Therapy For Recurrent Glioblastoma Research Articles

Association of 5-aminolevulinic acid fluorescence guided resection with photodynamic therapy in recurrent glioblastoma: a matched cohort study.

Glioblastoma is a malignant and aggressive brain tumour that, although there have been improvements in the first line treatment, there is still no consensus regarding the best standard of care (SOC) upon its inevitable recurrence. There are novel adjuvant therapies that aim to improve local disease control. Nowadays, the association of intraoperative photodynamic therapy (PDT) immediately after a 5-aminolevulinic acid (5-ALA) fluorescence-guided resection (FGR) in malignant gliomas surgery has emerged as a potential and feasible strategy to increase the extent of safe resection and destroy residual tumour in the surgical cavity borders, respectively. To assess the survival rates and safety of the association of intraoperative PDT with 5-ALA FGR, in comparison with a 5-ALA FGR alone, in patients with recurrent glioblastoma. This article describes a matched-pair cohort study with two groups of patients submitted to 5-ALA FGR for recurrent glioblastoma. Group 1 was a prospective series of 11 consecutive cases submitted to 5-ALA FGR plus intraoperative PDT; group 2 was a historical series of 11 consecutive cases submitted to 5-ALA FGR alone. Age, sex, Karnofsky performance scale (KPS), 5-ALA post-resection status, T1-contrast-enhanced extent of resection (EOR), previous and post pathology, IDH (Isocitrate dehydrogenase), Ki67, previous and post treatment, brain magnetic resonance imaging (MRI) controls and surgical complications were documented. The Mantel-Cox test showed a significant difference between the survival rates (p = 0.008) of both groups. 4 postoperative complications occurred (36.6%) in each group. As of the last follow-up (January 2024), 7/11 patients in group 1, and 0/11 patients in group 2 were still alive. 6- and 12-months post-treatment, a survival proportion of 71,59% and 57,27% is expected in group 1, versus 45,45% and 9,09% in group 2, respectively. 6months post-treatment, a progression free survival (PFS) of 61,36% and 18,18% is expected in group 1 and group 2, respectively. The association of PDT immediately after 5-ALA FGR for recurrent malignant glioma seems to be associated with better survival without additional or severe morbidity. Despite the need for larger, randomized series, the proposed treatment is a feasible and safe addition to the reoperation.

The value of salvage therapy in recurrent glioblastoma

The value of salvage therapy in recurrent glioblastoma

CTIM-07. PHASE IIB RANDOMIZED, BLINDED, CONTROLLED TRIAL EVALUATING NEOADJUVANT PD-1 BLOCKADE COMBINED WITH A2B5+ GLIOMA STEM-LIKE CELL LYSATE-LOADED DCV IN RECURRENT GLIOBLASTOMA (IDH1/2 -)- TRAIL IN PROGRESS

Abstract Our previous phase II randomized trials have determined that A2B5+ glioma stem-like cell lysate-loaded DC vaccine (GSC-DCV) demonstrates favorable safety and significantly extends the survival of glioblastoma (GBM) (NCT01567202). This study aims to investigate the clinical feasibility and efficacy of the GSC-DCV combined with aPD-1 mAbs neoadjuvant therapy in recurrent GBM (NCT04888611). GBM (IDH1/2 -) patients who had received radiotherapy and TMZ chemotherapy were enrolled in the study after pathologically confirmed recurrence. All patients received aPD-1 mAbs treatment (3mg/kg, up to 200mg) 14±5 days before surgery. Following surgery, eligible patients were randomized in a 1:1 ratio to receive either a combination treatment of aPD-1 mAbs with GSC-DCV or aPD-1 mAbs with placebo. The above-mentioned postoperative therapy was given every three weeks until disease progression or unacceptable toxicity. Besides evaluating treatment response using the iRANO criteria, MRI scans were conducted before each treatment and after surgery (in 72h) to evaluate tumor size/volume to analyze the relationship between tumor burden and prognosis. The primary endpoint of the study was overall survival, while the secondary endpoints included the evaluation of treatment-related adverse events (trAEs) and the measurement of indicators related to the immune response. From October 2021 through May 2023, a total of 22 patients were enrolled and successfully randomized. At the latest follow-up, the two groups were generally balanced with respect to baseline characteristics, encompassing age, gender, KPS, steroid use, MGMTp status, TERTp status, and tumor volume at registration. Notably, differences in survival were observed between the two groups, with respective follow-up periods ranging from 1.3 to 19.9 months and 1.0 to 12.1 months. The incidence of trAEs in all patients was 22.7%, with no grade 3 or higher trAEs observed thus far, and the main adverse event was reactive cutaneous capillary endothelial proliferation (RCCEP).

