Defining the Impact of Adjuvant Treatment on the Prognosis of Patients with Inoperable Glioblastoma Undergoing Biopsy-only: Does the Survival Benefit Outweigh the Treatment Effort?

Purpose: Patients with inoperable glioblastoma (GBM) usually experience worse prognosis compared to those in whom gross total resection (GTR) is achievable. Considering the treatment duration and its side effects identification of patients with survival benefit from treatment is essential to guarantee the best achievable quality of life. The aim of this study was to evaluate the survival benefit from radio-chemotherapy and to identify clinical, molecular, and imaging parameters associated with better outcome in patients with biopsied GBMs. Methods: Consecutive patients with inoperable GBM, who underwent tumor biopsy at our department from 2005 to 2019 were retrospectively analyzed. All patients had histologically confirmed GBM and were followed up until death. The overall survival (OS) was calculated from date of diagnosis to date of death. Clinical, radiological and molecular predictors of OS were evaluated. Results: A total of 95 patients with biopsied primary GBM were enrolled in the study. The mean age was 64.3±13.2 years, 56.8 % (54/95) were male and 43.2 % (41/95) female. Mean OS in the entire cohort was 9 months. After stratification for adjuvant treatment a higher median OS was found in the group with adjuvant treatment (7 months, range 2-88) compared to the group without treatment (1 month, range 1-5) Log-rank test, p<0.0001.Conclusion: Patients with inoperable GBM undergoing biopsy indeed experience a very limited OS. Adjuvant treatment is associated with significantly longer OS compared to patients not receiving treatment and should be considered, especially in younger patients with good clinical condition at presentation.

Role of Circulating Biomarkers in Platinum-Resistant Ovarian Cancer

Ovarian cancer (OC) is the second most common cause of death in women with gynecological cancer. Considering the poor prognosis, particularly in the case of platinum-resistant (PtR) disease, a huge effort was made to define new biomarkers able to help physicians in approaching and treating these challenging patients. Currently, most data can be obtained from tumor biopsy samples, but this is not always available and implies a surgical procedure. On the other hand, circulating biomarkers are detected with non-invasive methods, although this might require expensive techniques. Given the fervent hope in their value, here we focused on the most studied circulating biomarkers that could play a role in PtR OC.

Retinal granular cell tumor: a case report

Background To report a rare case of granular cell tumor invading the retina. Case presentation A 56-year-old female complained of blurred vision for 2 weeks in her left eye. An irregular-shaped retinal mass in the inferonasal and extending to the optic disc accompanied by dense exudation and extensive serous retinal detachment was observed. Several intravitreal bevacizumab injections were ineffective for stabilizing retinal exudation and intraocular pressure (IOP). Vitrectomy was performed to re-attach the retina and obtain a tumor biopsy specimen. Histopathological analysis revealed that the intraocular mass was a granular cell tumor. Immunohistochemical studies demonstrated that the tumor was positive for S100 and CD68, focal positive for neurofilaments, but negative for ERG and HMB-45. Local recurrence and distant metastasis were not found, but visual acuity had worsened to no light perception at the last visit due to uncontrolled intraocular pressure and retinal exudation after the surgery. Conclusions Granular cell tumor is a rare benign neoplasm, but it can lead to devastating visual loss if it invades the retina adjacent to the optic nerve head.

A bi-foraminal craniometric-guided approach to endoscopic third ventriculostomy and biopsy of a pineal tumour

