Citations

TPS8052 Background: The monoclonal antibody (MoAb) daratumumab (dara) has been approved for treatment of newly diagnosed Multiple Myeloma (NDMM) in combination with lenalidomide (len) and dexamethasone (DRd) in patients who are not eligible to undergo stem cell transplantation (SCT). Ongoing trials are examining the role of adding bortezomib (Btz) to DRd, but it remains unclear if all patients benefit from a quadruplet regimen. Availability of sensitive assays to detect measurable/minimal residual disease (MRD) in MM and emerging data demonstrating significant prognostic value for attaining MRD negativity, offers an unprecedented opportunity to develop individualized treatment approaches. An important question is to identify who benefits from adding a fourth drug to the MoAb-IMiD triplet, thus individualizing therapy based on depth of response. We hypothesize that prolonged intensive therapy with the addition of Btz for consolidation and maintenance after DRd induction therapy for NDMM will improve survival outcomes with a more pronounced effect when used in MRD positive patients. Methods: Patients with NDMM, R-ISS Stage I or II, who are not eligible to undergo SCT or those willing to defer SCT to first relapse and have not received more than 1 cycle of any NDMM therapy will be enrolled, provided they have measurable disease, adequate organ and marrow function, have received no more than once cycle of therapy for MM and significant peripheral neuropathy or chronic obstructive pulmonary disease. Importantly, a dominant clone should be identified by lymphotrack assay for future MRD monitoring. Once enrolled, induction therapy will be in 28 day cycles consisting of daraSC (1800 mg) weekly for 2 cycles, every other week for cycles 3-6 and then every 4 weeks for 9 cycles, along with len 25 mg days 1-21 of each cycle and dex 40 mg (20 mg for those > 75 years) weekly. At end of 9 cycles (induction), patients will undergo MRD testing by next generation sequencing and will be classified into MRD positive or negative subgroups. Using MRD as an integral biomarker, the trial employs a randomized biomarker-stratified design as proposed by Freidlin et al. to determine efficacy for each MRD subgroup. Patients will be stratified by MRD status and R-ISS stage and randomized to receive 9 cycles of consolidation with DRd, without (control arm) or with (experimental arm) Btz (1.3 mg/m2 weekly for 3 of 4 weeks), followed by DR maintenance until progression The primary endpoint is consolidation OS. Sample size considerations rest on estimates of MRD subgroup prevalence at the end of induction and operating characteristics establishing the treatment effect within the MRD positive subgroup as primary and MRD negative subgroup as key secondary. The total accrual goal is 1450 patients. Clinical trial information: NCT04566328.

8031 Background: New orally administered anticancer treatments have launched in recent years, promising gains in survival and quality of life, but with high prices.Financial difficulties encountered over the course of cancer diagnosis and treatment is a growing concern. These difficulties include inability to pay for basic necessities, presence of medical debt, and high out of pocket burdens relative to income. The primary objective of this study was to estimate the proportion of patients with multiple myeloma (MM) who experience financial difficulties in the past 12 months.Methods: Data collection entailed a comprehensive, theoretically grounded telephone survey and companion medical chart abstraction. Subjects included individuals with a current diagnosis of MM whose current or recent treatment included pharmaceutical-based care and who were not enrolled in a treatment-based trial. Practices eligible to recruit respondents included 44 NCORP affiliates of the Alliance. 14 geographically diverse NCORP affiliates participated between 11/2019 and 6/2020. The primary endpoint of the study was the proportion of subjects who reported financial difficulty in the past 12 months, as measured by the EORTC QLQ-C30 item #28. This proportion and 95% Wilson score confidence interval were estimated for all MM patients who responded to the financial difficulty question ((# reported financial difficulty)/(total # in that category who answered the question)). NCI Central IRB approved this study. Results: 393 subjects were recruited. 304 subjects completed the survey (77.4% response rate). Mean age was 67.5 years (SD 9.8), 143 (46.4%) were female, 24 (7.8%) self-reported race as ‘Black or African American’, 82 (26.6%) reported insured by government insurance Medicare only, 116 (38.2%) reported highest education as high school or below, and 94 (30.5%) reported high income. Mean time from diagnosis to survey enrollment was 3.6 years (SD 4.5). 292 (95.1%) were currently receiving treatment and 192 (62.5%) reported currently receiving a pre-defined ‘expensive’ oral pharmaceutical-based cancer treatment. 20.2% (95% CI:16.1%, 25.0%) reported financial difficulties. Conclusions: This is the first national study to systematically assess the prevalence of financial difficulties and its correlates among MM patients. Approximately 1 in 5 surveyed patients reported financial difficulties. Results of this study aim to inform efforts to improve financial navigation and resources for cancer patients.

