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BACKGROUND: Meningiomas occur in 80% of persons with neurofibromatosis 2 (NF2) and cause significant mortality and morbidity, yet there are no effective medical treatments. NF2-deficient tumors have constitutive activation of mammalian/mechanistic target of rapamycin (mTOR), and treatment with mTORC1 inhibitors results in growth arrest in a minority of tumors, with paradoxical activation of the mTORC2/AKT pathway. We studied the effect of vistusertib, a dual mTORC1/mTORC2 inhibitor, in NF2 patients with progressive or symptomatic meningiomas. METHODS: Vistusertib was administered orally at 125 mg twice daily for 2 consecutive days each week. The primary endpoint was the imaging response in the target meningioma, defined as a volume decrease of 20% compared with the baseline. Secondary endpoints included toxicity, imaging response of nontarget tumors, quality of life, and genetic biomarkers. RESULTS: Eighteen participants (13 female), median age of 41 (range, 18-61) years, were enrolled. In target meningiomas, the best response was partial response (PR) in 1/18 tumors (6%) and stable disease (SD) in 17/18 tumors (94%). For all measured intracranial meningiomas and vestibular schwannomas, the best imaging response was PR in 6/59 tumors (10%) and SD in 53 (90%). Treatment-related grade 3/4 adverse events occurred in 14 (78%) participants, and 9 participants discontinued treatment due to side effects. CONCLUSIONS: Although the study did not meet the primary endpoint, vistusertib treatment was associated with high rates of SD in progressive NF2-related tumors. However, this dosing regimen for vistusertib was poorly tolerated. Future studies of dual mTORC inhibitors for NF2 should focus on optimizing tolerability and evaluating the relevance of tumor stability in participants.

PurposeVEGF is upregulated in glioblastoma and may contribute to immunosuppression. We performed a phase II study of pembrolizumab alone or with bevacizumab in recurrent glioblastoma.Patients and methodsEighty bevacizumab-naïve patients with recurrent glioblastoma were randomized to pembrolizumab with bevacizumab (cohort A, n = 50) or pembrolizumab monotherapy (cohort B, n = 30). The primary endpoint was 6-month progression-free survival (PFS-6). Assessed biomarkers included evaluation of tumor programmed death-ligand 1 expression, tumor-infiltrating lymphocyte density, immune activation gene expression signature, and plasma cytokines. The neurologic assessment in neuro-oncology (NANO) scale was used to prospectively assess neurologic function.ResultsPembrolizumab alone or with bevacizumab was well tolerated but of limited benefit. For cohort A, PFS-6 was 26.0% [95% confidence interval (CI), 16.3-41.5], median overall survival (OS) was 8.8 months (95% CI, 7.7-14.2), objective response rate (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%. Tumor immune markers were not associated with OS, but worsened OS correlated with baseline dexamethasone use and increased posttherapy plasma VEGF (cohort A) and mutant IDH1, unmethylated MGMT, and increased baseline PlGF and sVEGFR1 levels (cohort B). The NANO scale contributed to overall outcome assessment.ConclusionsPembrolizumab was ineffective as monotherapy and with bevacizumab for recurrent glioblastoma. The infrequent radiographic responses to combinatorial therapy were durable. Tumor immune biomarkers did not predict outcome. Baseline dexamethasone use and tumor MGMT warrant further study as potential biomarkers in glioblastoma immunotherapy trials.

Abstract 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.

Abstract PURPOSE The neurologic assessment in neuro-oncology (NANO) scale was developed as a standardized metric to objectively measure neurologic function in brain tumor patients to complement radiographic assessment in defining overall outcome. A multicenter, phase 2 study of pembrolizumab with or without bevacizumab in patients with recurrent glioblastoma incorporated the NANO scale as an exploratory endpoint. METHODS Neurologic examination was evaluated at baseline and MRI assessments using the NANO scale until patients came off study. Statistical descriptive data analysis was performed using R (version 3.4.3). Correlation analysis utilized Fisher’s exact test. RESULTS NANO compliance rate was 94% in 80 patients accrued on the study. Of the 80 patients, 7 were missing NANO at baseline visit and were excluded from analysis for NANO response criteria. Fifteen patients did not have end of treatment NANO evaluation. Of 73 patients, 35 (48%) had a normal neurologic examination at baseline by NANO. Strength and language accounted for the majority of changes in neurologic function over the course of study treatment. Eighteen patients (25%) had neurologic progression by NANO, of whom 2 did not have concurrent radiographic progression. Three patients (pembrolizumab plus bevacizumab cohort) had a neurologic response associated with stable disease on MRI. NANO assessment prior to initiation of cycle 3 correlated with RANO response (p=0.011), change in KPS (p=0.002) and dexamethasone requirement (p=0.007) while those with NANO progression at this assessment had worse overall survival (291 vs 324 days), but this trend did not achieve statistical significance (p=0.2). CONCLUSIONS Evaluation of neurologic function by NANO scale was feasible in a multicenter prospective study in patients with GBM with a high compliance rate. The NANO scale objectively tracked stable neurologic function in most patients throughout the trial period and was associated with a trend for survival.

