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Abstract PURPOSE We investigated the long term impact of SRS and WBRT in two large prospective phase III trials. METHODS Patients with 1–4 BMs +/- resection were randomized to SRS or WBRT. Cognitive deterioration was a drop of >1 standard deviation from baseline in >2/6 cognitive measures (CM). Quality of life (QOL) scores were scored 0–100 point scale. CM and QOL scores were modeled using baseline adjusted Linear Mixed Models (LMM) with uncorrelated random intercept for subject and random slopes for time. Differences in trend over time between groups and the effect of >2 cognitive scores with >2 SD change from baseline were assessed. RESULTS 88 patients were included with median follow up of 24 months. We observed decreasing CM over time (SRS: 4/6; WBRT: 5/6). Mean CM was significantly higher in SRS for Total recall and Delayed Recall at 3, 6, 9, 12 months. More patients in WBRT arm declined 1 SD in >1 and >2 CM at the 3, 6, 9, and 12 months. A 1 SD decline in >3 CM at 1 year was 21% SRS vs 47% WBRT (p=0.02). SRS had fewer patients with a 2 SD decline in >1 CM at every time point. SRS had fewer patients with a 2 SD decline at >2 and >3 CM. WBRT had lower QOL at 3 months, but switched to SRS having lower QOL at 24 months for PWB, EWB, FWB, FactG, BR, and FactBR (p<0.05). A 2 SD decline in cognition decreased mean FWB by 6.4 units (95% CI: -11, -1.75; p=0.007) and decreased QOL by 5.1 units (95% CI: -7.7, -2.5; p<0.001). CONCLUSIONS We report the first pooled prospective study demonstrating the long term outcomes of patients with BMs after cranial radiation. WBRT was associated with worse cognitive outcomes. Impaired cognition is associated with worse QOL.

Abstract Background We report the analysis involving patients treated on the initial CODEL design. Methods Adults (>18) with newly diagnosed 1p/19q World Health Organization (WHO) grade III oligodendroglioma were randomized to radiotherapy (RT; 5940 centigray ) alone (arm A); RT with concomitant and adjuvant temozolomide (TMZ) (arm B); or TMZ alone (arm C). Primary endpoint was overall survival (OS), arm A versus B. Secondary comparisons were performed for OS and progression-free survival (PFS), comparing pooled RT arms versus TMZ-alone arm. Results Thirty-six patients were randomized equally. At median follow-up of 7.5 years, 83.3% (10/12) TMZ-alone patients progressed, versus 37.5% (9/24) on the RT arms. PFS was significantly shorter in TMZ-alone patients compared with RT patients (hazard ratio [HR] = 3.12; 95% CI: 1.26, 7.69; P = 0.014). Death from disease progression occurred in 3/12 (25%) of TMZ-alone patients and 4/24 (16.7%) on the RT arms. OS did not statistically differ between arms (comparison underpowered). After adjustment for isocitrate dehydrogenase (IDH) status (mutated/wildtype) in a Cox regression model utilizing IDH and RT treatment status as covariables (arm C vs pooled arms A + B), PFS remained shorter for patients not receiving RT (HR = 3.33; 95% CI: 1.31, 8.45; P = 0.011), but not OS ((HR = 2.78; 95% CI: 0.58, 13.22, P = 0.20). Grade 3+ adverse events occurred in 25%, 42%, and 33% of patients (arms A, B, and C). There were no differences between arms in neurocognitive decline comparing baseline to 3 months. Conclusions TMZ-alone patients experienced significantly shorter PFS than patients treated on the RT arms. The ongoing CODEL trial has been redesigned to compare RT + PCV versus RT + TMZ.