TPS2659 Background: Leukocyte-Associated Immunoglobulin-like Receptor (LAIR)-1 and LAIR-2 are members of the Leukocyte Receptor Complex (LRC) (An & Brodsky, 2016). LAIR-1 is a co-inhibitory receptor expressed on several subsets of immune cells, and functions to delimit immune responses (Meyaard et al., 1997). LAIR-2 is a secreted protein with homology to the transmembrane protein LAIR-1 (Lebbink et al., 2008). In cancer, it is hypothesized that LAIR-1 expression on several subsets of leukocytes prevents optimal immune responses by limiting both innate and adaptive immune functionality. LAIR-1 serves to suppress anti-tumor immunity through the inhibition of stimulatory signaling pathways. Specifically, LAIR-1 is a checkpoint and adhesion receptor on T cells that limits T cell activation and increases adhesion to collagens (Meyaard, 2008). LAIR-2 is capable of blocking LAIR-1 functional interactions with ligands, resulting in improved immune function on multiple immune cell subsets. Dysregulation of LAIR-1 ligands in the tumor microenvironment results in excessive production of collagens and complement C1q as well as altered forms of collagens, that leads to immune inhibition through binding to LAIR-1+ immune cells. NC410 is a dimeric form of the LAIR-2 protein fused to a human Fc domain of the immunoglobulin (Ig) subtype IgG1. The rationale for developing NC410 as a cancer therapeutic is based on nonclinical data demonstrating LAIR-1 signaling blockade can improve the immune response. Because LAIR-2 binds to ligands shared with LAIR-1 with increased affinity, NC410 acts as a decoy receptor for LAIR-1 ligands releasing suppression from myeloid cells and T cells and promoting anti-tumor immunity. NC410 may also mediate remodeling of the tumor extracellular matrix, further contributing to anti-tumor activity. Methods: This is a multi-center, first in human, phase 1/2, open-label, single-armed study to determine the safety and tolerability, define maximum tolerated dose (MTD) and/or pharmacologically active dose, assess preliminary efficacy, and explore predictive and pharmacodynamic biomarkers of NC410 in subjects with advanced or metastatic solid tumors. Key eligibility criteria include measurable disease based on RECIST v1.1 and being able to consent for collection of biopsies at screening and on treatment. Phase 1 is a classic 3+3 dose escalation design to determine the safety, tolerability, DLT, MTD and recommended phase 2 dose (RP2D) (NCT04408599). Ongoing exploratory analyses include the assessment of predictive biomarkers associated with treatment benefit, and pharmacodynamic markers associated with study drug activity. Phase 2 is going to enroll ovarian, colorectal, NSCLC, H&N, and gastric carcinomas and other tumors depending on biomarker data available from the Phase 1 part of the study. Clinical trial information: 04408599.

