Citations

TPS468 Background: Trastuzumab (T), a monoclonal antibody (mAb) targeting HER2, is standard of care palliative 1st-line therapy for advanced HER2+ GEJ/GC patients (pts). M, an Fc-engineered anti-HER2 mAb, targets the same HER2 epitope but with higher affinity for both 158V (high binding) and 158F (low binding) alleles of activating Fc receptor CD16A. M coordinately enhanced both innate and adaptive immunity, including antigen-specific T-cell responses to HER2. PD-1 and LAG-3 are T-cell checkpoint molecules that suppress T-cell function. MGA012 (INCMGA00012) is a humanized, hinge-stabilized, IgG4 κ anti-PD-1 mAb blocking binding of PD-L1 or PD-L2 to PD-1. MGD013 is a humanized Fc-bearing bispecific tetravalent protein that binds to both PD-1 and LAG-3, inhibiting their respective ligand binding. We previously reported that a CTX-free regimen of M+PD-1 blockade was well tolerated in GEJ/GC pts, and induced a 30% objective response rate (ORR). This was 2- to 3-fold greater than in historical controls with checkpoint inhibitors alone. This registration-directed trial assesses efficacy, safety, and tolerability of M+checkpoint inhibition ± CTX in metastatic/locally advanced, treatment-naïve, HER2+ GEJ/GC pts. Methods: This is a 2-cohort, adaptive open-label phase 2/3 study. The first single arm, CTX-free cohort A evaluates M+MGA012 in HER2+ (immunohistochemistry [IHC] 3+) and PD-L1+ (excluding microsatellite instability high) pts. After 40 pts are evaluated for response/safety, 60 more pts will be enrolled if the threshold for continuation is met. In randomized cohort B, HER2+ (IHC 3+ or 2+/fluorescent in situ hybridization+) pts are enrolled irrespective of PD-L1 status. Part 1 randomizes pts to 1 of 4 arms (50 pts each): control arm (T+CTX) or 1 experimental arm (M+CTX; M+CTX+MGA012; M+CTX+MGD013). CTX is investigator’s choice XELOX or mFOLFOX-6. Part 2 consists of control (T+CTX) vs 1 experimental arm (M+CTX) + either MGA012 or MGD013, depending on results from part 1; with 250 pts each. The primary efficacy endpoint for cohort A (both parts) is ORR per RECIST 1.1; for cohort B part 2 it is overall survival.

AbstractBackgroundThe AdaptivCRT (aCRT) algorithm continuously adjusts cardiac resynchronization therapy (CRT) according to intrinsic atrioventricular conduction, providing synchronized left ventricular pacing in patients with normal PR interval and adaptive BiV pacing in patients with prolonged PR interval. Previous analyses demonstrated an association between aCRT and clinical benefit. We evaluated the incidence of patient mortality and atrial fibrillation (AF) with aCRT compared with standard CRT in a real‐world population.Methods and ResultsPatients enrolled in the Medtronic Personalized CRT Registry and implanted with a CRT from 2013‐2018 were divided into aCRT ON or standard CRT groups based upon device‐stored data. A Frailty survival model was used to evaluate the potential survival benefit of aCRT, accounting for patient heterogeneity and center variability. Daily AF burden and first device‐detected AF episodes of various durations were recorded by the device during follow‐up.A total of 1814 CRT patients with no reported long‐standing AF history at implant were included. Mean follow‐up time was 26.1 ± 16.5 months and 1162 patients (64.1%) had aCRT ON. Patient survival probability at 36 months was 88.3% for aCRT ON and 83.7% for standard CRT (covariate‐adjusted hazard ratio [HR] = 0.71, 95% CI: 0.53‐0.96, P = .028). Mean AF burden during follow‐up was consistently lower in aCRT ON patients compared with standard CRT. At 36 months, the probability of AF was lower in patients with aCRT ON, regardless of which AF definition threshold was applied (6 minutes‐30 days, all P < .001).ConclusionUse of the AdaptivCRT algorithm was associated with improved patient survival and lower incidence of AF in a real‐world, prospective, nonrandomized registry.