Depth of Radiographic Response and Time to Tumor Regrowth Predicts Overall Survival Following Anti-VEGF Therapy in Recurrent Glioblastoma.

Antiangiogenic therapies are known to cause high radiographic response rates due to reduction in vascular permeability resulting in a lower degree of contrast extravasation. In this study, we investigate the prognostic ability for model-derived parameters describing enhancing tumor volumetric dynamics to predict survival in recurrent glioblastoma treated with antiangiogenic therapy. N = 276 patients in two phase II trials were used as training data, including bevacizumab ± irinotecan (NCT00345163) and cabozantinib (NCT00704288), and N = 74 patients in the bevacizumab arm of a phase III trial (NCT02511405) were used for validation. Enhancing volumes were estimated using T1 subtraction maps, and a biexponential model was used to estimate regrowth (g) and regression (d) rates, time to tumor regrowth (TTG), and the depth of response (DpR). Response characteristics were compared to diffusion MR phenotypes previously shown to predict survival. Optimized thresholds occurred at g = 0.07 months-1 (phase II: HR = 0.2579, P = 5 × 10-20; phase III: HR = 0.2197, P = 5 × 10-5); d = 0.11 months-1 (HR = 0.3365, P < 0.0001; HR = 0.3675, P = 0.0113); TTG = 3.8 months (HR = 0.2702, P = 6 × 10-17; HR = 0.2061, P = 2 × 10-5); and DpR = 11.3% (HR = 0.6326, P = 0.0028; HR = 0.4785, P = 0.0206). Multivariable Cox regression controlling for age and baseline tumor volume confirmed these factors as significant predictors of survival. Patients with a favorable pretreatment diffusion MRI phenotype had a significantly longer TTG and slower regrowth. Recurrent glioblastoma patients with a large, durable radiographic response to antiangiogenic agents have significantly longer survival. This information is useful for interpreting activity of antiangiogenic agents in recurrent glioblastoma.

Depth of radiographic response (DpR) and time to tumor regrowth (TTG) to predict overall survival following anti-VEGF therapy in recurrent glioblastoma.

2063 Background: Anti-angiogenic therapies, anti-VEGF agents, cause high radiographic response rates due to reduction in vascular permeability. However, we theorized the degree of tumor shrinkage combined with the duration of response might be a more meaningful measure of tumor control and may better reflect real patient benefit. In the current study, we investigate the association between model-derived parameters describing enhancing tumor volumetric dynamics and overall survival (OS) in recurrent glioblastoma treated with anti-VEGF therapy from multiple clinical trials. Methods: N=134 patients treated with bevacizumab +/- irinotecan (BRAIN Trial; NCT00345163) and N=121 patients treated with cabozantinib (XL184-201; NCT00704288) were used to identify potential imaging biomarkers, and N=63 patients in the bevacizumab control arm in a phase III trial (GLOBE Trial; NCT02511405) were used as a validation dataset. Enhancing tumor volumes were estimated using T1 subtraction maps, and a biexponential model was used to model tumor response ( d) and regrowth ( g) rates, as well as time to tumor regrowth ( TTG), the inflection point where the tumor stops shrinking and starts to regrow, and the depth of response ( DpR) after initiation of anti-VEGF therapy for each patient. Log-rank, univariate, and multivariable Cox regression were used to quantify the relationship of these parameters and OS. Results: Optimized thresholds based on maximum hazard ratio occurred at d =0.11 months-1 ( P=5x10-9 training; P=0.0082 validation); g=0.07 months-1 ( P=5x10-20 training; P&lt;0.0001 validation); TTG of 3.8 months ( P=6x10-17training; P&lt;0.0001 validation); and DpR of 11.3% ( P=0.0026 training; P=0.0177 validation). Univariate and multivariable Cox regression using these thresholds and controlling for age and baseline tumor volume confirmed that d, g, TTG, and DpR were all significant and independent predictors of OS in both phase II training and phase III validation datasets ( P&lt;0.01). Additionally, patients exhibiting combinations of a high DpR and/or long TTG showed differential median OS, while patients with favorable diffusion MR phenotypes exhibited a longer OS and significantly longer TTG. Conclusions: Volumetric response and regrowth rates, TTG, and DpR using a biexponential model are significant and independent predictors of OS in recurrent glioblastoma treated with anti-VEGF therapy. Clinical trial information: NCT00345163 ; NCT00704288 ; NCT02511405 .