Background: Pineal tumors are very rarely encountered, with an incidence of <1% of intracranial lesions in adults. Life-threatening hydrocephalus due to obstruction of the third ventricle can result from the location of these tumours. Endoscopic third ventriculostomy (ETV) and tumor biopsy is a safe and feasible strategy, particularly if the tumor appears benign. This mitigates the high risks of uncontrollable venous bleeding from open and stereotactic biopsies. While typically performed using either ipsilateral single or dual bur holes, the location of the tumor may require modifications to the standard endoscopic techniques. Case Description: A 55-year-old male presented with signs of intracranial hypertension and was found to have obstructive hydrocephalus due to a pineal tumour. The tumour displayed a right-sided dominance when the pre-operative imaging was assessed, which would risk forniceal injury if biopsied via a right-sided burr hole. Craniometric measurements revealed a superior trajectory to the tumour via the left foramen of Monro. A biforaminal approach was performed, with a traditional ETV using a right coronal bur hole and biopsy via a left frontal bur hole. This minimized forniceal stretching and allowed a safe biopsy. Conclusion: The bi-foraminal approach has not been widely described in the literature but can potentially avoid morbidity with biopsy in patients with right-sided pineal tumours. We believe this technique should be considered, particularly in low-resource settings where neuroendoscopy is not commonly done, and where the use of ipsilateral single or dual-bur holes may lead to forniceal injury.

Phase 2 Study of Nivolumab in Epstein-Barr Virus (EBV)-Positive Lymphoproliferative Disorders and EBV-Positive Non-Hodgkin Lymphomas

Introduction: Immune tolerance and evasion plays a significant role in the pathogenesis of EBV+ lymphoproliferative disorders (LPD) and non-Hodgkin lymphomas (NHL). Programmed cell death protein-1 (PD-1) is a signaling molecule on the surface of T-cells that suppresses the cytotoxic effects of T-cells on tumor cells. PD-L1 expression is a marker of poor prognosis in aggressive lymphomas and most EBV+ LPDs demonstrate high levels of PD-L1 expression. Chronic viral infections, such as EBV, also result in T-cell exhaustion that can be reversed by PD-1 blockade. Nivolumab is a fully human IgG4 monoclonal anti-PD-1 antibody which has demonstrated activity and favorable safety in lymphoid malignancies. We hypothesized that PD-1 blockade may reverse the inactivation of tumor-specific effector T-cells and result in anti-tumor responses in EBV+ LPD and NHL. Methods: Relapsed/refractory (R/R) EBV+ LPD and B-cell NHL pts age ≥ 12y with adequate organ function are eligible. Untreated pts are eligible if EBV+ LPD. Exclusions include prior use of PD-1/PD-L1/PD-L2/CD137/CTLA-4 antibodies, prior solid organ transplant and HIV. Pts with immunodeficiency or autoimmune illness are eligible if not requiring steroids or immunosuppression. CNS involvement is permitted if no seizure activity within 4 weeks of study. Nivolumab 480mg IV is given every four weeks for up to 2y. Pts who achieve CR discontinue nivolumab after 1y of treatment. Baseline evaluation includes CT, PET, MRI brain, flow cytometry of peripheral blood and CSF, BM biopsy along with optional tumor biopsy. CT scans are performed after cycles 3, 6, 13 and 19 and end of treatment (EoT). PET is performed after cycles 1, 3 and EoT. Surveillance CT scans are performed q3m for 1y, q6m for yrs 2-5, and annually thereafter. Results: 9 pts, 7 (78%) R/R and 2 (22%) untreated, enrolled between April 2018 and May 2021; 5 (56%) with EBV+ LPD [4 G1-2 lymphomatoid granulomatosis (LYG) and 1 chronic active EBV disease (CAEBV)] and 4 (44%) with EBV+ NHL (all DLBCL, NOS). Median age was 48y (range 30-63) and all pts (100%) had stage III/IV disease. Four pts (44%) had elevated LDH (all DLBCL). Median baseline CD4 and CD8 count (cells/mcL) was 378 (range 99-984) and 86 (range 22-1237), respectively, for LPD and 190 (range 133-255) and 90 (range 9-630), respectively, for NHL. Median EBV VL at baseline (Log10 IU/mL) was 2.55 (range 0-6.78) and 2.53 (range 0-5.33) for LPD and NHL, respectively. Eight (89%) pts had extranodal disease with pulmonary involvement most common in 6 (67%). Median prior therapies were 1 (range 0-1) and 2 (range 1-4) for LPD and NHL pts, respectively. Three (43%) R/R pts were refractory (i.e., &lt;PR) to last therapy. Of 9 pts enrolled, 7 were evaluable for response (1 NHL pt died prior to restaging and 1 NHL pt has not yet been restaged). In 6 measurable pts, tumor reduction was observed in 67% (Fig 1A). ORR and CR rate was 57% (4/7) and 43% (3/7), respectively; 60% (3/5) and 40% (2/5) in LPD and 50% (1/2) and 50% (1/2) in NHL. Median TTR was 3.0m with 3 (75%) of 4 responses ongoing from 6.9m to 35.2m after first response (Fig 1B). Most common adverse events (AEs) (% pts) included maculopapular rash (38%), ALT elevation (25%), AST elevation (25%), CPK elevation (25%) and fatigue (25%). One pt discontinued therapy due to G2 immune-mediated myositis that required prolonged steroid therapy. &gt;G3 AEs included AST elevation in 1 (13%) pt with no G4/G5 or serious adverse events. With a median potential follow up of 12.6m, 12-month PFS and OS was 50.8% (95% CI: 15.7-78.1) and 75.0% (95% CI: 31.5-93.1). In LPD pts, 12-month PFS and OS was 80% (95% CI: 20.4-96.9) and 100%. Three (75%) NHL pts progressed and 2 (50%) died of disease progression. One NHL pt stopped therapy due to apparent disease progression after 2 cycles but later developed CR without further therapy and remains in remission 35.2m after stopping therapy. Conclusion: Nivolumab appears safe in pts with EBV+ LPD and NHL without unexpected toxicities. Preliminary clinical activity, including CRs, is noted in pts with EBV+ LPD and NHL. Additional pts are needed for a better assessment of true activity in these rare entities and correlates of response including PD-1/PD-L1 expression and/or 9p24.1 alterations are ongoing and will be presented at the meeting. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Nivolumab for EBV+ LPD and EBV+ NHL.