Background. Despite extensive evaluation processes to determine candidacy for kidney transplantation, variability in graft failure exists. The role of patient socioeconomic status (SES) in transplantation outcomes is poorly understood because of limitations of conventional SES measures. Methods. This population-based retrospective cohort study assessed whether a validated objective and individual-level housing-based SES index (HOUSES) would serve as a predictive tool for graft failure in patients (n = 181) who received a kidney transplant in Olmsted County, MN (January 1, 1998 to December 8, 2016). Associations were assessed between HOUSES (quartiles: Q1 [lowest] to Q4 [highest]) and graft failure until last follow-up date (December 31, 2016) using Cox proportional hazards. The mean age (SD) was 46.1 (17.2) years, 109 (60.2%) were male, 113 (62.4%) received a living kidney donor transplant, and 40 (22.1%) had a graft failure event. Results. Compared with Q1, patients with higher HOUSES (Q2–Q4) had significantly lower graft failure rates (adjusted hazard ratio, 0.47; 95% confidence interval, 0.24-0.92; P < 0.029), controlling for age, sex, race, previous kidney transplantation, and donor type. Conclusions. Although criteria for kidney transplant recipients are selective, patients with higher HOUSES had lower graft failure rates. Thus, HOUSES may enable transplantation programs to identify a target group for improving kidney transplantation outcomes.

Diffuse large B-cell lymphoma is a heterogeneous disease, commonly described by cell-of-origin (COO) molecular subtypes. We sought to identify novel patient subgroups through an unsupervised analysis of a large public dataset of gene expression profiles from newly diagnosed de novo DLBCL patients, yielding two biologically distinct subgroups characterized by differences in the tumor microenvironment. Pathway analysis and immune deconvolution algorithms identified higher B-cell content and a strong proliferative signal in subgroup A and enriched T-cell, macrophage, and immune/inflammatory signals in subgroup B, reflecting similar biology to published DLBCL stratification research. A gene expression classifier, featuring 26 gene expression scores, was derived from the public dataset to discriminate subgroup A (classifier-negative, immune-low) and subgroup B (classifier-positive, immune-high) patients. Subsequent application to an independent series of diagnostic biopsies and replicated the subgroups with immune cell composition confirmed via immunohistochemistry. Avadomide, a CRL4CRBN E3 ubiquitin ligase modulator, demonstrated clinical activity in relapsed/refractory DLBCL patients, independent of COO subtypes. Given the immunomodulatory activity of avadomide and need for a patient selection strategy, we applied the gene expression classifier to pretreatment biopsies from relapsed/refractory DLBCL patients receiving avadomide (NCT01421524). Classifier-positive patients demonstrated an enrichment in response rate and progression-free survival of 44% and 6.2 months versus 19% and 1.6 months for classifier-negative patients (HR=0.49 [0.280, 0.86]; P=.0096). The classifier was not prognostic for R-CHOP or salvage immunochemotherapy. The classifier described here discriminates DLBCL tumors based on tumor and non-tumor composition and has potential utility to enrich for clinical response to immunomodulatory agents including avadomide.

Abstract Background Although 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies in individuals of European ancestry, much of its heritability remains unexplained and the genes responsible largely unknown. Methods To discover novel pancreatic cancer risk loci and possible causal genes, we performed a pancreatic cancer transcriptome-wide association study in Europeans using three approaches: FUSION, MetaXcan, and Summary-MulTiXcan. We integrated genome-wide association studies summary statistics from 9040 pancreatic cancer cases and 12 496 controls, with gene expression prediction models built using transcriptome data from histologically normal pancreatic tissue samples (NCI Laboratory of Translational Genomics [n = 95] and Genotype-Tissue Expression v7 [n = 174] datasets) and data from 48 different tissues (Genotype-Tissue Expression v7, n = 74–421 samples). Results We identified 25 genes whose genetically predicted expression was statistically significantly associated with pancreatic cancer risk (false discovery rate &lt; .05), including 14 candidate genes at 11 novel loci (1p36.12: CELA3B; 9q31.1: SMC2, SMC2-AS1; 10q23.31: RP11-80H5.9; 12q13.13: SMUG1; 14q32.33: BTBD6; 15q23: HEXA; 15q26.1: RCCD1; 17q12: PNMT, CDK12, PGAP3; 17q22: SUPT4H1; 18q11.22: RP11-888D10.3; and 19p13.11: PGPEP1) and 11 at six known risk loci (5p15.33: TERT, CLPTM1L, ZDHHC11B; 7p14.1: INHBA; 9q34.2: ABO; 13q12.2: PDX1; 13q22.1: KLF5; and 16q23.1: WDR59, CFDP1, BCAR1, TMEM170A). The association for 12 of these genes (CELA3B, SMC2, and PNMT at novel risk loci and TERT, CLPTM1L, INHBA, ABO, PDX1, KLF5, WDR59, CFDP1, and BCAR1 at known loci) remained statistically significant after Bonferroni correction. Conclusions By integrating gene expression and genotype data, we identified novel pancreatic cancer risk loci and candidate functional genes that warrant further investigation.