Immune Activity and Response Differences of Oncolytic Viral Therapy in Recurrent Glioblastoma: Gene Expression Analyses of a Phase IB Study.

Previously, clinical trials of experimental virotherapy for recurrent glioblastoma multiforme (GBM) demonstrated that inoculation with a conditionally replication-competent Δγ134.5 oncolytic herpes simplex virus (oHSV), G207, was safe. Following the initial safety study, a phase Ib trial enrolled 6 adult patients diagnosed with GBM recurrence from which tumor tissue was banked for future studies. Here, we analyzed tumor RNA sequencing (RNA-seq) data obtained from pre- and posttreatment (collected 2 or 5 days after G207 injection) biopsies from the phase Ib study patients. Using a Spearman rank-order correlation analysis, we identified approximately 500 genes whose expression pattern correlated with survival duration. Many of these genes were enriched for the intrinsic IFN-mediated antiviral and adaptive immune functional responses, including immune cell chemotaxis and antigen presentation to T-cells. Furthermore, we show that the expression of several T-cell-related genes was highest in the patient with the longest survival after G207 inoculation. Our data support that the oHSV-induced type I IFN production and the subsequent recruitment of an adaptive immune response differed between enrolled patients and showed association with survival duration in patients with recurrent malignant glioma after treatment with an early generation oHSV.

EXTH-47. SAFETY AND EFFECTS OF TRANSCRANIAL MAGNETIC STIMULATION ON GLIOBLASTOMA MEASURED IN VITRO

Abstract BACKGROUND Although gross total resection (GTR) with chemoradiation is the standard of care for treating glioblastoma (GBM), tumor infiltration and treatment sequelae can impair activity of eloquent regions. Transcranial magnetic stimulation (TMS) has been explored as an adjunct therapy to rehabilitation for post-stroke motor deficits. TMS could be effective for postoperative rehabilitation in GBM, but its effect on GBM cells has not been evaluated. While TMS utilizes magnetic fields to induce electrical currents at low frequencies to cause neuronal excitation or inhibition, tumor-treating fields (TTF) utilize electrical currents with intermediate frequency to exert anti-mitotic effects, demonstrating promise as an adjunctive therapy in recurrent GBM. Although similarities exist between electrical and magnetic fields, the effects of magnetically induced electrical currents at low frequencies via TMS must be studied systematically in vitro on GBM cell lines. METHODS We studied the effect of theta burst stimulation (TBS), a form of patterned TMS, on in vitro G55 cell viability using colony forming assays. We compared TMS-treated cells to controls using a combination of parameters: continuous versus intermittent TBS (cTBS and iTBS), 300 versus 600 pulses, stimulation intensity of 32% versus 60%, and no pre-TMS chemotherapy versus 100 nM or 100 µM temozolomide (TMZ). Viability measurements between controls and TMS were analyzed using analysis of variance (ANOVA). Independent t-tests were used to analyze effects of stimulation parameters on viability percent difference within each TMZ condition. RESULTS There was no statistically significant increase in viability between control and TMS conditions for any of the stimulation parameters (+/- TMZ) while some showed decreased viability of GBM cells. CONCLUSIONS TMS did not significantly increase GBM viability compared to controls. Future studies include validation in other cell lines and characterization of the effects of stimulation parameters in conjunction with TMZ and dexamethasone, (often administered concurrently with GBM treatment).

347MO 5-Aminolevulinic acid sonodynamic therapy in recurrent glioblastoma: A first-in-human phase 0/1 clinical trial

5-aminoleveulinic acid sonodynamic therapy (5-ALA SDT) is a drug-device strategy that exploits the metabolic liabilities of cancer. Following systemic administration of 5-ALA, incomplete tumor metabolism leads to accumulation of a photosensitive intermediary, protoporphyrin-IX (PpIX). Activation of PpIX by non-invasive, non-ablative magnetic resonance-guided focused ultrasound (MRgFUS) induces cytotoxic reactive oxygen species and tumor cell death. This first-in-human phase 0/1 study investigates the feasibility, safety, and biological effects of 5-ALA SDT in recurrent glioblastoma patients (GBM).

