Citations

8020 Background: Patients with R/R DLBCL ineligible for autologous stem cell transplant (ASCT) have a poor prognosis. In these patients, tafasitamab (anti-CD19 antibody) plus lenalidomide (LEN) has shown encouraging results in the open-label, single-arm, phase II L-MIND study (n = 81; NCT02399085). To evaluate the contribution of tafasitamab to the activity of this doublet, we conducted a global, real-world study of patients treated with LEN monotherapy (RE-MIND; NCT04150328). Here we present the primary analysis of a 1:1 patient-level matched comparison between the L-MIND and RE-MIND cohorts. Methods: Patients treated with LEN monotherapy for R/R DLBCL were enrolled in the observational, retrospective RE-MIND cohort. As in L-MIND, patients had 1–3 prior systemic therapies, including ≥1 CD20-targeting regimen; were aged ≥18 years; and were not eligible for ASCT. A 1:1 estimated propensity score (ePS) matching methodology ensured balancing of nine pre-specified baseline covariates. The primary analysis set, Matched Analysis Set 25 (MAS25), included patients who received a LEN starting dose of 25 mg/day. The primary endpoint was investigator-assessed best objective response rate (ORR). Key secondary endpoints included overall survival (OS) and complete response (CR) rate. Results: 490 patients were enrolled in RE-MIND across 58 centers in the US and Europe, of which 140 fulfilled the ePS matching criteria. The MAS25 included 76 patients each from the two cohorts. Baseline characteristics between cohorts were comparable. The primary endpoint was met with a significantly better ORR of 67.1% (95% CI: 55.4–77.5) for the L-MIND cohort versus 34.2% (95% CI: 23.7–46.0) for the RE-MIND cohort (odds ratio 3.89; 95% CI: 1.90–8.14; p < 0.0001). The CR rate was 39.5% (95% CI: 28.4–51.4) in the L-MIND cohort and 13.2% (95% CI: 6.5–22.9) in the RE-MIND cohort. A significant difference in OS favored the L-MIND cohort (HR = 0.499; 95% CI: 0.317–0.785). ORR and CR outcomes in the RE-MIND cohort were similar to the published literature for LEN monotherapy in R/R DLBCL. Conclusions: Significantly better ORR, CR and OS indicate potential synergistic effects of the tafasitamab + LEN combination in ASCT-ineligible R/R DLBCL. ePS-based 1:1 matching allows robust estimation of the treatment effect of tafasitamab when added to LEN. RE-MIND demonstrates the utility of real-world data in interpreting non-randomized trials. Clinical trial information: NCT04150328 .

e16062 Background: Lynch syndrome (Ly) but not Sporadic (Sp) CRC patients are responsive to immunotherapies. We have shown micorbiota from CRC patients induces precancerous colonic lesions in germ-free mice. The aim was to investigate microbiota linked compromised anti tumor immune response. Methods: We compared 1) Whole metagenomic fecal microbiotas of CRC patients [Sp, n = 53+Ly, n = 19] to controls (n = 90) or being first degree relatives of Ly patients (n = 14), respectively; 2) Tumoral to normal mucosa-adherent microbiota (16sRNA sequences); 3) Normal to tumoral tissues’ mRNA RT-PCRs of IL1b, IL4, IL6, IL8, IL17, TNFa, TGFb, FasL, Granzyme A&B, Thy1; 4) CD3, CD4, CD8, Granzym, KL1, FoxP3, RORgT, MastCell, cells in tumor tissues quantified by immunohistochemistry (IHC), between subgroups. Associations between bacteria, tissue immune cell infiltrates and clinical data (3-yrs follow up or death) were established by using unsupervised Systems Biology and Bioinformatics analyses (Institut Pasteur Shaman platform and Qlucor program). Anti tumoral immune response links with bacteria were based on differences between Ly and Sp CRC patients. Tumor tolerance links with bacteria were identified using germ-free mice (n = 185) who orally received microbiota (9 Sp CRC patients vs 9 controls) with colonic mucosa examined 3 months after human fecal transfer (whole exome sequencing, methylchips, IHC for CD3, CD11b, FoxP3, RORgT, ILC3). Results: Enrichment in Peptostreptococcus, Thermodesulfovibrio and diminution in Ruminococcus, Eubacterium, Coprococcus were linked with FoxP3 and IL-17 over expressions in tumor tissues. Enrichment in Escherichia, Enterobacter, Thioalkalimicrobium, and diminution in Eubacterium, Faecalibacterium and Butyrovibrio were associated with higher FoxP3, FasL, Granzyms A&B, Perforin, Thy1 mRNAs/mRNACD3. Diminution of Eubacterium, Dorea, Faecalibacterium genera and enrichment in Fusobacterium, E. Coli/Shigella were associated with higher CD3, FoxP3, GranzymA and B and FOXP3-RORgT cells in tumor tissues. Higher fecal enrichments in oral bacteria (parvimonas micra) and lack of Thermodesulfovibrio enrichment were associated with higher FoxP3-RORgt cells and short survival; in mice ILC3 and FoxP3-RORgT cells were linked with Sp CRC dysbiosis. Species linked with immunotolerance are identified. Conclusions: Fecal and tissue microbiota can impact failure of anti tumoral immune response in sporadic CRC patients by enhancing overexpression of IL-17 and reducing cytotoxic T-cell infiltration in tumors. Clinical trial information: NCT01270360 .

