Clinical outcome and prognostic factors for central neurocytoma: twenty year institutional experience

Central neurocytomas are uncommon intraventricular neoplasms whose optimal management remains controversial due to their rarity. We assessed outcomes for a historical cohort of neurocytoma patients and evaluated effects of tumor atypia, size, resection extent, and adjuvant radiotherapy. Progression-free survival (PFS) was measured by Kaplan-Meier and Cox proportional hazards methods. A total of 28 patients (15 males, 13 females) were treated between 1995 and 2014, with a median age at diagnosis of 26 years (range 5-61). Median follow-up was 62.2 months and 3 patients were lost to follow-up postoperatively. Thirteen patients experienced recurrent/progressive disease and 2-year PFS was 75% (95% CI 53-88%). Two-year PFS was 48% for MIB-1 labeling >4% versus 90% for ≤4% (HR 5.4, CI 2.2-27.8, p = 0.0026). Nine patients (32%) had gross total resections (GTR) and 19 (68%) had subtotal resections (STR). PFS for >80% resection was 83 versus 67% for ≤80% resection (HR 0.67, CI 0.23-2.0, p = 0.47). Three STR patients (16%) received adjuvant radiation which significantly improved overall PFS (p = 0.049). Estimated 5-year PFS was 67% for STR with radiotherapy versus 53% for STR without radiotherapy. Salvage therapy regimens were diverse and resulted in stable disease for 54% of patients and additional progression for 38 %. Two patients with neuropathology-confirmed atypical neurocytomas died at 4.3 and 113.4 months after initial surgery. For central neurocytomas, MIB-1 labeling index >4% is predictive of poorer outcome and our data suggest that adjuvant radiotherapy after STR may improve PFS. Most patients requiring salvage therapy will be stabilized and multiple modalities can be effectively utilized

Phase I/randomized phase II trial of TRC105 plus bevacizumab versus bevacizumab in recurrent glioblastoma: North Central Cancer Treatment Group N1174 (Alliance)

Background Patients with glioblastoma (GBM) have a poor prognosis and limited effective treatment options. Bevacizumab has been approved for treatment of recurrent GBM, but there is questionable survival benefit. Based on preclinical and early clinical data indicating that CD105 upregulation may represent a mechanism of resistance to bevacizumab, we hypothesized that combining bevacizumab with the anti-CD105 antibody TRC105 may improve efficacy in recurrent GBM.Methods Phase I dose-escalation/comparative randomized phase II trial in patients with GBM. During phase I, the maximum tolerated dose (MTD) of TRC105 in combination with bevacizumab was determined. In phase II, patients were randomized 1:1 to TRC105 and bevacizumab or bevacizumab monotherapy. Patients receivedTRC105 (10 mg/kg) weekly and bevacizumab (10 mg/kg) every 2 weeks. Efficacy, as assessed by progression-free survival (PFS), was the primary endpoint; safety, quality of life, and correlative outcomes were also evaluated.Results In total, 15 patients were enrolled in phase I and 101 in phase II; 52 patients were randomized to TRC105 with bevacizumab and 49 to bevacizumab monotherapy. The MTD was determined to be 10 mg/kg TRC105 weekly plus bevacizumab 10 mg/kg every 2 weeks. An increased occurrence of grade >= 3 adverse events was seen in the combination arm, including higher incidences of anemia. Median PFS was similar in both treatment arms: 2.9 months for combination versus 3.2 months for bevacizumab monotherapy (HR = 1.16, 95% CI = 0.75-1.78, P = .51). Quality of life scores were similar for both treatment arms.Conclusions TRC105 in combination with bevacizumab was well tolerated in patients with recurrent GBM, but no difference in efficacy was observed compared to bevacizumab monotherapy

Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma.

Glioblastoma is the most common primary malignant brain tumor in adults and is associated with poor survival. The Ivy Foundation Early Phase Clinical Trials Consortium conducted a randomized, multi-institution clinical trial to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical programmed cell death protein 1 (PD-1) blockade alone. Neoadjuvant PD-1 blockade was associated with upregulation of T cell- and interferon-γ-related gene expression, but downregulation of cell-cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells and a decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor

A randomized controlled phase III study of VB-111 combined with bevacizumab vs bevacizumab monotherapy in patients with recurrent glioblastoma (GLOBE)

BACKGROUND: Ofranergene obadenovec (VB-111) is an anticancer viral therapy that demonstrated in a phase II study a survival benefit for patients with recurrent glioblastoma (rGBM) who were primed with VB-111 monotherapy that was continued after progression with concomitant bevacizumab. METHODS: This pivotal phase III randomized, controlled trial compared the efficacy and safety of upfront combination of VB-111 and bevacizumab versus bevacizumab monotherapy. Patients were randomized 1:1 to receive VB-111 1013 viral particles every 8 weeks in combination with bevacizumab 10 mg/kg every 2 weeks (combination arm) or bevacizumab monotherapy (control arm). The primary endpoint was overall survival (OS), and secondary endpoints were objective response rate (ORR) by Response Assessment in Neuro-Oncology (RANO) criteria and progression-free survival (PFS). RESULTS: Enrolled were 256 patients at 57 sites. Median exposure to VB-111 was 4 months. The study did not meet its primary or secondary goals. Median OS was 6.8 versus 7.9 months in the combination versus control arm (hazard ratio, 1.20; 95% CI: 0.91-1.59; P = 0.19) and ORR was 27.3% versus 21.9% (P = 0.26). A higher rate of grades 3-5 adverse events was reported in the combination arm (67% vs 40%), mainly attributed to a higher rate of CNS and flu-like/fever events. Trends for improved survival with combination treatment were seen in the subgroup of patients with smaller tumors and in patients who had a posttreatment febrile reaction. CONCLUSIONS: In this study, upfront concomitant administration of VB-111 and bevacizumab failed to improve outcomes in rGBM. Change of treatment regimen, with the lack of VB-111 monotherapy priming, may explain the differences from the favorable phase II results. CLINICAL TRIALS REGISTRATION: NCT02511405

A randomized controlled phase III study of VB-111 combined with bevacizumab vs bevacizumab monotherapy in patients with recurrent glioblastoma (GLOBE).