DDRE-19. PHASE 0/I TRIAL OF MYCOPHENOLATE MOFETIL COMBINED WITH RADIATION TO OVERCOME GLIOBLASTOMA TREATMENT RESISTANCE BY TARGETING DE-NOVO PURINE METABOLISM

BACKGROUNDRadiation resistance is one of the major limitations for effective control of glioblastoma. Guanosine triphosphate (GTP) supplementation promotes glioblastoma radioresistance. Conversely, GTP depletion overcomes glioblastoma radioresistance by slowing the repair of radiation-induced DNA damage. Mycophenolate mofetil (MMF) inhibits de novo GTP synthesis by inhibiting the key enzyme, inosine-5′-monophosphate dehydrogenase, and radiosensitizes glioblastoma in mice. These pre-clinical findings have led to Phase 0/I Dose Escalation Study of Mycophenolate Mofetil Combined with Radiation Therapy in Recurrent Glioblastoma (NCT04477200) to measure the concentration of active metabolite of MMF in glioblastoma, and to determine the safe dose of MMF when given in combination with radiation.METHODSKey eligibility criteria are age ≥18, patients with Karnofsky Performance Scale score ≥60, and recurrent glioblastoma or gliosarcoma with clinical indication for re-irradiation (phase I) or re-resection or biopsy (phase 0). Those with tumor involving ≥3 lobes or leptomeningeal space or bevacizumab use within 8 weeks are excluded. Eight participants will receive MMF 500–2000 mg PO BID for one week before surgery (phase 0). Approximately 30 subjects will receive MMF 250–2000 mg PO BID (starting: 1000mg) on TITE-CRM dose escalation model (phase I).RESULTSFrom 7/2020 to 11/2020, two phase 0 and three phase I subjects have completed MMF treatment without notable toxicity. Additionally, correlative measurements of the activity of de novo GTP synthesis are explored. The anticipated study duration is 48 months.CONCLUSIONThe results of this trial will aid in designing a randomized clinical trial to determine the efficacy of MMF combined with chemoradiation in glioblastoma, and to define potential biomarkers for effectiveness. MMF is widely available and inexpensive, so if positive efficacy result is observed, a brisk acceptance of MMF combined with the standard of care is anticipated.

MR spectroscopic imaging predicts early response to anti-angiogenic therapy in recurrent glioblastoma.

BackgroundDetermining failure to anti-angiogenic therapy in recurrent glioblastoma (GBM) (rGBM) remains a challenge. The purpose of the study was to assess treatment response to bevacizumab-based therapy in patients with rGBM using MR spectroscopy (MRS).MethodsWe performed longitudinal MRI/MRS in 33 patients with rGBM to investigate whether changes in N-acetylaspartate (NAA)/Choline (Cho) and Lactate (Lac)/NAA from baseline to subsequent time points after treatment can predict early failures to bevacizumab-based therapies.ResultsAfter stratifying based on 9-month survival, longer-term survivors had increased NAA/Cho and decreased Lac/NAA levels compared to shorter-term survivors. ROC analyses for intratumoral NAA/Cho correlated with survival at 1 day, 2 weeks, 8 weeks, and 16 weeks. Intratumoral Lac/NAA ROC analyses were predictive of survival at all time points tested. At the 8-week time point, 88% of patients with decreased NAA/Cho did not survive 9 months; furthermore, 90% of individuals with an increased Lac/NAA from baseline did not survive at 9 months. No other metabolic ratios tested significantly predicted survival.ConclusionsChanges in metabolic levels of tumoral NAA/Cho and Lac/NAA can serve as early biomarkers for predicting treatment failure to anti-angiogenic therapy as soon as 1 day after bevacizumab-based therapy. The addition of MRS to conventional MR methods can provide better insight into how anti-angiogenic therapy affects tumor microenvironment and predict patient outcomes.

Phase II study of pembrolizumab plus SurVaxM for glioblastoma at first recurrence.