3552 Background: Delta-like 3 (DLL3) is highly and specifically expressed in solid tumors, such as neuroendocrine carcinomas (NECs), malignant melanoma (MM), and medullary thyroid carcinoma (MTC). Rovalpituzumab tesirine (Rova-T) is a DLL3-targeting antibody-drug conjugate. Methods: This Phase 1/2 study (NCT02709889) enrolled patients with relapsed/refractory DLL3+ (>1% by IHC) advanced solid tumors and ECOG performance status of 0-1. Rova-T was given IV at 0.2, 0.3, or 0.4 mg/kg on d 1 of each 6-wk cycle (q6wk) for dose escalation (3+3 design) in disease-specific cohorts in Phase I. The recommended Phase 2 dose (RP2D) was tested in Phase II. Safety and dose-limiting toxicities (DLTs) were primary endpoints; efficacy outcomes were secondary endpoints. Results: The study enrolled 200 patients; 101 had NECs (large cell NEC [n=13], neuroendocrine prostate cancer [n=21], high-grade gastroenteropancreatic NEC [n=36], other [n=31]) and 99 had other solid tumors (MM [n=20], MTC [n=13], glioblastoma [GBM; n=23], other [n=43]). The median age was 61 y (range, 28-84); 63% were male. The RP2D was 0.3 mg/kg q6wk for 2 cycles in all cohorts. There were 7 DLTs in 5 patients: 2 with 0.2 mg/kg (Grade [Gr] 3 photosensitivity reaction, Gr 3 dyspnea), 2 with 0.3 mg/kg (1 with Gr 2 effusion, Gr 3 tumor lysis syndrome, and Gr 3 rhabdomyolysis; 1 with Gr 4 kidney injury), and 1 with 0.4 mg/kg (Gr 4 thrombocytopenia). Despite only 1 DLT identified with 0.4 mg/kg, the totality of the safety data suggested that this dose is not well tolerated. Common adverse events (AEs) in patients given 0.3 mg/kg (n=145) are shown (Table). Serious AEs occurred in 77/145 patients (53%), most commonly (≥3%) malignant neoplasm progression (n=18; 12%), pleural effusion (n=7; 5%), pericardial effusion (n=6; 4%), and dyspnea (n=5; 3%). The objective response rate (ORR) was 11% (21/200): 14 had NEC, 2 had MM, 2 had MTC, 2 had small cell carcinoma (SCC) not of lung origin (all partial responses), and 1 had GBM (complete response). In patients with NECs given 0.3 mg/kg, ORR, clinical benefit rate, and progression-free survival trended in favor of those with high DLL3-expressing tumors (≥50% by IHC) which represented 51% of NECs. Conclusions: Rova-T was tolerable in patients with advanced solid tumors at 0.3 mg/kg q6wk for 2 cycles. Antitumor activity was observed in patients with NEC, MM, MTC, SCC, and GBM. Clinical trial information: NCT02709889 . [Table: see text]