Abstract Glioblastoma is a devastating disease with poor prognosis. Few effective chemotherapeutics are currently available, and much effort has been expended to identify new drugs capable of slowing tumor progression. The phase 0 trial design was developed to facilitate early identification of promising agents for cancer that should undergo accelerated approval. This design features an early in-human study that enrolls a small number of patients who receive subtherapeutic doses of medication with the goals of describing pharmacokinetics through drug blood level measurements and determining intratumoral concentrations of the investigational compound as well as pharmacodynamics by studying the biochemical and physiological effects of drugs. In neuro-oncology, however, the presence of the blood–brain barrier and difficulty in obtaining brain tumor tissue warrant a separate set of considerations. In this paper, we critically reviewed the protocols used in all brain tumor related in-human phase 0 and phase 0–like (“window of opportunity”) studies between 1993 and 2018, as well as ongoing clinical trials, and identified major challenges in trial design as applied to central nervous system tumors that include surgical specimen collection and storage, brain tumor drug level analysis, and confirmation of drug action. We therefore propose that phase 0 trials in neuro-oncology should include (i) only patients in whom a resection of the tumor is planned, (ii) use of clinical doses of an investigational agent, (iii) tissue sampling from enhancing and non-enhancing portions of the tumor, and (iv) assessment of drug-specific target effects. Standardization of clinical protocols for phase 0/window of opportunity studies can help accelerate the development of effective treatments for glioblastoma.

Abstract Despite the widespread clinical use of dynamic susceptibility contrast (DSC) MRI, DSC-MRI methodology has not been standardized, hindering its utilization for response assessment in multicenter trials. Recently, the DSC-MRI Standardization Subcommittee of the Jumpstarting Brain Tumor Drug Development Coalition issued an updated consensus DSC-MRI protocol compatible with the standardized brain tumor imaging protocol (BTIP) for high-grade gliomas that is increasingly used in the clinical setting and is the default MRI protocol for the National Clinical Trials Network. After reviewing the basis for controversy over DSC-MRI protocols, this paper provides evidence-based best practices for clinical DSC-MRI as determined by the Committee, including pulse sequence (gradient echo vs spin echo), BTIP-compliant contrast agent dosing (preload and bolus), flip angle (FA), echo time (TE), and post-processing leakage correction. In summary, full-dose preload, full-dose bolus dosing using intermediate (60°) FA and field strength-dependent TE (40–50 ms at 1.5 T, 20–35 ms at 3 T) provides overall best accuracy and precision for cerebral blood volume estimates. When single-dose contrast agent usage is desired, no-preload, full-dose bolus dosing using low FA (30°) and field strength-dependent TE provides excellent performance, with reduced contrast agent usage and elimination of potential systematic errors introduced by variations in preload dose and incubation time.

TPS2573 Background: Brain metastases, most commonly derived from melanoma, lung and breast cancers, are the most common brain tumor, with approximately 200,000 cases diagnosed annually in the United States. Median survival is on the order of months. For patients with clinically symptomatic brain metastases, approximately half succumb due to intracranial progression. In preclinical work, we demonstrated that brain metastases and primary tumors are often genetically distinct with frequent alterations in the CDK and PI3K pathway (Brastianos, Carter et al. Cancer Discovery 2015). Methods: We are currently accruing to a prospective multi-arm phase II study of CDK, PI3K/mTOR, and NTRK/ROS1 inhibitors in patients with brain metastases harboring alterations associated with sensitivity to these inhibitors (abemaciclib, paxalisib and entrectinib), respectively. Patients with new, recurrent or progressive brain metastases are eligible for this trial. Previously obtained tissue from brain metastases and extracranial sites (primary or extracranial metastases) are screened for the presence of these alterations, and if present in both tumor sites, patients will receive the appropriate corresponding targeted treatment. Screening is carried out with the SNaPshot NGS assay, which is a fully validated clinical test designed and developed at the MGH Center for Integrated Diagnostics. The primary endpoint of response rate (RR) in the central nervous system as per RANO criteria will be evaluated separately for each inhibitor, stratified by histology within each arm. There will be 21 evaluable patients assigned to each of the CDK and PI3K inhibitor and tumor type cohorts (breast, lung and other) and 10 patients assigned to the NTRK/ROS1 inhibitor cohort (lung) for a total of 136 evaluable patients. Although current systemic therapy for brain metastases is often ineffective, we hypothesize that targeted therapies will demonstrate efficacy in patients harboring the appropriate mutations. This study represents a novel individualized therapeutic approach in brain metastases, a disease with a critical need for effective therapy. Support: U10CA180821, U10CA180882, https://acknowledgments.alliancefound.org ; Genentech, Kazia Therapeutics Limited, Eli Lilly; Clinical trial information: NCT03994796 .