TPS2581 Background: Glioblastoma is the most common primary malignant brain tumor with median survival of approximately 15-16 months. Following first recurrence, progression free survival at six months ~15%. There is no therapy in recurrent glioblastoma associated with any survival benefit and there is an urgent need for better therapeutic options. Immunotherapy is one promising option for patients with cancer. This is being explored in glioblastoma and a number of forms of active specific vaccination and immune checkpoint based approaches have been devised and are being investigated in glioblastoma. Methods: Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) with high specificity of binding to the programmed cell death 1 (PD-1) receptor. Survivin is a 16.5 kDa intracellular protein that belongs to the inhibitor of apoptosis protein (IAP) family. SurVaxM is a 15 amino acid antigenic peptide that targets surviving capable of binding several human MHC class I molecules. Primary Objective is to assess clinical activity of Pembrolizumab and SurVaxM in patients with recurrent glioblastoma using progression free survival at 6 months (PFS-6) as determined using RANO criteria. Secondary Objective(s) includes safety and tolerability of combination, response rates, progression free survival and overall survival. Exploratory Objective include measuring cellular and humoral immune responses during concurrent administration of Pembrolizumab and SurVaxM. This is a phase II study of two arms in patients with recurrent glioblastoma. Arm A is patients with first recurrence of glioblastoma who have failed prior chemotherapy and radiation but have not received any immunotherapy. Arm B is an exploratory arm of glioblastoma patients who have failed prior anti-PD1 therapy. This clinical trial will enroll 41 patients with glioblastoma at first recurrence (bevacizumab naïve) in arm 1.This will include a 6-patient toxicity/safety run-in. There will an exploratory cohort of 10 patients who have failed prior PD1 blockade for a total of 51 patients in 2 arms. Key inclusion criteria include diagnosis of glioblastoma, Age ≥18 years old, Previous first line treatment with at least radiotherapy with or without temozolomide and Documented first recurrence of GBM and Karnofsky performance status of 70 and normal organ function. Key exclusion criteria include more than one recurrence of GBM, presence of extracranial metastatic or leptomeningeal disease, patients with &gt; 1 cm midline shift on imaging. Patients must not require &gt; 10 mg daily of prednisone equivalent. Clinical trial information: NCT04013672 .

Identification of Early Response to Anti-Angiogenic Therapy in Recurrent Glioblastoma: Amide Proton Transfer-weighted and Perfusion-weighted MRI compared with Diffusion-weighted MRI.

Background Amide proton transfer (APT) MRI has the potential to demonstrate antitumor effects by reflecting biologically active tumor portion, providing different information from diffusion-weighted imaging (DWI) or dynamic susceptibility contrast (DSC) imaging. Purpose To evaluate whether a change in APT signal intensity after antiangiogenic treatment is predictive of early treatment response in recurrent glioblastoma. Materials and Methods In this retrospective study, APT MRI, DWI, and DSC imaging were performed in patients with recurrent glioblastoma from July 2015 to April 2019, both before treatment and 4-6 weeks after initiation of bevacizumab (follow-up). Progression was based on pathologic confirmation or clinical-radiologic assessment, and progression patterns were defined as local enhancing or diffuse nonenhancing. Changes in mean and histogram parameters (fifth and 95th percentiles) of APT signal intensity, apparent diffusion coefficient, and normalized cerebral blood volume (CBV) between imaging time points were calculated. Predictors of 12-month progression and progression-free survival (PFS) were determined by using logistic regression and Cox proportional hazard modeling and according to progression type. Results A total of 54 patients were included (median age, 56 years [interquartile range, 49-64 years]; 24 men). Mean APT signal intensity change after bevacizumab treatment indicated a low 12-month progression rate (odds ratio [OR], 0.36; 95% confidence interval [CI]: 0.13, 0.90; P = .04) and longer PFS (hazard ratio: 0.38; 95% CI: 0.20, 0.74; P = .004). High mean normalized CBV at follow-up was associated with a high 12-month progression rate (OR, 20; 95% CI: 2.7, 32; P = .04) and shorter PFS (hazard ratio, 9.4; 95% CI: 2.3, 38; P = .002). Mean APT signal intensity change was a significant predictor of diffuse nonenhancing progression (OR, 0.27; 95% CI: 0.06, 0.85; P = .047), whereas follow-up 95th percentile of the normalized CBV was a predictor of local enhancing progression (OR, 7.1; 95% CI: 2.4, 15; P = .04). Conclusion Early reduction in mean amide proton transfer signal intensity at 4-6 weeks after initiation of antiangiogenic treatment was predictive of a better response at 12 months and longer progression-free survival in patients with recurrent glioblastoma, especially in those with diffuse nonenhancing progression. © RSNA, 2020 Online supplemental material is available for this article.

Hypertension and proteinuria as clinical biomarkers of response to bevacizumab in glioblastoma patients.