TPS595 Background: Patients (pts) with HER2+ early breast cancer (EBC) and invasive residual disease (RD) after neoadjuvant therapy (NAT) have a higher risk of relapse than pts with a pathologic complete response (pCR). Post neoadjuvant T-DM1 has improved invasive disease-free survival (iDFS), but pts with estrogen receptor (ER)-negative or nodal RD have suboptimal outcomes and recurrences in the central nervous system are a problem. More effective treatment strategies are needed. The CompassHER2 trials, EA1181 and A011801, leverage pCR to tailor post neoadjuvant therapy in HER2+ EBC. EA1181 is a NAT de-escalation trial of a taxane, trastuzumab and pertuzumab (THP) in clinical stage II-III HER2+ EBC; pts with a pCR complete HP +/- adjuvant radiation (RT) +/- endocrine therapy (ET). A011801 is an escalation trial for pts with high risk HER2+ RD after NAT, examining addition of the HER2 selective tyrosine kinase inhibitor (TKI) tucatinib to adjuvant T-DM1. Methods: Eligibility and Intervention: Pts. with high-risk HER2+ RD (e.g. ER-,node-positive, or both) after a predefined course of neoadjuvant HER2-directed treatment are randomized 1:1 to adjuvant T-DM1+ placebo (pb), vs. T-DM1 and tucatinib with adjuvant RT +/- ET. Eligibility criteria include completion of ≥ 6 cycles of NAT, including ≥ 9 weeks of T and H +/- P. All chemotherapy (CT) must be completed preoperatively unless participating in EA1181 (̃15-30% enrollees); these pts must receive postoperative CT to complete ≥ 6 cycles prior to enrollment on A011801. Pts who received prior HER2-targeted TKIs or antibody-drug conjugates are ineligible. Objectives: The primary objective is to determine if iDFS is higher with addition of T-DM1 to tucatinib in pts with HER2+ EBC with RD after NAT; secondary endpoints include overall survival, breast cancer free survival, distant recurrence-free survival, brain metastases-free survival and disease-free survival. Correlative objectives include the association of i) tumor infiltrating lymphocyte (TILs) levels in the primary tumor and RD with iDFS, ii) TILs with tucatinib benefit, iii) iDFS and circulating tumor cells (CTC) at serial timepoints and iv) the magnitude of benefit of tucatinib (iDFS) in pts with/without detectable pretreatment CTCs. Quality of life and pharmacokinetic endpoints will also be evaluated. Statistics: A011801 is a prospective, double-blind, randomized, phase III superiority trial; stratified by i) receipt of postoperative CT (Y/N), ii) hormone receptor-status (+/-),and iii) pathologic lymph node status (+/-). The study targets an absolute difference of 5% in iDFS (control vs. experimental arm 82% & 87%, HR = 0.7), with a two-sided alpha of 0.05 and power of 80%. The sample size is 981; target accrual = 1031 pts; activation and completion dates are 01/6/21 and ̃ 01/2028. Support: U10CA180821, U10CA180882; Seagen Inc; ClinicalTrials.gov Identifier: NCT04457596 Clinical trial information: NCT04457596.

Introduction: Practice guidelines recommend use of subcutaneous implantable cardioverter-defibrillators (ICD) in patients (pts) at risk of sudden cardiac death and high risk for infection. This has prompted a need to better identify pts at high risk of infection to assist in de novo device selection. The objective of this study is to estimate infection incidence in de novo transvenous (TV) ICD implants and assess risk factors associated with infection in a large Medicare population. Methods: A retrospective cohort study was conducted using 100% Medicare administrative and claims data to identify pts who underwent de novo TV-ICD implantation between 7/2016 and 1/2018. Device-related infection within 2 years of implantation was identified using ICD-10 diagnosis and procedure codes. Baseline pt factors associated with infection were identified by univariable logistic regression analysis of all variables of interest, including factors in Charlson and Elixhauser comorbidity indices, followed by stepwise selection criteria with a p≤0.25 for inclusion in a multivariable model and a backwards, stepwise elimination process with p≤0.1 to remain in the model. A time-to-event analysis was also conducted. Results: Among 26,742 pts with de novo TV-ICD, 519 (1.9%) had a device-related infection over 2 years. The mean pt age with and without infection was 68 and 71 years, respectively. While more than half (54%) of infections occurred within 90 days post implant, infections continued to be diagnosed with 16% of infections occurring between years 1 and 2. Multivariable analysis revealed several significant predictors of infection (Figure) including age <70 years, end stage renal disease with chronic dialysis and diabetes with complications. Conclusion: The rate of de novo TV-ICD infection in a large real-world Medicare population is clinically significant. The factors associated with increased infection risk identified here can be used to help determine device selection.

Abstract Considerable efforts have been made to characterize active enhancer elements, which can be annotated by accessible chromatin and H3 lysine 27 acetylation (H3K27ac). However, apart from poised enhancers that are observed in early stages of development and putative silencers, the functional significance of cis-regulatory elements lacking H3K27ac is poorly understood. Here we show that macroH2A histone variants mark a subset of enhancers in normal and cancer cells, which we coined ‘macroH2A-Bound Enhancers’, that negatively modulate enhancer activity. We find macroH2A variants enriched at enhancer elements that are devoid of H3K27ac in a cell type-specific manner, indicating a role for macroH2A at inactive enhancers to maintain cell identity. In following, reactivation of macro-bound enhancers is associated with oncogenic programs in breast cancer and its repressive role is correlated with the activity of macroH2A2 as a negative regulator of BRD4 chromatin occupancy. Finally, through single cell epigenomic profiling, we show that the loss of macroH2A2 leads to increased cellular heterogeneity that may help to explain the role of macroH2A variants in defining oncogenic transcriptional dependencies.