Abstract Background We assessed glioma incidence and disparities in postglioma survival rate in the Olmsted County, Minnesota, population. Methods This population-based study assessed the incidence of pathologically confirmed primary gliomas between January 1, 1995, and December 31, 2014. Age- and sex-adjusted incidence rates per 100 000 person-years were calculated and standardized to the US white 2010 population. We compared incidence trends of glioma during our study period with previously published Olmsted County data from 1950 to 1990. We assessed postglioma survival rates among individuals with different socioeconomic status (SES), which was measured by a validated individual HOUsing-based SES index (HOUSES). Results We identified 135 incident glioma cases (93% white) with 20 pediatric (50% female) and 115 adult cases (44% female). Overall incidence rate during our study period, 5.51 per 100 000 person-years (95% CI: 4.56-6.46), showed no significant changes and was similar to that seen in 1950 to 1990, 5.5 per 100 000 person-years. The incidence of pediatric (age &lt; 20 years) glioma was 2.49 (95% CI: 1.40-3.58), whereas adult glioma incidence was 6.47 (95% CI: 5.26-7.67). Among those with grade II to IV gliomas, individuals with lower SES (&lt; median HOUSES) had significantly lower 5-year survival rates compared to those with higher SES, adjusted hazard ratio 1.61 (95% CI: 1.01-2.85). Conclusion In a well-defined North American population, long-term glioma incidence appears stable since 1950. Significant socioeconomic disparities exist for postglioma survival.

AbstractThe active involvement of citizen scientists in setting research agendas, partnering with academic investigators to conduct research, analyzing and disseminating results, and implementing learnings from research can improve both processes and outcomes. Adopting a citizen science approach to the practice of precision medicine in clinical care and research will require healthcare providers, researchers, and institutions to address a number of technical, organizational, and citizen scientist collaboration issues. Some changes can be made with relative ease, while others will necessitate cultural shifts, redistribution of power, recommitment to shared goals, and improved communication. This perspective, based on a workshop held at the 2018 AMIA Annual Symposium, identifies current barriers and needed changes to facilitate broad adoption of a citizen science-based approach in healthcare.

Smokers are at increased risk for surgical complications. Despite the known benefits of smoking cessation, many perioperative health care providers do not routinely provide smoking cessation interventions. The variation in delivery of perioperative smoking cessation interventions may be due to limited high-level evidence for whether smoking cessation interventions used in the general population are effective and feasible in the surgical population, as well as the challenges and barriers to implementation of interventions. Yet smoking is a potentially modifiable risk factor for improving short- and long-term patient outcomes. The purpose of the Society for Perioperative Assessment and Quality Improvement (SPAQI) Consensus Statement on Perioperative Smoking Cessation is to present recommendations based on current scientific evidence in surgical patients. These statements address questions regarding the timing and intensity of interventions, roles of perioperative health care providers, and behavioral and pharmacological interventions. Barriers and strategies to overcome challenges surrounding implementation of interventions and future areas of research are identified. These statements are based on the current state of knowledge and its interpretation by a multidisciplinary group of experts at the time of publication.

