Pembrolizumab in brain metastases of diverse histologies: phase 2 trial results.

Brain metastases (BMs) are an emerging challenge in oncology due to increasing incidence and limited treatments. Here, we present results of a single-arm, open-label, phase 2 trial evaluating intracranial efficacy of pembrolizumab, a programmed cell death protein 1 inhibitor, in 9 patients with untreated BMs (cohort A) and 48 patients with recurrent and progressive BMs (cohort B) across different histologies. The primary endpoint was the proportion of patients achieving intracranial benefit, defined by complete response, partial response or stable disease. The primary endpoint was met with an intracranial benefit rate of 42.1% (90% confidence interval (CI): 31-54%). The median overall survival, a secondary endpoint, was 8.0 months (90% CI: 5.5-8.7 months) across both cohorts, 6.5 months (90% CI: 4.5-18.7 months) for cohort A and 8.1 months (90% CI: 5.3-9.6 months) for cohort B. Seven patients (12.3%), encompassing breast, melanoma and sarcoma histologies, had overall survival greater than 2 years. Thirty patients (52%; 90% CI: 41-64%) had one or more grade-3 or higher adverse events that were at least possibly treatment related. Two patients had grade-4 adverse events (cerebral edema) that were deemed at least possibly treatment related. These results suggest that programmed cell death protein 1 blockade may benefit a select group of patients with BMs, and support further studies to identify biomarkers and mechanisms of resistance. ClinicalTrials.gov identifier: NCT02886585.

Novel Systemic Approaches for the Management of Meningiomas: Immunotherapy and Targeted Therapies.

Meningiomas, the most prevalent primary intracranial tumor, arise from the arachnoid cap cells in the meninges, the membranes that surround the brain and the spinal cord. The field has long sought effective predictors of meningioma recurrence and malignant transformation, as well as therapeutic targets to guide intensified treatment such as early radiation or systemic therapy. Novel and more targeted approaches are currently being tested in numerous clinical trials for patients who have progressed after surgery and/or radiation. In this review, the authors discuss relevant molecular drivers that have therapeutic implications and examine recent clinical trial data evaluating targeted therapies and immunotherapies.

Multiplatform molecular profiling uncovers two subgroups of malignant peripheral nerve sheath tumors with distinct therapeutic vulnerabilities.

Malignant peripheral nerve sheath tumor (MPNST) is a highly aggressive sarcoma, and a lethal neurofibromatosis type 1-related malignancy, with little progress made on treatment strategies. Here, we apply a multiplatform integrated molecular analysis on 108 tumors spanning the spectrum of peripheral nerve sheath tumors to identify candidate drivers of MPNST that can serve as therapeutic targets. Unsupervised analyses of methylome and transcriptome profiles identify two distinct subgroups of MPNSTs with unique targetable oncogenic programs. We establish two subgroups of MPNSTs: SHH pathway activation in MPNST-G1 and WNT/ß-catenin/CCND1 pathway activation in MPNST-G2. Single nuclei RNA sequencing characterizes the complex cellular architecture and demonstrate that malignant cells from MPNST-G1 and MPNST-G2 have neural crest-like and Schwann cell precursor-like cell characteristics, respectively. Further, in pre-clinical models of MPNST we confirm that inhibiting SHH pathway in MPNST-G1 prevent growth and malignant progression, providing the rational for investigating these treatments in clinical trials.

Loss of H3K27me3 in meningiomas.

BACKGROUND: There is a critical need for objective and reliable biomarkers of outcome in meningiomas beyond WHO classification. Loss of H3K27me3 has been reported as a prognostically unfavorable alteration in meningiomas. We sought to independently evaluate the reproducibility and prognostic value of H3K27me3 loss by immunohistochemistry (IHC) in a multicenter study. METHODS: IHC staining for H3K27me3 and analyses of whole slides from 181 meningiomas across three centers was performed. Staining was analyzed by dichotomization into loss and retained immunoreactivity, and using a 3-tiered scoring system in 151 cases with clear staining. Associations of grouping with outcome were performed using Kaplan-Meier survival estimates. RESULTS: A total of 21 of 151 tumors (13.9%) demonstrated complete loss of H3K27me3 staining in tumor with retained endothelial staining. Overall, loss of H3K27me3 portended a worse outcome with shorter times to recurrence in our cohort, particularly for WHO grade 2 tumors which were enriched in our study. There were no differences in recurrence-free survival (RFS) for WHO grade 3 patients with retained vs loss of H3K27me3. Scoring by a 3-tiered system did not add further insights into the prognostic value of this H3K27me3 loss. Overall, loss of H3K27me3 was not independently associated with RFS after controlling for WHO grade, extent of resection, sex, age, and recurrence status of tumor on multivariable Cox regression analysis. CONCLUSIONS: Loss of H3K27me3 identifies a subset of WHO grade 2 and possibly WHO grade 1 meningiomas with increased recurrence risk. Pooled analyses of a larger cohort of samples with standardized reporting of clinical definitions and staining patterns are warranted.

Determining the Optimal Adjuvant Therapy for Improving Survival in Elderly Patients with Glioblastoma: A Systematic Review and Network Meta-analysis.

PURPOSE: Older patients with glioblastoma (GBM) are underrepresented in clinical trials. Several abbreviated and standard chemoradiotherapy regimens are advocated with no consensus on the optimal approach. Our objective was to quantitatively evaluate which of these regimens would provide the most favorable survival outcomes in older patients with GBM using a network meta-analysis. EXPERIMENTAL DESIGN: MEDLINE, Embase, Google Scholar, and the Cochrane Library were searched. Patients >60 years of age with histologically confirmed GBM were included. Primary outcome of interest was the pooled HR from randomized controlled trials (RCTs). Secondary outcomes of interest included pooled HR from studies controlling for MGMT promoter methylation status, and safety. RESULTS: Fourteen studies, including 5 RCTs, reporting 4,561 patients were included. Using highest quality data from RCTs, our network-based approach demonstrated that standard radiotherapy (SRT) and temozolomide (TMZ) provided similar survival benefit when compared with hypofractionated radiotherapy (HRT) and TMZ [HR = 0.90; 95% confidence interval (CI), 0.43-1.87], TMZ alone (HR 1.25; 95% CI, 0.69-2.26), HRT alone (HR = 1.34; 95% CI, 0.73-2.45), or SRT alone (HR = 1.43; 95% CI, 0.87-2.36). HRT-TMZ had the highest probability (85%) of improving survival in older patients with GBM followed by SRT-TMZ (72%). Pooled analysis of trials controlling for MGMT promoter methylation status demonstrated that TMZ monotherapy confers similar survival benefit to combined chemoradiotherapy. CONCLUSIONS: Statistical comparisons using a network approach demonstrates that the common treatment regimens for older patients with GBM in previous RCTs confer similar survival benefits. Adjustments for MGMT promoter methylation status demonstrated that radiotherapy alone was inferior to TMZ-based approaches. Head-to-head comparison of TMZ monotherapy to combined TMZ and radiation is warranted.