Arterial hypertension and proteinuria are common side effects of antiangiogenic treatment and might represent a biomarker of response in patients with glioblastoma. The aim of this study was to assess the impact of these side effects in predicting therapeutic response to second line chemotherapy with bevacizumab. We evaluated clinical and survival data of glioblastoma patients who underwent treatment with bevacizumab after progression under temozolomide, at CHUSJ between 2010 and 2017. We analysed treatment-related arterial hypertension, proteinuria grade, thrombotic and haemorrhagic events during treatment. Overall survival (OS) and progression free survival (PFS) under bevacizumab were calculated according to the Kaplan-Meier method. Multivariate analysis was performed using Cox proportional hazards method. We evaluated 140 patients. Arterial hypertension and proteinuria occurred in 23 (16.3%) and 17 (12.1%) patients, respectively. PFS during treatment with bevacizumab was 12months (95% CI 7.9-16.1) in the hypertensive group and 4months (95% CI 3.2-4.8) in the normotensive group (p = 0.005). Patients with proteinuria had a PFS of 10months (95% CI 4.9-15.0) versus 4months (95% CI 3.4-4.8) in patients without proteinuria (p = 0.002). Multivariate analysis revealed hypertension and proteinuria as independent prognostic factors of PFS and OS. Our data suggest that hypertension and proteinuria can be effective predictors of response to antiangiogenic therapy in recurrent glioblastoma and are associated with longer disease control.

Abstract 5271: Molecular imaging of pyruvate kinase M2 (PKM2) with [18F]DASA-23 detects temozolomide- and tumor treating fields (TTFields)-induced changes in glycolysis in glioblastoma

Abstract Introduction: Pyruvate kinase M2 (PKM2) is an enzyme that catalyzes the final step in glycolysis, a key step in tumor metabolism and growth, making PKM2 an important marker of cancer glycolytic reprogramming. The 1-((2-fluoro-6-[18F]fluorophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine ([18F]DASA-23) radiotracer has been developed to measure the expression of PKM2. Glioblastoma (GBM) is traditionally treated with surgical resection, temozolomide (TMZ) chemotherapy, and radiation therapy. Tumor treating fields (TTFields), the application of alternating electric fields (100-500 kHz, 1-4 V/cm) to tumors, is emerging as the fourth therapeutic modality in GBM. There is an important need to assess early on whether a patient’s GBM is responding to a given standard-of-care or experimental therapy. In this study we evaluated the ability of [18F]DASA-23 to detect changes in metabolism in response to standard-of-care (TMZ) and emerging (TTFields) therapies, in cell culture and an orthotopic murine model of human GBM. Methods: Human U87-MG GBM cells were subjected to either 200 kHz TTFields or the IC50 of TMZ for three or six days (n≥3/condition), followed by evaluation of 30-minute cellular uptake of [18F]DASA-23. In parallel experiments, immunofluorescence for PKM2 was performed to confirm the [18F]DASA-23 uptake results. Finally, U87-MG human GBM cells were orthotopically implanted in nude mice (N=5), and evaluated with 7T small animal magnetic resonance imaging (MRI) and [18F]DASA-23 microPET/CT before and one week post-initiation of vehicle or TMZ therapy. Results: There was a significant interaction between the treatment (vehicle, TMZ, or TTFields) and treatment duration (3 or 6 days) on PKM2 expression as measured by cellular uptake of [18F]DASA-23 (p=0.005, 2-way ANOVA). Immunofluorescence for PKM2 in TTFields-exposed and unexposed U87-MG cells revealed reduced cell count and less intense PKM2 staining due to TTFields. In the orthotopic mouse model, the tumor/normal brain (T/N) [18F]DASA-23 uptake ratio (unitless) at one week post-treatment was divided by the pre-treatment T/N ratio. The resulting ratio of ratios was significantly smaller in the TMZ cohort (1.0±0.4) compared to in the vehicle cohort (2.2±0.2), p=0.004. Conclusion: Together, these data suggest the potential for non-invasive assessment of GBM’s response to various therapies using [18F]DASA-23, a radiotracer that measures PKM2 expression. Clinical studies are currently being completed to evaluate the diagnostic ability of [18F]DASA-23 in patients with intracranial malignancies and future studies will evaluate the ability of [18F]DASA-23 to predict responders vs. non-responders to therapy in recurrent GBM. Citation Format: Chirag B. Patel, Corinne Beinat, Yuanyang Xie, Edwin Chang, Sanjiv S. Gambhir. Molecular imaging of pyruvate kinase M2 (PKM2) with [18F]DASA-23 detects temozolomide- and tumor treating fields (TTFields)-induced changes in glycolysis in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5271.

