Brown, Paul D.

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 Tumor Treating Fields (TTFields) are non-invasive, loco-regional, anti-mitotic treatment modality comprising alternating electric fields. TTFields have demonstrated efficacy in preclinical non-small cell lung cancer (NSCLC) models. TTFields treatment to the brain was safe and extended overall survival in newly-diagnosed glioblastoma. The objective of the METIS study [NCT02831959] is evaluation of the efficacy and safety of TTFields in NSCLC patients with brain metastases. METHODS NSCLC patients (N=270) with 1–10 brain metastases were randomized 1:1 to stereotactic radio surgery (SRS) followed by continuous TTFields ((150 kHz, > 18 hours/day) within 7 days of SRS or supportive care. The portable device delivered TTFields to the brain using 4 transducer arrays, while patients received the best standard-of-care for systemic disease. Patients were followed every two months until second intracranial progression. Key inclusion criteria: KPS ≥70, new diagnosis of 1 inoperable or 2–10 supra- and/or infratentorial brain metastases from NSCLC amenable to SRS; and optimal therapy for extracranial disease. Prior WBRT, surgical resection of metastases, or recurrent brain metastases were exclusionary. Primary endpoint was time to 1st intracranial progression. Secondary endpoints included time to neurocognitive failure (HVLT, COWAT and TMT), overall survival, radiological response rate (RANO-BM and RECIST V1.1); quality-of-life; adverse events; time to first/second intracranial progression for patients with 1–4 and 5–10 brain metastases; bi-monthly intracranial progression rate from 2–12 months; and time to second intracranial and distant progression. The sample size (N=270) was calculated using a log-rank test (Lakatos 1988 and 2002) with 80% power at two sided alpha of 0.05 to detect a hazard ratio of 0.57. On September, 2019, an independent Data Monitoring Committee (DMC) reviewed METIS trial data collected to that point. The DMC concluded that no unexpected safety issues had emerged and recommended continuation of the METIS study as planned.

Abstract Background We investigated differences in radiation-induced grade 3+ lymphopenia (G3+L), defined as an absolute lymphocyte count (ALC) nadir of <500 cells/µL, after proton therapy (PT) or X-ray (photon) therapy (XRT) for patients with glioblastoma (GBM). Methods Patients enrolled in a randomized phase II trial received PT (n = 28) or XRT (n = 56) concomitantly with temozolomide. ALC was measured before, weekly during, and within 1 month after radiotherapy. Whole-brain mean dose (WBMD) and brain dose-volume indices were extracted from planned dose distributions. Univariate and multivariate logistic regression analyses were used to identify independent predictive variables. The resulting model was evaluated using receiver operating characteristic (ROC) curve analysis. Results Rates of G3+L were lower in men (7/47 [15%]) versus women (19/37 [51%]) (P < 0.001), and for PT (4/28 [14%]) versus XRT (22/56 [39%]) (P = 0.024). G3+L was significantly associated with baseline ALC, WBMD, and brain volumes receiving 5‒40 Gy(relative biological effectiveness [RBE]) or higher (ie, V5 through V40). Stepwise multivariate logistic regression analysis identified being female (odds ratio [OR] 6.2, 95% confidence interval [CI]: 1.95‒22.4, P = 0.003), baseline ALC (OR 0.18, 95% CI: 0.05‒0.51, P = 0.003), and whole-brain V20 (OR 1.07, 95% CI: 1.03‒1.13, P = 0.002) as the strongest predictors. ROC analysis yielded an area under the curve of 0.86 (95% CI: 0.79–0.94) for the final G3+L prediction model. Conclusions Sex, baseline ALC, and whole-brain V20 were the strongest predictors of G3+L for patients with GBM treated with radiation and temozolomide. PT reduced brain volumes receiving low and intermediate doses and, consequently, reduced G3+L.