Abstract Context Previous studies have demonstrated the effectiveness of osteopathic manipulative treatment (OMT) for various headache types, with limited evidence of its use for headaches related to mild traumatic brain injury (MTBI). No studies prior studies were found regarding OMT for headaches in patients with postconcussion syndrome (PCS), defined as symptom persistence for longer than 3 months after MTBI. Objectives To evaluate OMT for headaches in patients with PCS. Methods A controlled pilot study was conducted of patients with PCS who presented to an outpatient interdisciplinary rehabilitation clinic; patients with symptoms lasting longer than 3 months were enrolled and randomly assigned to an OMT treatment group or a control group. Primary outcome measures were immediate change in headache scores according to a Visual Analog Scale (VAS) and change in the six item Headache Impact Test (HIT-6) between baseline and follow up visits. The participants in the control group completed the HIT-6 between baseline and follow up visits but did not receive OMT and did not complete the VAS. Mean immediate VAS score change for the treatment group and mean improvement in HIT-6 scores for both groups between baseline and follow up were analyzed for statistical significance. Results A total of 26 patients were included in this study: 13 (50%) in the treatment group and 13 (50%) in the control group. Six patients (23.1%), three from each group, did not complete the study, so 10 subjects in each group were included in the final analysis. Statistically significant improvement in VAS scores was seen immediately after OMT in the treatment group (mean change, 2.1;p=0.002). Mean HIT-6 scores showed improvement in the treatment group compared with the control group, although the change was not statistically significant (p=0.15) from baseline to follow up visit. No adverse effects from treatments were noted. Conclusions Patients with headaches secondary to PCS showed immediate benefit in headache pain intensity after OMT. However, no sustained benefit was found on the follow up visit compared with the control group.

AbstractThrough our involvement in KEYNOTE‐059, we unexpectedly observed durable responses in two patients with metastatic gastroesophageal adenocarcinoma (mGEA) who received ramucirumab (anti‐VEGFR‐2)/paclitaxel after immune checkpoint inhibition (ICI). To assess the reproducibility of this observation, we piloted an approach to administer ramucirumab/paclitaxel after ICI in more patients, and explored changes in the immune microenvironment. Nineteen consecutive patients with mGEA received ICI followed by ramucirumab/paclitaxel. Most (95%) did not respond to ICI, yet after irRECIST‐defined progression on ICI, all patients experienced tumor size reduction on ramucirumab/paclitaxel. The objective response rate (ORR) and progression‐free survival (PFS) on ramucirumab/paclitaxel after ICI were higher than on the last chemotherapy before ICI in the same group of patients (ORR, 58.8% vs 11.8%; PFS 12.2 vs 3.0 months; respectively). Paired tumor biopsies examined by imaging mass cytometry showed a median 5.5‐fold (range 4‐121) lower frequency of immunosuppressive forkhead box P3+ regulatory T cells with relatively preserved CD8+ T cells, post‐treatment versus pre‐treatment (n = 5 pairs). We then compared the outcomes of these 19 patients with a separate group who received ramucirumab/paclitaxel without preceding ICI (n = 68). Median overall survival on ramucirumab/paclitaxel was longer with (vs without) immediately preceding ICI (14.8 vs 7.4 months) including after multivariate analysis, as was PFS. In our small clinical series, outcomes appeared improved on anti‐VEGFR‐2/paclitaxel treatment when preceded by ICI, in association with alterations in the immune microenvironment. However, further investigation is needed to determine the generalizability of these data. Prospective clinical trials to evaluate sequential treatment with ICI followed by anti‐VEGF(R)/taxane are underway.

Abstract Traditional Hardy–Weinberg equilibrium (HWE) tests (the χ2 test and the exact test) have long been used as a metric for evaluating genotype quality, as technical artifacts leading to incorrect genotype calls often can be identified as deviations from HWE. However, in data sets composed of individuals from diverse ancestries, HWE can be violated even without genotyping error, complicating the use of HWE testing to assess genotype data quality. In this manuscript, we present the Robust Unified Test for HWE (RUTH) to test for HWE while accounting for population structure and genotype uncertainty, and to evaluate the impact of population heterogeneity and genotype uncertainty on the standard HWE tests and alternative methods using simulated and real sequence data sets. Our results demonstrate that ignoring population structure or genotype uncertainty in HWE tests can inflate false-positive rates by many orders of magnitude. Our evaluations demonstrate different tradeoffs between false positives and statistical power across the methods, with RUTH consistently among the best across all evaluations. RUTH is implemented as a practical and scalable software tool to rapidly perform HWE tests across millions of markers and hundreds of thousands of individuals while supporting standard VCF/BCF formats. RUTH is publicly available at https://www.github.com/statgen/ruth.