Clinical Efficacy of Liver Tumor Biopsy With Radiofrequency Ablation of the Puncture Route Using a Co-access Needle

Background/Aim: Tumor biopsy are needed frequency for accurate diagnosis. However, percutaneous liver tumor biopsy presents a risk of complications such as bleeding and tumor seeding. We investigated the feasibility of liver tumor biopsy, followed by cauterization with expandable radiofrequency ablation. Patients and Methods: Tumor biopsies using a co-access needle were performed in 102 patients. Expandable radiofrequency ablation was used to ensure cauterization and hemostasis of the puncture route. We evaluated the clinical background and complications. Results: The average (±standard deviation) tumor diameter was 56.87±39.45 mm. Pathological diagnosis was possible in all cases. In 20 patients, the postoperative pathological diagnosis differed from the preoperative diagnosis. No significant anemia progression was observed in any patients after biopsy, and no peritoneal seeding was observed during a mean follow-up observation period of 18.5 months. Conclusion: Liver tumor biopsy, followed by cauterization with expandable radiofrequency ablation via a co-access needle, is safe and useful for obtaining reliable diagnoses.

CTNI-41. INITIAL RESULTS OF A PHASE I WINDOW OF OPPORTUNITY TRIAL EVALUATING A FIRST-IN-CLASS CD29 INHIBITOR, OS2966, IN RECURRENT HIGH-GRADE GLIOMA

