Radiotherapy may synergize with programmed cell death 1 (PD1)/PD1 ligand (PD-L1) blockade. The purpose of this study was to determine the recommended phase II dose, safety/tolerability, and preliminary efficacy of combining pembrolizumab, an anti-PD1 monoclonal antibody, with hypofractionated stereotactic irradiation (HFSRT) and bevacizumab in patients with recurrent high-grade gliomas (HGGs). Eligible subjects with recurrent glioblastoma or anaplastic astrocytoma were treated with pembrolizumab (100 or 200 mg based on dose level Q3W) concurrently with HFSRT (30 Gy in 5 fractions) and bevacizumab 10 mg/kg Q2W. Thirty-two patients were enrolled (bevacizumab-naïve, n = 24; bevacizumab-resistant, n = 8). The most common treatment-related adverse events (TRAEs) were proteinuria (40.6%), fatigue (25%), increased alanine aminotransferase (25%), and hypertension (25%). TRAEs leading to discontinuation occurred in 1 patient who experienced a grade 3 elevation of aspartate aminotransferase. In the bevacizumab-naïve cohort, 20 patients (83%) had a complete response or partial response. The median overall survival (OS) and progression-free survival (PFS) were 13.45 months (95% CI: 9.46–18.46) and 7.92 months (95% CI: 6.31–12.45), respectively. In the bevacizumab-resistant cohort, PR was achieved in 5 patients (62%). Median OS was 9.3 months (95% CI: 8.97–18.86) with a median PFS of 6.54 months (95% CI: 5.95–18.86). The majority of patients (n = 20/26; 77%) had tumor-cell/tumor-microenvironment PD-L1 expression <1%. The combination of HFSRT with pembrolizumab and bevacizumab in patients with recurrent HGG is generally safe and well tolerated. These findings merit further investigation of HFSRT with immunotherapy in HGGs.

Recurrent high-grade glioma (HGG) remains incurable with inevitable evolution of resistance and high inter-patient heterogeneity in time to progression (TTP). Here, we evaluate if early tumor volume response dynamics can calibrate a mathematical model to predict patient-specific resistance to develop opportunities for treatment adaptation for patients with a high risk of progression. A total of 95 T1-weighted contrast-enhanced (T1post) MRIs from 14 patients treated in a phase I clinical trial with hypo-fractionated stereotactic radiation (HFSRT; 6 Gy × 5) plus pembrolizumab (100 or 200 mg, every 3 weeks) and bevacizumab (10 mg/kg, every 2 weeks; NCT02313272) were delineated to derive longitudinal tumor volumes. We developed, calibrated, and validated a mathematical model that simulates and forecasts tumor volume dynamics with rate of resistance evolution as the single patient-specific parameter. Model prediction performance is evaluated based on how early progression is predicted and the number of false-negative predictions. The model with one patient-specific parameter describing the rate of evolution of resistance to therapy fits untrained data ( ${\mathrm{R}}^2=0.70$ ). In a leave-one-out study, for the nine patients that had T1post tumor volumes ≥1 cm³, the model was able to predict progression on average two imaging cycles early, with a median of 9.3 (range: 3–39.3) weeks early (median progression-free survival was 27.4 weeks). Our results demonstrate that early tumor volume dynamics measured on T1post MRI has the potential to predict progression following the protocol therapy in select patients with recurrent HGG. Future work will include testing on an independent patient dataset and evaluation of the developed framework on T2/FLAIR-derived data.

Leptomeningeal metastasis is a consequence of advanced solid malignancies and has limited treatment options. It is possible that it is becoming more common as the leptomeninges act as a sanctuary site for recurrence from systemic cancer. Potential targeted and immunotherapy agents for the most common types of solid-tumor leptomeningeal metastasis are reviewed, as are their dosing/delivery strategies and novel, immunological approaches. Historically, patients with leptomeningeal metastasis have been excluded from clinical trials, and data on the management of leptomeningeal metastasis come from single case reports and retrospective analyses. For the first time ever, published reports suggest the tide may be turning in this challenging disease.

A growing body of evidence indicates that epigenetic silencing of genes involved in antigen processing and immune recognition results in immune escape and resistance to immunotherapy. Pre-clinical experiments have shown that use of histone deacetylases inhibitors such as vorinostat can restore tumor immune recognition and synergize with anti-PD 1/PD-L1 antibodies. Moreover, vorinostat has radiosensitizing properties. This report describes an ongoing phase I trial of vorinostat in combination with an antibody against PD1 (pembrolizumab), radiotherapy and temozolomide (TMZ) in patients (pts) with newly diagnosed glioblastoma (GBM). METHOD: This study employs a standard 3 + 3 dose escalation design exploring 2 sequential dose escalation cohorts of vorinostat. Eligible pts are treated with concurrent radiotherapy (60 Gy in 30 fractions) with TMZ (75 mg/m2/day) followed by 6 cycles of maintenance TMZ. Pembrolizumab (200 mg) is administered intravenously once every 3 weeks. Dose level 1 is consistent of vorinostat 200 mg/day orally on days 1–5 every week during radiotherapy and 300 mg/day orally 1 week on 1 week off after radiotherapy. At dose level 2, pts receive 300 mg of vorinostat on days 1–5 every week during radiotherapy and 400 mg/day orally 1 week on 1 week off after radiotherapy. Once the recommended phase II dose (RP2D) of vorinostat is determined, an additional 20 pts will be enrolled in an expansion safety cohort. The primary study objectives are to determine safety and the RP2D of vorinostat administered with above combination in pts with GBM. Secondary endpoints include determination of the 12 and 24 month survival rates and exploring tissue and blood biomarkers. As of June 4, 2018, enrollment to dose level 1 has been completed. So far no does limiting adverse event has been observed. Thrombocytopenia and fatigue are the most common adverse events. Updated safety and efficacy results will be presented.

Immunotherapeutic agents, especially checkpoint inhibitors, have emerged as the mainstay of therapy for several solid and hematological malignancies. These therapies are under investigation for the treatment of high-grade gliomas and brain metastases. This article reviews the unique challenges encountered when evaluating changes on magnetic resonance imaging (MRI) of glioblastomas seen in response to immunotherapy and checkpoint inhibitors and how to effectively incorporate MRI findings into the response assessment of high-grade gliomas to these emerging therapies. An increase in tumor size or the appearance of new lesions on MRI may represent either an immune-mediated inflammatory response or true tumor progression, which may precede the subsequent stabilization or response of high-grade gliomas to immunotherapy. These MRI findings should not result in the mandatory cessation of immunotherapy in patients with high-grade glioma. Although immunotherapy Response Assessment for Neuro-Oncology criteria have been developed to assist with response assessment of high-grade gliomas to immunotherapy and to provide guidance with treatment decisions, these criteria have not been validated in prospective clinical trials. In patients with brain tumors who are receiving immunotherapy, MRI findings suggestive of disease progression should be evaluated with caution to prevent premature discontinuation of potentially beneficial therapies. Close, clinical monitoring with appropriate short-term, follow-up imaging is often necessary, and histopathological analysis may be required in some cases to confirm disease progression before a decision on continuation of these novel therapies can accurately be made.