PURPOSENRG Oncology/RTOG 9802 (ClinicalTrials.gov Identifier: NCT00003375 ) is a practice-changing study for patients with WHO low-grade glioma (LGG, grade II), as it was the first to demonstrate a survival benefit of adjuvant chemoradiotherapy over radiotherapy. This post hoc study sought to determine the prognostic and predictive impact of the WHO-defined molecular subgroups and corresponding molecular alterations within NRG Oncology/RTOG 9802.METHODSIDH1/2 mutations were determined by immunohistochemistry and/or deep sequencing. A custom Ion AmpliSeq panel was used for mutation analysis. 1p/19q codeletion and MGMT promoter methylation were determined by copy-number arrays and/or Illumina 450K array, respectively. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Hazard ratios (HRs) were calculated using the Cox proportional hazard model and tested using the log-rank test. Multivariable analyses (MVAs) were performed incorporating treatment and common prognostic factors as covariates.RESULTSOf the eligible patients successfully profiled for the WHO-defined molecular groups (n = 106/251), 26 (24%) were IDH-wild type, 43 (41%) were IDH-mutant/non-codeleted, and 37(35%) were IDH-mutant/codeleted. MVAs demonstrated that WHO subgroup was a significant predictor of PFS after adjustment for clinical variables and treatment. Notably, treatment with postradiation chemotherapy (PCV; procarbazine, lomustine (CCNU), and vincristine) was associated with longer PFS (HR, 0.32; P = .003; HR, 0.13; P < .001) and OS (HR, 0.38; P = .013; HR, 0.21; P = .029) in the IDH-mutant/non-codeleted and IDH-mutant/codeleted subgroups, respectively. In contrast, no significant difference in either PFS or OS was observed with the addition of PCV in the IDH-wild-type subgroup.CONCLUSIONThis study is the first to report the predictive value of the WHO-defined diagnostic classification in a set of uniformly treated patients with LGG in a clinical trial. Importantly, this post hoc analysis supports the notion that patients with IDH-mutant high-risk LGG regardless of codeletion status receive benefit from the addition of PCV.

Abstract Background We report the analysis involving patients treated on the initial CODEL design. Methods Adults (&gt;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.

12007 Background: Up to 96% of patients with high grade glioma (HGG) report moderate to severe fatigue. Armodafinil, the R-enantiomer of modafinil, is a psychostimulant with low potential for abuse that has shown potential for improving severe fatigue in HGG patients. Methods: In this phase III double blinded placebo-controlled study, adults with HGG and moderate to severe fatigue, > 4 weeks after completing radiotherapy, were randomized to receive armodafinil daily (150 mg or 250 mg) or placebo for a total of 8 weeks. The primary outcome was efficacy in treating severe fatigue. Secondary outcomes included evaluation of tolerability, neurocognitive function, and quality of life. Patients were evaluated at baseline, 4 and 8 weeks. Results: A total of 328 patients were enrolled between 6/3/13-3/1/19. There were 103 (150 mg arm), 97 (250 mg arm) and 97 (placebo arm) evaluable patients with primary endpoint data available. The median age was 60 years (20-85) with a median Brief Fatigue Inventory (BFI) worst fatigue score of 8 (6-10). 60.3% were male, 80.5% received concomitant chemotherapy, and 39.7% were on corticosteroids. The global fatigue score at end of weeks 4 and 8 were lower than at baseline (p<0.0001) and in the 250 mg arm than placebo (p=0.0356) and was higher for corticosteroid users than non-users (p=0.0002). There was no statistically significant difference for clinically meaningful improvement in BFI usual fatigue score from baseline to end of week 8 between the three arms (p=0.9601). Patients reported an improvement in concentration at week 4 from baseline on the 150 mg arm(P=0.0311). There was no statistically significant difference on neurocognitive tests from baseline to end of week 4 (p>0.05) or week 8 (p>0.05) between arms. More patients reported insomnia on the 250 mg arm (p=0.0083). Conclusions: There is no meaningful benefit of the use of armodafinil to reduce moderate to severe fatigue in patients with HGG. In certain cases there may be benefit of armodafinil 150 mg to aid concentration without the risk of insomnia.Support: UG1CA189823;U10CA180868 (NRG). Clinical trial information: NCT01781468 .

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 .