2502 Background: Patients with progressive or recurrent meningiomas have limited treatment options. Clinical trials of systemic therapies for meningiomas have failed to demonstrate benefit. FAK inhibition has a synthetic lethal relationship with NF2 loss. Given the predominance of NF2 mutations in meningiomas, we evaluated the efficacy of GSK2256098, a FAK inhibitor, as part of the first genomically-driven phase II study in recurrent or progressive grade I-III meningiomas. Methods: Eligible patients (pts) whose tumors screened positively for NF2 mutations were treated with GSK2256098 750mg po bid until progressive disease in 2 separate cohorts: grade I or II/III meningiomas. Two co-primary endpoints were used: progression-free survival at 6 months (PFS6) and response rate (RR) by Macdonald criteria; per study design, the trial would be declared positive if either endpoint was met. RR was evaluated across the overall cohort; PFS6 was evaluated within each subgroup. Historical benchmark data was obtained from Kaley et al. Neuro Oncol 2014. In the grade I group, 12 evaluable pts provided >79% power to detect a PFS6 rate >65% (vs. null hypothesis of 25%; alpha=0.014). In the grade II/III group, 24 evaluable pts provided >85% power to detect a PFS6 >41.5% (vs. null 15%; alpha=0.02). The threshold for promising results for PFS6 was: 7+/12(grade I) and 8+/24(grade II/III) pts. For RR, 36 evaluable pts provided >94% power to detect RR >20% (vs. null 2.5%; alpha= 0.012). Results: Of 322 pts screened for all mutation cohorts of the study, 36 eligible and evaluable pts with NF2 mutations were enrolled. Across all grades, one pt had a partial response and 24 had stable disease as best response to treatment. In Grade I pts, the observed PFS6 rate was 83% (10/12 pts; 95% CI: 52-98%). In Grade II/III pts, the observed PFS6 rate was 33% (8/24 pts; 95% CI: 16-55%). The study met PFS6 efficacy endpoint both for the Grade I and the Grade II/III cohorts. Treatment was well tolerated. Only 7 patients had a maximum grade-3 adverse event that was at least possibly related to treatment; toxicities across these pts included: proteinuria (2), rash (1), pain (1), ALT (1), AST (1), cholecystitis (1), hypertriglyceridemia (1), apraxia (1), and lymphopenia (1) with no grade 4 or 5 events. Conclusions: GSK2256098 had excellent tolerability andresulted in an improved PFS6 rate in pts with recurrent or progressive NF2-mutated meningiomas. Trial endpoint was met. FAK inhibition warrants further evaluation in this patient population. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org Clinical trial information: NCT02523014 .

Abstract Glioblastomas are the most common form of malignant primary brain tumor and an important cause of morbidity and mortality. In recent years there have been important advances in understanding the molecular pathogenesis and biology of these tumors, but this has not translated into significantly improved outcomes for patients. In this consensus review from the Society for Neuro-Oncology (SNO) and the European Association of Neuro-Oncology (EANO), the current management of isocitrate dehydrogenase wildtype (IDHwt) glioblastomas will be discussed. In addition, novel therapies such as targeted molecular therapies, agents targeting DNA damage response and metabolism, immunotherapies, and viral therapies will be reviewed, as well as the current challenges and future directions for research.

