges such as competing for the highly limited glioblastoma patient resource (fewer than 20 000 new cases diagnosed in the United States each year5). Therefore, it is critical that glioblastoma clinical trials become more efficient. One way of achieving this goal is to explore surrogate endpoints for OS. To contribute to this field, we conducted our analysis. Our data and analysis led to 2 major findings supporting our surrogacy conclusion: (i) a strong correlation between PFS and OS hazard ratio (HR) estimates in non–bevacizumab-containing comparative studies and (ii) a significant lead time that could be gained by using PFS instead of OS as endpoint. One of the minor findings we observed was that a moderate-to-good correlation exists between point estimates of median PFS and OS within groups. Although this was not intended to contribute to the surrogacy question, it still adds value to overall understanding of the relationship between these endpoints. We respectfully disagree with Alexander et al statement that “the strong correlation between PFS and OS reported by Han et al provides evidence that postprogression heterogeneity is limited (as in EORTC 26981/NCIC CE.3), thereby refuting one of the strongest arguments to use PFS.” First, the correlation between median PFS and OS demonstrated in our paper is only moderate to good (R2 = 0.7) and, more importantly, to our knowledge there has been no comprehensive study supporting the assumption that “for glioblastoma, strong correlation between PFS and OS can therefore be at least partially explained by the short SPP (survival post-progression)”. On the contrary, several studies (eg, Tang et al 2007 JCO6) have shown coexistence of long SPP and a moderate-to-good correlation between PFS and OS, the same as shown in our paper. Second, we have demonstrated a very significant lead time (a concept similar to SPP) that is close to half of the median OS (see above) of glioblastoma patients: 7.4 months and 4.2 months in newly diagnosed and recurrent cases, respectively, in Figure 5 in our paper. Finally, Figure 5 in our paper also illustrated the large postprogression heterogeneity of patients included in our analysis. The lead time ranged from 1.4 to 18 months in newly diagnosed patients and from 1.8 to 8.1 months in recurrent patients. The framework introduced by Broglio et al7 is certainly very useful, but it also needs to be kept in mind that the framework was mainly based on simulations, while clinical data come with much more variation and complexity. As extensively discussed in our paper, the applicability of the linear relationship between the HR of OS and PFS to anti-VEGF agents (ie, agents targeting VEGF or VEGFR) may require further validation because none of the trials in our HR correlation analysis contained an anti-VEGF agent such as bevacizumab (an anti-VEGF antibody) or cediranib (a VEGFR tyrosine kinase inhibitor). Therefore, discussion of AVAglio, RTOG-0825, and therapeutics affecting the ability to assess progression, as well as the use of them as examples (eg, in paragraphs 3, 5 and 7 in Alexander et al1) may be outside the scope, although we agree that it is important to standardize the definition and criteria for PFS in glioblastoma. We also cannot fully agree with Alexander et al comment that “In non-adaptive trials, OS data is ultimately collected without the need to make decisions in the intervening few months. Small lead-time gains using PFS are outweighed by the uncertainty of the relationship with OS.” As discussed at the beginning of this manuscript, the decade-long unmet medical need of this oncology indication and the challenges faced by the pharmaceutical industry put an emphasis on early decision-making. Given the significant lead time demonstrated in our paper, it is possible that making correct decisions in the intervening few months could benefit a significant portion of glioblastoma patients. Furthermore, early efficacy evaluation and early decision-making in early phases of drug development are critical for the viability and sustainability of the current drug development model of the pharmaceutical industry. The implication of our analysis was not to replace OS with PFS. Instead, our analysis suggested that PFS may be an appropriate surrogate marker for early efficacy evaluation and decision-making, especially in early phases of drug development. As is true for any endpoint, PFS possesses both advantages and disadvantages. Use of PFS as a surrogate marker for OS may lead to opportunities for early efficacy evaluation and clinical trials that are more efficient and less confounded by subsequent therapies. At the same time, the use of PFS, especially in glioblastoma, demands continuous efforts in the advancement of imaging technologies and the standardization of progression criteria. Reward and risk will always coexist in any field, and further evaluation weighing the reward and risk of using PFS is always warranted. Conflict of interest statement. Kelong Han is an employee of Genentech and holds stock in F. Hoffmann–La Roche. Melanie Ren was an employee of Genentech at the time the manuscript was written. Wolfgang Wick has acted as a consultant for F. Hoffmann–La Roche, Eli Lilly (uncompensated), and MSD and has received research support from Apogenix, Boehringer Ingelheim, Eli Lilly, and MSD. Lauren Abrey is an employee of F. Hoffmann–La Roche and holds stock in F. Hoffmann–La Roche. Asha Das is an employee of Genentech and holds stock in F. Hoffmann–La Roche. Jin Jin is an employee of Genentech and holds stock in F. Hoffmann–La Roche and Eli Lilly. David A. Reardon has received remuneration (other than research funding, honoraria, and consultancy fees) from F. Hoffmann–La Roche/Genentech and Merck & Co.