BackgroundWe evaluated apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) as a schwannoma tumor suppressor and explored its utilization in a schwannoma gene therapy strategy that may be translated to clinical use.MethodsASC protein expression and mRNA level were assessed in human schwannoma by immunohistochemistry and quantitative PCR, respectively. Methylation- specific PCR was used to assess ASC promoter methylation. The effect of ASC overexpression in schwannoma cells was evaluated through ATP-based viability, lactate dehydrogenase release, and apoptosis staining. Western blotting and colorimetric assay were used to test the effect of ASC overexpression on endogenous pro-apoptotic pathways. Bioluminescence imaging, behavioral testing, and immunohistochemistry in human xenograft and murine allograft schwannoma models were used to examine the efficacy and toxicity of intratumoral injection of adeno-associated virus (AAV) vector encoding ASC.ResultsASC expression was suppressed via promoter methylation in over 80% of the human schwannomas tested. ASC overexpression in schwannoma cells results in cell death and is associated with activation of endogenous caspase-9, caspase-3, and upregulation of BH3 interacting-domain death agonist. In a human xenograft schwannoma model, AAV1-mediated ASC delivery reduced tumor growth and resolved tumor-associated pain without detectable toxicity, and tumor control was associated with reduced Ki67 mitotic index and increased tumor-cell apoptosis. Efficacy of this schwannoma gene therapy strategy was confirmed in a murine schwannoma model.ConclusionWe have identified ASC as a putative schwannoma tumor suppressor with high potential clinical utility for schwannoma gene therapy and generated a vector that treats schwannomas via a novel mechanism that does not overlap with current treatments.

Background The role of tyrosine kinase inhibitors (TKIs) in early-stage and metastatic oncogene-driven non–small cell lung cancer (NSCLC) is established, but it remains unknown how best to integrate TKIs with concurrent chemoradiotherapy (cCRT) in locally advanced disease. The phase 2 ASCENT trial assessed the efficacy and safety of afatinib and cCRT with or without surgery in locally advanced epidermal growth factor receptor (EGFR)-mutant NSCLC. Patients and Methods Adults ≥18 years with histologically confirmed stage III (AJCC 7th edition) NSCLC with activating EGFR mutations were enrolled at Mass General and Dana-Farber/Brigham Cancer Centers, Boston, Massachusetts. Patients received induction afatinib 40 mg daily for 2 months, then cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 IV every 3 weeks during RT (definitive or neoadjuvant dosing). Patients with resectable disease underwent surgery. All patients were offered consolidation afatinib for 2 years. The primary endpoint was the objective response rate (ORR) to induction TKI. Secondary endpoints were safety, conversion to operability, progression-free survival (PFS), and overall survival (OS). Analyses were performed on the intention-to-treat population. Results Nineteen patients (median age 56 years; 74% female) were enrolled. ORR to induction afatinib was 63%. Seventeen patients received cCRT; 2/9 previously unresectable became resectable. Ten underwent surgery; 6 had a major or complete pathological response. Thirteen received consolidation afatinib. With a median follow-up of 5.0 years, median PFS and OS were 2.6 (95% CI, 1.4-3.1) and 5.8 years (2.9-NR), respectively. Sixteen recurred or died; 6 recurrences were isolated to CNS. The median time to progression after stopping consolidation TKI was 2.9 months (95% CI, 1.1-7.2). Four developed grade 2 pneumonitis. There were no treatment-related deaths. Conclusion We explored the efficacy of combining TKI with cCRT in oncogene-driven NSCLC. Induction TKI did not compromise subsequent receipt of multimodality therapy. PFS was promising, but the prevalence of CNS-only recurrences and rapid progression after TKI discontinuation speak to unmet needs in measuring and eradicating micrometastatic disease. [ABSTRACT FROM AUTHOR]

Inhibition of the vascular endothelial growth factor (VEGF) pathway has failed to improve overall survival of patients with glioblastoma (GBM). We previously showed that angiopoietin-2 (Ang-2) overexpression compromised the benefit from anti-VEGF therapy in a preclinical GBM model. Here we investigated whether dual Ang-2/VEGF inhibition could overcome resistance to anti-VEGF treatment. We treated mice bearing orthotopic syngeneic (Gl261) GBMs or human (MGG8) GBM xenografts with antibodies inhibiting VEGF (B20), or Ang-2/VEGF (CrossMab, A2V). We examined the effects of treatment on the tumor vasculature, immune cell populations, tumor growth, and survival in both the Gl261 and MGG8 tumor models. We found that in the Gl261 model, which displays a highly abnormal tumor vasculature, A2V decreased vessel density, delayed tumor growth, and prolonged survival compared with B20. In the MGG8 model, which displays a low degree of vessel abnormality, A2V induced no significant changes in the tumor vasculature but still prolonged survival. In both the Gl261 and MGG8 models A2V reprogrammed protumor M2 macrophages toward the antitumor M1 phenotype. Our findings indicate that A2V may prolong survival in mice with GBM by reprogramming the tumor immune microenvironment and delaying tumor growth.