e13516 Background: Breast cancer affects thousands of women each year. Epithelial to Mesenchymal transition (EMT) has been associated with increased metastatic potential of cancer cells as well as resistance to chemotherapy. Predicatively, presence of EMT leads to worse prognosis. We have recently showed that Aurora-A plays a key role in development of EMT and increased ability of breast cancer cells for self renewal. Therefore we hypothesized that inhibition of Aurora-A will lead to increased sensitivity to chemotherapy. Methods: The hypothesis was tested in vitro. Cellular proliferation was tested using MTT assay and protein levels were determined on Western blots. Results: In ER+ cell line, MCF7, constitutive activation of Raf-1/MAPK signaling pathway leads to aberrant activation of Aurora-A kinase activity. These cells have decreased sensitivity to treatment with paclitaxel when compared to parental MCF7 cells. This effect is even more pronounced with over-expression of Aurora-A. The sensitivity to paclitaxel was restored with inhibition of Aurora-A by novel inhibitor, Alisertib. This was further explored in triple negative cells (MDA-MB-231) and cells expressing Her-2/neu (BT474) which express higher levels of Aurora-A. Combination of Alisertib and paclitaxel was superior when compared to either therapy alone. Similar effect was seen with use of anthracyclines. Inhibition of Aurora-A resulted in decreased SMAD5 expression as well as decreased Akt phosphorylation. Current studies are investigating a role of Aurora-A in developing chemoresistance through activating SMAD5. In vivo experiments evaluating combination therapies in breast cancer animal model are ongoing. Conclusions: Inhibition of Aurora-A by Alisertib resulted in decreased SMAD5 nuclear phosphorylation and increased effectiveness of chemotherapeutic agents in breast cancer cells. These results contribute to better understanding of signaling pathways involved in resistance of breast cancer cells to chemotherapy. This knowledge could be extremely useful in developing more effective treatments for breast cancer patients both in neo-adjuvant, adjuvant and metastatic settings.

2031 Background: The mammalian target of rapamycin (mTOR) functions within the PI3K/Akt pathway as a critical modulator of cell survival. Preclinical studies in GBM indicate that the combination of mTOR inhibitors, such as everolimus (RAD001), with either radiation therapy (RT) or temozolomide (TMZ) provide increased tumor cell killing. Methods: Newly diagnosed GBM pts were eligible for the study. RAD001 was dosed orally at 70 mg/week weekly, starting 1 week prior to RT/TMZ, and continued throughout RT/TMZ, adjuvant TMZ and then until progression. This was a single arm phase II design powered to detect a true overall survival at 12 months (OS12) of 73% (vs 58% in historical controls). Secondary endpoints were toxicity, response rate, and time to progression (TTP). A subgroup of patients with measurable residual disease were eligible for the PET imaging component of the study, consisting of an 18FLT-PET/CT scan performed before and after the initial two doses of RAD001 but before the first dose of RT or TMZ. Results: 103 patients were accrued to phase II of which 100 were evaluable. The median age was 60.5 years (23-81), median ECOG PS was 1, 46 patients had GTR, 33 STR, and the remainder had biopsy at diagnosis. Treatment tolerance was acceptable: 17% patient had at least one grade 3 hematologic toxicity; 14% had at least one grade 4 hematologic toxicity, 42% had at least one grade 3 non-heme toxicity, while 12% had at least one grade 4 non-heme toxicity. No increased incidence of infectious complications was observed and there were no treatment related deaths. Median PFS was 5.3 months (1.3-21.4), with 22 patients progression free. Mature OS data will be available at the meeting. MGMT methylation status analysis is ongoing. Of the pts who had evaluable FLT-PET data, three of eight (37.5%) had a drop in SUVmax >25% after two treatments of RAD001. Conclusions: RAD001 with standard of care chemoradiation had moderate toxicity. Serial 18FLT-PET was feasible for evaluating drug-induced changes in tumor proliferation following RAD001. Final outcome data and association of MGMT status with outcome will be reported at the meeting.