1011 Background: Several trials have shown 25-30% pathologic complete response (pCR) rates in patients with HER2+ BC treated with LT therapy (+ endocrine therapy if ER+), but no chemotherapy (CTX). We hypothesize that a multiparameter classifier, comprised of HER2 gene and protein levels, intratumor heterogeneity (ITH), HER2-enriched (E) subtype, and PIK3CA mutation status can identify patients whose tumors are “addicted” to HER2 signaling and are likely to achieve pCR from a CTX-sparing de-escalation strategy. Methods: Baseline specimens from 2 trials (TBCRC023 [NCT00999804] and PAMELA [NCT01973660]) of neoadjuvant CTX-sparing LT (+ endocrine therapy if ER+) in HER2+ BC were used. HER2 protein and ITH (scored for % 3+ by IHC), and gene amplification (HER2:CEP17 ratio and copy number (CN) by CISH) were measured on the same slide by the dual gene protein assay (GPA). HER2-E and PIK3CA mutation status were assessed by research-based PAM50 and MSK-IMPACT platforms, respectively. A decision tree algorithm was used to determine the GPA cutoffs and to construct the classifier of response (by pCR) in TBCRC023, which was then validated in PAMELA. Results: Of the evaluable patients from TBCRC023 (N = 130) and PAMELA (N = 151), GPA data were available for 121 and 94 cases, respectively. Both cohorts exhibited similar distributions for HER2 ratio, CN, and % 3+, and a strong correlation between HER2 ratio and CN (R > 0.92). In TBCRC023, 73 cases had data from GPA, PAM50, and IMPACT, of which 15 had pCR. Recursive partitioning identified cutoffs of HER2 ratio > 4.6 and % 3+ > 97.5% in both the GPA data cohort (N = 121) and complete data cohort (N = 73). With PAM50 and IMPACT data, the model added HER2-E and PIK3CA wild-type (wt). For practical reasons, the classifier was locked as HER2 ratio ≥ 4.5 AND % 3+ ≥ 90% AND PIK3CA-wt AND HER2-E, which yielded a PPV of 55% and NPV of 94%. Validation in PAMELA using 45 cases with data for all 3 assays yielded PPV of 44% and NPV of 82%. 29 TBCRC023 cases without IMPACT data could be predicted to be non-pCR, of which 26 were correct (NPV = 89%). In PAMELA, 66 additional cases could be predicted to be non-pCR, of which 54 were correct (NPV = 81%). Conclusions: We have constructed a multiparameter classifier that can predict pCR with targeted therapy alone that compare to pCR rates of CTX + dual anti-HER2 in unselected patients. Prospective validation in a clinical trial is warranted. [Table: see text]