BackgroundTreatment options for patients with non-small cell lung cancer (NSCLC) with brain metastases are limited. Patupilone (EPO906), a blood-brain barrier-penetrating, microtubule-targeting, cytotoxic agent, has shown clinical activity in phase 1/2 studies in patients with NSCLC. This study evaluates the efficacy, pharmacokinetics, and safety of patupilone in NSCLC brain metastases.MethodsAdult patients with NSCLC and confirmed progressive brain metastases received patupilone intravenously at 10 mg/m(2) every 3 weeks. The primary endpoint of this multinomial 2-stage study combined early progression (EP; death or progression within 3 weeks) and progression-free survival at 9 weeks (PFS9w) to determine drug activity.ResultsFifty patients with a median age of 60 years (range, 33-74 years) were enrolled; the majority were men (58%), and most had received prior therapy for brain metastases (98%). The PFS9w rate was 36%, and the EP rate was 26%. Patupilone blood pharmacokinetic analyses showed mean areas under the concentration-time curve from time zero to 504 hours for cycles 1 and 3 of 1544 and 1978 ng h/mL, respectively, and a mean steady state distribution volume of 755 L/m(2) . Grade 3/4 adverse events (AEs), regardless of their relation with the study drug, included diarrhea (24%), pulmonary embolisms (8%), convulsions (4%), and peripheral neuropathy (4%). All patients discontinued the study drug: 31 (62%) for disease progression and 13 (26%) for AEs. Twenty-five of 32 deaths were due to brain metastases. The median time to progression and the overall survival were 3.2 and 8.8 months, respectively.ConclusionsThis is the first prospective study of chemotherapy for recurrent brain metastases from NSCLC. In this population, patupilone demonstrated activity in heavily treated patients.

PurposePatients with high-grade gliomas (HGG) are frequently excluded from first-in-human solid tumor trials because of perceived poor prognosis, excessive toxicities, concomitant drug interactions, and poor efficacy. We conducted an analysis of outcomes from select, single-agent phase I studies in patients with HGG. We compared outcomes to pooled analysis of published studies in solid tumors with various molecular and cytotoxic drugs evaluated as single agents or as combinations.Patient and methodsIndividual records of patients with recurrent HGG enrolled onto Adult Brain Tumor Consortium trials of single-agent, cytotoxic or molecular agents from 2000 to 2008 were analyzed for baseline characteristics, toxicities, responses, and survival.ResultsOur analysis included 327 patients with advanced, refractory HGG who were enrolled onto eight trials involving targeted molecular (n=5) and cytotoxic (n=3) therapies. At enrollment, patients had a median Karnofsky performance score of 90 and median age of 52 years; 62% were men, 63% had glioblastoma, and the median number of prior systemic chemotherapies was one. Baseline laboratory values were in an acceptable range to meet eligibility criteria. Patients were on the study for a median of two cycles (range, ConclusionPatients with HGG who meet standard eligibility criteria may be good candidates for solid tumor phase I studies with single-agent molecular or cytotoxic drugs with favorable preclinical rationale and pharmacokinetic properties in this population.

Mucolipidosis IV (MLIV) is caused by mutations in the gene MCOLN1. Patients with MLIV have severe neurologic deficits and very little is known about the brain pathology in this lysosomal disease. Using an accurate mouse model of mucolipidosis IV, we observed early behavioral deficits which were accompanied by activation of microglia and astrocytes. The glial activation that persisted during the course of disease was not accompanied by neuronal loss even at the late stage. In vivo [Ca(2+)]-imaging revealed no changes in resting [Ca(2+)] levels in Mcoln1(-/-) cortical neurons, implying their physiological health. Despite the absence of neuron loss, we observed alterations in synaptic plasticity, as indicated by elevated paired-pulse facilitation and enhanced long-term potentiation. Myelination deficits and severely dysmorphic corpus callosum were present early and resembled white matter pathology in mucolipidosis IV patients. These results indicate the early involvement of glia, and challenge the traditional view of mucolipidosis IV as an overtly neurodegenerative condition.