Eight-year survival of a recurrent glioblastoma patient treated with molecularly tailored therapy: a case report

Treatment options for recurrent glioblastoma are scarce; targeted therapy trials were disappointing, probably due to enrollment of patients without molecular selection. We treated with bevacizumab and erlotinib a 66-year-old male suffering from recurrent glioblastoma, IDH-wildtype and MGMT unmethylated, after three neurosurgeries. Treatment was tailored on molecular profile of recurrent tumor-namely, EGFRvIII positivity, VEGF overexpression, normal PTEN, low total VEGF and VEGF-121 mRNA-and resulted in complete, exceptionally durable response (51-month progression-free survival). Notably, histology of further recurrence after therapy was reminiscent of sarcoma. We suggest a thorough molecular screening for personalization of targeted therapy in recurrent glioblastoma.

Bevacizumab combined with chemotherapy vs single-agent therapy in recurrent glioblastoma: evidence from randomized controlled trials.

BackgroundRecent studies showed inconsistent results of bevacizumab combined with chemotherapy vs single-agent therapy in terms of their safety and efficacy for the treatment of recurrent glioblastoma. Therefore, we performed a meta-analysis to explore the value of bevacizumab combined with chemotherapy and single-agent therapy in recurrent glioblastoma treatment.MethodsDatabases such as MEDLINE, Embase, and Cochrane Library were searched for randomized controlled trials (RCTs) related to the topic of bevacizumab combined with chemotherapy and single-agent therapy as treatments for recurrent glioblastoma from January 1980 to April 2018. Subsequent articles were then sorted, evaluated, and analyzed.ResultsWe pooled 1,169 patient cases from seven RCTs. Bevacizumab combined with chemotherapy showed a significantly improved progression-free survival (PFS) (HR=0.65; 95% CI 0.57–0.74; P<0.001) compared to single-agent therapy. In addition, the overall survival (OS) rate showed insignificant differences between the two groups (HR=0.96; 95% CI 0.83–1.12; P=0.622). Simultaneously, we found that bevacizumab combined with chemotherapy had a higher objective response rate (ORR) (OR=2.10; 95% CI 1.32–3.33; P=0.002), but also higher incidence of adverse events (AEs) (OR=1.85; 95% CI 1.26–2.71; P=0.002). However, in subgroup analysis, we found that AEs showed insignificant differences between the two treatment methods when bevacizumab was used as the single-agent therapy subgroup (P=0.058). In addition, in the subgroup with low corticosteroid use rate at baseline (N<50%), ORR (P=0.108) and AEs (P=0.134) showed insignificant differences between the two groups.ConclusionBevacizumab combined with chemotherapy can significantly improve PFS and ORR, but did not prolong OS in these studies, and can even lead to higher odds of AEs. In addition, bevacizumab may play a dominant role and corticosteroid may be an unfavorable factor in the combination therapy of recurrent glioblastoma.

The Safety of Bevacizumab Administered Shortly after Laser Interstitial Thermal Therapy in Glioblastoma: A Case Series

Laser interstitial thermal therapy (LITT) enables ablation of lesions using thermal energy with minimal damage to surrounding regions. Bevacizumab has been used as an adjuvant therapy in recurrent glioblastoma (GBM). At present, bevacizumab is administered at least 4-6 weeks after surgical intervention; however, given the minimally invasive nature of LITT, we suggest that bevacizumab can be safely administered at a shorter interval after LITT. Three patients who showed evidence of recurrent GBM on magnetic resonance imaging (MRI), underwent LITT, and were subsequently administered bevacizumab within 4 weeks were identified retrospectively. Postoperative MRI was performed 24 hours after treatment and before follow-up. All 3 patients were placed on dexamethasone taper postoperatively. The ablated tumors were analyzed radiographically, and bevacizumab symptoms were monitored carefully. The patients ranged in age from 39 to 69 years. The median duration of follow-up was 26 weeks (range, 13-51 weeks). All 3 patients expired due to disease progression. The median progression-free survival (PFS) was 17 weeks (range, 12-22 weeks), and the median overall survival (OS) was 32 weeks (range, 12-51 weeks). There were no postoperative complications or complications due to hemorrhage, infection, or thrombosis (complication rate, 0%; 95% confidence interval 0-56%). This case series suggests that bevacizumab administration is safe within 1 month after LITT, thus showing promise in treating recurrent GBM. Larger studies are warranted to assess the efficacy of combined bevacizumab and LITT.