BACKGROUND OS2966 is a first-in-class, humanized and deimmunized monoclonal antibody which antagonizes CD29/β1integrin, a mechanosignaling receptor prominently upregulated in glioblastoma. Preclinical studies in mice and non-human primates have demonstrated safety and encouraging efficacy. A two-part, ascending concentration, phase I clinical trial was therefore initiated to evaluate the safety and feasibility of delivering OS2966 directly to the site of disease via convection-enhanced delivery (CED) in recurrent high-grade glioma patients. METHODS This study has a 2-part design: In part 1, patients undergo stereotactic tumor biopsy followed by placement of a multiport CED catheter for delivery of OS2966 to the bulk contrast enhancing tumor. Subsequently, patients undergo a clinically-indicated tumor resection followed by placement of two CED catheters and delivery of OS2966 to the surrounding tumor-infiltrated brain. A unique concentration-based accelerated titration design is utilized for dose escalation. Given availability of pre and post infusion samples, pharmacodynamic data will be analyzed to explore mechanism of action of OS2966. RESULTS Two subjects have been treated at two corresponding dose levels (0.2mg/mL and 0.4 mg/mL). No dose-limiting toxicity or unexpected safety issues have been identified. To date, reported adverse events were mild (i.e., grade 1) and consistent with underlying disease and surgical procedures. No adverse events were attributed to OS2966 or CED catheter placement. Further, no clinically significant changes from baseline neurological exam have been noted for either patient through initial follow-up. Maximal tumor coverage and concomitant gross total resection were achieved for both patients. Tumor volume measured 1.63 cm3 and 16 cm3 for Patient 1 and 2 respectively with an intratumoral Vd/Vi ratio of 1.3. and 0.94. Pharmacodynamic analysis via tissue-level biomarkers is ongoing and will be presented. CONCLUSION Initial data demonstrates the safety and feasibility of direct intracranial delivery of OS2966.

CTIM-20. FINAL RESULTS OF CONTROLLED IL-12 MONOTHERAPY AND IN COMBINATION WITH PD-1 INHIBITOR IN ADULT SUBJECTS WITH RECURRENT GLIOBLASTOMA

Ad-RTS-hIL-12(Ad) is a gene therapy candidate conditionally expressing IL-12 under the transcriptional control of veledimex(V) acting via the RheoSwitch Therapeutic System® gene switch. Veledimex plasma and tumor PK demonstrated a dose-response relationship and crossing the BBB. PD-1+ T-cells were increased in tumor biopsy samples after treatment with Controlled-IL-12 in a phase-l study. This finding was the rationale for conducting 2 trials of Controlled-IL-12 in combination with PD-1-inhibitor to enhance T-cell-mediated anti-tumor effects. Data from two completed phase-I studies (presented in SNO2020), and an ongoing phase-II study of Controlled-IL-12 with cemiplimab study for the treatment of recurrent glioblastoma (rGBM) will be discussed. Ziopharm has conducted 3 phase-I (NCT02026271/NCT03679754 (monotherapy), NCT03636477 (combination with nivolumab)) and one phase-ll (NCT04006119) multicenter, open-label, single-arm trial in subjects with rGBM is evaluating Ad (single intratumoral injection, 2 x 1011-viral-particles, Day0) with oral V dosing (20mg, Days 0-14) with cemiplimab infusions (350 mg IV) on Days -7, 15, then Q3W. Systemic biomarkers (serum cytokines, and immune-activation-markers), local effects (tumor cytokines, T-cell immunobiology, pathology), neoepitope, and imaging will be assessed. Subject characteristics (Controlled IL-12 monotherapy (n=75); combination (Controlled IL-12 with anti-PD-1s) (n=61) were consistent across all 3 studies. Safety profiles were comparable between monotherapy and in combination with anti-PD-1s. Adverse reactions (ARs) after nivolumab or cemiplimab were consistent with labeling of anti-PD-1s. ARs related to Controlled IL-12 were all manageable and reversible with no synergistic toxicities in combination with anti-PD-1s. Increases in serum cytokine levels and pathology findings consistent with immune-mediated anti-tumor effect were observed in subjects who received Controlled-IL-12 monotherapy and in combination with anti-PD-1s. Final survival data and results from neoepitope analysis will be presented. Further investigation is warranted to understand the impact of monotherapy vs. combination, concurrent steroids use and unifocal vs. multifocal disease on overall survival in subjects with rGBM receiving Controlled-IL-12.