BackgroundOfranergene obadenovec (VB-111) is an anticancer viral therapy that demonstrated in a phase II study a survival benefit for patients with recurrent glioblastoma (rGBM) who were primed with VB-111 monotherapy that was continued after progression with concomitant bevacizumab.MethodsThis pivotal phase III randomized, controlled trial compared the efficacy and safety of upfront combination of VB-111 and bevacizumab versus bevacizumab monotherapy. Patients were randomized 1:1 to receive VB-111 1013 viral particles every 8 weeks in combination with bevacizumab 10 mg/kg every 2 weeks (combination arm) or bevacizumab monotherapy (control arm). The primary endpoint was overall survival (OS), and secondary endpoints were objective response rate (ORR) by Response Assessment in Neuro-Oncology (RANO) criteria and progression-free survival (PFS).ResultsEnrolled were 256 patients at 57 sites. Median exposure to VB-111 was 4 months. The study did not meet its primary or secondary goals. Median OS was 6.8 versus 7.9 months in the combination versus control arm (hazard ratio, 1.20; 95% CI: 0.91-1.59; P = 0.19) and ORR was 27.3% versus 21.9% (P = 0.26). A higher rate of grades 3-5 adverse events was reported in the combination arm (67% vs 40%), mainly attributed to a higher rate of CNS and flu-like/fever events. Trends for improved survival with combination treatment were seen in the subgroup of patients with smaller tumors and in patients who had a posttreatment febrile reaction.ConclusionsIn this study, upfront concomitant administration of VB-111 and bevacizumab failed to improve outcomes in rGBM. Change of treatment regimen, with the lack of VB-111 monotherapy priming, may explain the differences from the favorable phase II results.Clinical trials registrationNCT02511405

Randomized trial of neoadjuvant vaccination with tumor-cell lysate induces T cell response in low-grade gliomas

BACKGROUND. Long-term prognosis of WHO grade II low-grade gliomas (LGGs) is poor, with a high risk of recurrence and malignant transformation into high-grade gliomas. Given the relatively intact immune system of patients with LGGs and the slow tumor growth rate, vaccines are an attractive treatment strategy. METHODS. We conducted a pilot study to evaluate the safety and immunological effects of vaccination with GBM6-AD, lysate of an allogeneic glioblastoma stem cell line, with poly-ICLC in patients with LGGs. Patients were randomized to receive the vaccines before surgery (arm 1) or not (arm 2) and all patients received adjuvant vaccines. Coprimary outcomes were to evaluate safety and immune response in the tumor. RESULTS. A total of 17 eligible patients were enrolled — 9 in arm 1 and 8 in arm 2. This regimen was well tolerated with no regimen-limiting toxicity. Neoadjuvant vaccination induced upregulation of type-1 cytokines and chemokines and increased activated CD8+ T cells in peripheral blood. Single-cell RNA/T cell receptor sequencing detected CD8+ T cell clones that expanded with effector phenotype and migrated into the tumor microenvironment (TME) in response to neoadjuvant vaccination. Mass cytometric analyses detected increased tissue resident–like CD8+ T cells with effector memory phenotype in the TME after the neoadjuvant vaccination. CONCLUSION. The regimen induced effector CD8+ T cell response in peripheral blood and enabled vaccine-reactive CD8+ T cells to migrate into the TME. Further refinements of the regimen may have to be integrated into future strategies

The State of Neuro-Oncology During the COVID-19 Pandemic: A Worldwide Assessment

To assess the impact of the pandemic on the field, we performed an international web-based survey of practitioners, scientists, and trainees from 21 neuro-oncology organizations across 6 continents from April 24 through May 17. Of 582 respondents, 258 (45%) were in the US, and 314 (55%) were international. 80.4% were affiliated with academic institutions. 94% respondents reported changes in clinical practice; 95% reported conversion to telemedicine for at least some appointments. However, almost 10% practitioners felt the need to see patients in person specifically because of billing concerns and perceived institutional pressure. Over 50% believed neuro-oncology patients were at increased risk of contracting COVID-19. 67% practitioners suspended enrollment for at least one clinical trial: 53% suspended phase II and 62% suspended phase III trial enrollment. 71% clinicians feared for their or their families’ safety, specifically because of their clinical duties. 20% percent said they did not have enough PPE to work safely; about the same percentage were unhappy with their institutions’ response to the pandemic. 43% believed the pandemic would negatively affect their academic career, and 52% fellowship program directors were worried about losing funding for their training programs. While 69% respondents reported increased stress, 44% were offered no psychosocial support. 37% had their salary reduced. 36% researchers had to temporarily close their laboratories. In contrast, the pandemic created positive changes in perceived patient and family satisfaction, quality of communication, and use of technology to deliver care and interactions with other practitioners. CONCLUSIONS: The pandemic has altered standard treatment schedules and limited investigational treatment options for patients. In some cases, clinicians felt institutional pressure to continue conducting billable in-person visits when telemedicine visits would have sufficed. A lack of institutional support created anxiety among clinicians and researchers. We make specific recommendations to guide clinical and scientific infrastructure moving forward