VEGF-121 plasma level as biomarker for response to anti-angiogenetic therapy in recurrent glioblastoma

BackgroundVascular endothelial growth factor (VEGF) isoforms, particularly the diffusible VEGF-121, could play a major role in the response of recurrent glioblastoma (GB) to anti-angiogenetic treatment with bevacizumab. We hypothesized that circulating VEGF-121 may reduce the amount of bevacizumab available to target the heavier isoforms of VEGF, which are the most clinically relevant.MethodsWe assessed the plasma level of VEGF-121 in a brain xenograft model, in human healthy controls, and in patients suffering from recurrent GB before and after bevacizumab treatment. Data were matched with patients’ clinical outcome.ResultsIn athymic rats with U87MG brain xenografts, the level of plasma VEGF-121 relates with tumor volume and it significantly decreases after iv infusion of bevacizumab. Patients with recurrent GB show higher plasma VEGF-121 than healthy controls (p = 0.0002) and treatment with bevacizumab remarkably reduced the expression of VEGF-121 in plasma of these patients (p = 0.0002). Higher plasma level of VEGF-121 was significantly associated to worse PFS and OS (p = 0.0295 and p = 0.0246, respectively).ConclusionsQuantitative analysis of VEGF-121 isoform in the plasma of patients with recurrent GB could be a promising predictor of response to anti-angiogenetic treatment.

Third-line therapy in recurrent glioblastoma: is it another chance for bevacizumab?

Standard glioblastoma therapy is long-lasting. Among second-line therapy, choices could be bevacizumab and nitrosoureas depending on National Agencies approval. There is no consensus on 3rd line therapy or clinical trials specifically designed for this setting. We reviewed our institutional database on all consecutive patients who received 3rd line therapy for glioblastoma. Data on 168 out of 1337 (12.6%) glioblastoma patients who underwent 3rd line therapy treatment were collected. Third line treatments were bevacizumab or chemotherapy (nitrosourea, temozolomide or carboplatin plus etoposide). Median progression free survival was 2.9months and median survival time was 6.6 months from the start of 3rd line therapy. Bevacizumab significantly improved progression-free survival (4.7 vs. 2.6months, p = .020) and survival from 3rd line start (8.0 vs. 6.0months, p = .014) in respect to chemotherapy. Toxicity of grade ≥ 3 occurred in 13.7% of patients. In multivariate analysis, survival in 3rd line treatment depends on MGMT methylation (p = .006) and treatment with Bevacizumab (p = .011). Third line therapy in selected glioblastoma patients may be feasible and well tolerated. Bevacizumab improved outcome in 3rd line in respect to chemotherapy.

Nivolumab for patients with recurrent glioblastoma progressing on bevacizumab: A retrospective case series.

e13538 Objective: A single institution retrospective evaluation of nivolumab following disease progression on bevacizumab in adults with recurrent glioblastoma (GBM) with an objective of determining progression free survival (PFS). Background: There is no accepted therapy for recurrent GBM after failure of bevacizumab. Methods: 16 adults, ages 52-72 years (median 62), with recurrent GBM were treated. All patients had previously been treated with surgery, concurrent radiotherapy and temozolomide, and post-radiotherapy temozolomide. Bevacizumab (with or without lomustine) was administered to all patients at first recurrence. Patients were treated with nivolumab only (3mg/kg) once every 2 weeks at second recurrence. One cycle of nivolumab was defined as 2 treatments. Neurological evaluation was performed bi-weekly and neuroradiographic assessment every 4 weeks. Results: A total of 37 treatment cycles (median 2) were administered of nivolumab in which there were 14 Grade 2 adverse events (AEs) and Grade 3 AEs in 2 patients. No Grade 4 or 5 AEs were seen. Following 1 month of nivolumab, 7 patients’ demonstrated progressive disease and discontinued therapy. No patient demonstrated a response though 9 patients demonstrated neuroradiographic stable response. Survival in the entire cohort ranged from 2 - 6 months with a median of 3.5 months (CI: 2.8, 4.2). Median and 6-month PFS at 6 months was 2.0 months (range 1-5 months; CI: 1.3, 2.7) and 0% respectively. Conclusions: Nivolumab salvage therapy demonstrated no survival advantage in patients with recurrent bevacizumab refractory GBM emphasizing a continued unmet need in neuro-oncology.