PATH-08. PROGNOSTIC IMPLICATIONS FROM LONG-TERM SURVIVORS (LTS) OF GLIOBLASTOMA

Glioblastoma (GBM) is the most aggressive primary brain malignancy with &lt; 45% living a year beyond diagnosis which drops to 7% at five years. However, there have been reports of long-term survivors (LTS) living three to ten years beyond diagnosis. Few studies have reported on molecular factors in tumors from LTS cohorts. We identified GBM (IDH1/2 wildtype) patients living at least 3 years post diagnosis (N=25), including 16 with pre-treatment tumor tissue, from our Natural History Study. Available pre- or post-treatment tumors were analyzed with targeted panel sequencing and methylation analysis for classification, MGMT promoter status and copy number changes. Classical clinical prognostic features such as limited resection or older age did not preclude long-term survival as patients with tumor biopsy (n=1) or subtotal resection (n= 5) and patients &gt; 60 were included in the LTS cohort. Furthermore, tumors with molecular features typically associated with poor prognosis were also in this GBM LTS group. MGMT promoter was unmethylated in 17% of tumors; EGFRvIII mutation in 13%, EGFR amplification in 33%, CDKN2A homozygous loss in 30% and complete chromosome 7 gain with 10 loss in 55%. Additionally, the methylation classifier found a higher-than-expected incidence of mesenchymal tumors (29%) and RTK II (57%). Tumors had a higher percent of TP53 mutations (44%) but lower pTERT (76%) compared to TCGA. These data suggest an individual patient’s prognosis cannot easily be predetermined based on classical clinical and molecular data. This underscores the need for further analyses to discover additional factors leading to their unexpected, prolonged survival and elucidate the role of factors typically associated with poor prognosis. Future work will include RNA-sequencing and germline whole genome sequencing to determine tumor specific gene expression and identify any possible genomic alterations that confer improved survival.

CTIM-08. SAFETY, EFFICACY, AND SURVIVAL RESULTS FROM A PHASE 1 STUDY OF THE ONCOLYTIC ADENOVIRUS DNX-2401 FOLLOWED BY STANDARD OF CARE RADIOTHERAPY FOR NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)

BACKGROUND Diffuse intrinsic pontine glioma (DIPG) is the most lethal pediatric brain tumor. Median overall survival (OS) with standard of care radiation therapy (RT) is approximately 8-10 months and 2-year survival is &lt; 10%. A Phase 1 single-center study was conducted to evaluate the oncolytic adenovirus, DNX-2401 (tasadenoturev), followed by RT for DIPG. METHODS Newly-diagnosed DIPG patients 1-18 years old received a tumor biopsy through the cerebellar peduncle followed by intratumoral injection of 1e10 – 5e10 vp DNX-2401 and conventional RT 1-3 weeks later. RESULTS Subjects were enrolled (n=12) from December 2017 to January 2020 and had a median age of 9 years (range 3-18) and Lansky/Karnofsky performance scores of 90-100 (n=4; 33%) or 70-80 (n=8; 67%). Genetic assessment was completed for 11 subjects (92%) and histone 3 K27M mutations were identified in 10 subjects, including H3F3A (n=8), HIST2H3C (n=1), and HIST1H3B (n=1); 1 subject was H3 wildtype (n=1). TP53 mutations were identified in 5 subjects (42%). DNX-2401 was administered followed by RT (n=11; 92%). No dose-limiting toxicities were observed and the treatment regimen was well-tolerated. The most commonly reported adverse events (≥ 5 subjects), regardless of study drug relationship, include asthenia, headache, vomiting, pyrexia, and neurological deterioration. Three serious adverse events were reported including grade 3 abdominal pain, grade 3 lymphopenia, and grade 3 clinical deterioration. Tumor reductions were reported for 9 subjects (75%), including 2 confirmed (17%) and 2 unconfirmed (17%) responses per RAPNO criteria. As of the data cutoff, median OS is 19.7 months and OS-24 is 32% with follow-up ongoing for 3 subjects (26.9, 25.6, 13.7 months). CONCLUSIONS DNX-2401 followed by RT can be safely administered to DIPG. Survival outcomes are encouraging, thus warranting further evaluation in a Phase 2 study.