Catheter ablation has brought major advances in the management of patients with atrial fibrillation (AF). As evidenced by multiple randomized trials, AF catheter ablation can reduce the risk of recurrent AF and improve quality of life. In some studies, AF ablation significantly reduced cardiovascular hospitalizations. Despite the existing data on AF catheter ablation, numerous knowledge gaps remain concerning this intervention. This report is based on a recent virtual workshop convened by the National Heart, Lung, and Blood Institute to identify key research opportunities in AF ablation. We outline knowledge gaps related to emerging technologies, the relationship between cardiac structure and function and the success of AF ablation in patient subgroups in whom clinical benefit from ablation varies, and potential platforms to advance clinical research in this area. This report also considers the potential value and challenges of a sham ablation randomized trial. Prioritized research opportunities are identified and highlighted to empower relevant stakeholders to collaborate in designing and conducting effective, cost-efficient, and transformative research to optimize the use and outcomes of AF ablation.

Abstract Background: There is a significant variation in disease incidence and outcomes among Multiple Myeloma (MM) patients (pts) from different ethnic backgrounds. Currently, there is a paucity of data regarding the influence of demographics and ethnicity on behavioral patterns of pts, their attitudes, beliefs, and knowledge about MM and its treatment, which could in turn affect outcomes. We conducted a questionnaire-based study to examine behavioral patterns of MM pts, especially focusing on ethnic minorities and how this may impact patient awareness and symptom complex related to the disease and its treatment. Methods: Apaper-basedquestionnaire consisting of 61 questions encompassing four broad categories was provided to participating pts at the University of Southern California Medical Centers. These included demographics, disease/treatment related quality of life (QoL), satisfaction regarding treatment, and satisfaction regarding treating physician/healthcare staff. Information on clinical characteristics and MM-related treatment was collected through an IRB-approved protocol. Pts were stratified by age, gender, and ethnicity (Hispanics vs. Non-Hispanics). Any missing patient responses were withdrawn from the final analysis of that question. Categorical and continuous variables were compared among groups using Chi-square and Kruskal-Wallis tests, respectively. All statistical analysis utilized SAS software (v9.3) with a two-sided significance level of 0.05. Results: A total of 89 pts (males: 40, females: 49) from March 2012 to October 2013 responded to the questionnaire of the 100 pts that were consented (81%). Median age was 59 (range: 23-81) years and 43 (48%) pts were Hispanic while 46 (52%) were Non-Hispanic. Baseline clinical characteristics are shown in Table 1A. As compared to Non-Hispanics, Hispanic pts were less likely to have completed college (70% vs. 30%, p<0.001), attend myeloma support groups (90% vs. 10%, p=0.026), feel they had sufficient disease/treatment-related information (72% vs. 22.5%, p<0.001). Hispanic pts were more likely to report being unemployed/without any income (57.5% vs. 9%, p<0.001), have 3-4 people living in the house (57.5% vs. 26 %, p=0.009), feeling ill (43% vs. 21%, p=0.029), have concern about deterioration in clinical condition (66% vs. 41%, p=0.022), and inability to work due to symptoms from MM or its treatment (38.6% vs. 11.9%, p=0.005) when compared to Non-Hispanics. With respect to MM treatment, Hispanic pts were less likely to report that side effects were as expected (34% vs. 57%, p=0.036) and believe that treating staff worked towards the same goal (88% vs. 100%, p=0.020) as them. Hispanic pts also reported a lower level of satisfaction with their doctor /treatment staff, as compared to Non-Hispanic pts and this difference was statistically significant as shown in Table 1B. Using gender as the stratification factor, we noted that female pts were more likely to report lack of energy (p=0.037), pain (p=0.010), satisfaction with discussion on emotional health (p=0.012) as compared to males. With age as the stratification factor, patients < 60 years of age were less likely to report expected effectiveness from treatment (p=0.031), satisfaction regarding appropriateness of treatment (p=0.008) or explanation of test results by their doctor (p=0.036), and were more likely to worry about deterioration in their condition (p=0.014). We did not find a statistically significant association between age, gender, or ethnicity and response to initial myeloma treatment. Conclusions: We found a significant association between MM patient ethnicity and the pts responses to questions pertaining to their QoL, satisfaction with treatment and treating physician. This difference in disease/treatment related knowledge and attitudes may be related to socio-cultural and behavioral patterns and may contribute to factors such as treatment compliance, effectiveness and symptom complex burden amongst others, that can impact outcomes among ethnic subgroups of MM pts. Efforts to mitigate these differences should focus on improving methods of patient education, spread more awareness among ethnic minorities, integration of psychosocial care into cancer therapy and promoting health psychology research. Disclosures No relevant conflicts of interest to declare.