504 Background: For PM patients (pts) with locally advanced ER+ HER2- BC, NET improves breast conservation surgery (BCS) rates, and modified preoperative endocrine prognostic index (mPEPI) 0, defined as pT1-2 pN0 Ki67< 2.7%, or pathologic complete response (pCR: no invasive disease in breast or lymph node) is associated with low risk of recurrence without adjuvant chemotherapy (CT). The ALTERNATE trial was initiated to assess if the endocrine-sensitive disease rate (ESDR: number of mPEPI 0 pts/number of eligible pts initiating NET) with fulvestrant (F) or F+anastrozole (A) is improved relative to A alone (reported here) and if the 5-year (yr) recurrence-free survival (RFS) rate for pts with mPEPI 0 on A alone without CT is ≥ 95% (awaits further follow-up). Methods: PM pts with clinical stage II/III ER+ HER2- BC were randomized 1:1:1 to 1 mg A po daily, 500 mg F IM every 4 week (wk)s after loading dose, or A+F for 6 months. Ki67 was tested centrally on biopsies acquired prior to NET, wk 4, wk 12 and at surgery. Pts with Ki67 >10% at wk 4 or 12 were recommended to go off protocol-directed ET and switch to CT. Pts with mPEPI 0 at surgery were recommended to continue assigned ET for 1.5 yrs followed by A for a total of 5 yrs ET (and not to receive CT). The primary endpoint of the neoadjuvant phase was ESDR. ESDR of each F arm was compared to that of the A alone arm. With 425 pts per arm, a one-tailed alpha = 0.025 chi-square test of two independent proportions has 84% power to detect an increase of ≥10% in ESDR for F or F+A compared to the A arm, assuming ESDR ≤30% in A. Results: 1362 pts (A 452; F 454; A+F 456) were enrolled Feb 2014 to Nov 2018. 63 pts were excluded (did not start NET). Of the remaining 1299 pts (A 434; F 431, A+F 434), 42% were cN1-3 and 73% were considered candidates for BCS. ESDR was 18.6% (95%CI: 15.1-22.7%) with A, 22.7% (95%CI: 18.9-27.0%) with F, and 20.5% (95%CI: 16.8-24.6%) with A+F. No significant difference in ESDR was found between A and F (p=0.15) or A and A+F (p=0.55). Among the 825 pts with wk 4 Ki67 < 10% who completed NET and surgery, ESDR and the BCS rate were 27.7% and 70.3% with A; 29.6% and 68.1% with F, and 26.8% and 69.9% with A+F, respectively. Conclusion: Neither F nor F+A significantly improved ESDR compared to A alone in PM pts with locally advanced ER+ HER2- BC. RFS data are awaited. Support: U10CA180821, U10CA180882, U24CA196171, https://acknowledgments.alliancefound.org ; NCI BIQSFP, BCRF, Genentech, AstraZeneca. Clinical trial information: NCT01953588 .

Abstract Splicing alterations are common in diseases such as cancer, where mutations in splicing factor genes are frequently responsible for aberrant splicing. Here we present an alternative mechanism for splicing regulation in T-cell acute lymphoblastic leukemia (T-ALL) that involves posttranslational stabilization of the splicing machinery via deubiquitination. We demonstrate there are extensive exon skipping changes in disease, affecting proteasomal subunits, cell-cycle regulators, and the RNA machinery. We present that the serine/arginine-rich splicing factors (SRSF), controlling exon skipping, are critical for leukemia cell survival. The ubiquitin-specific peptidase 7 (USP7) regulates SRSF6 protein levels via active deubiquitination, and USP7 inhibition alters the exon skipping pattern and blocks T-ALL growth. The splicing inhibitor H3B-8800 affects splicing of proteasomal transcripts and proteasome activity and acts synergistically with proteasome inhibitors in inhibiting T-ALL growth. Our study provides the proof-of-principle for regulation of splicing factors via deubiquitination and suggests new therapeutic modalities in T-ALL. Significance: Our study provides a new proof-of-principle for posttranslational regulation of splicing factors independently of mutations in aggressive T-cell leukemia. It further suggests a new drug combination of splicing and proteasomal inhibitors, a concept that might apply to other diseases with or without mutations affecting the splicing machinery. This article is highlighted in the In This Issue feature, p. 1241

Since the declaration of the global pandemic of COVID-19 by the World Health Organization on 11 March 2020, we have continued to see a steady rise in the number of patients infected by SARS-CoV-2. However, there is still very limited data on the course and outcomes of this serious infection in a vulnerable population of pregnant patients and their fetuses. International perinatal societies and institutions including SMFM, ACOG, RCOG, ISUOG, CDC, CNGOF, ISS/SIEOG, and CatSalut have released guidelines for the care of these patients. We aim to summarize these current guidelines in a comprehensive review for patients, healthcare workers, and healthcare institutions. We included 15 papers from 10 societies through a literature search of direct review of society’s websites and their journal publications up till 20 April 2020. Recommendations specific to antepartum, intrapartum, and postpartum were abstracted from the publications and summarized into Tables. The summary of guidelines for the management of COVID-19 in pregnancy across different perinatal societies is fairly consistent, with some variation in the strength of recommendations. It is important to recognize that these guidelines are frequently updated, as we continue to learn more about the course and impact of COVID-19 in pregnancy.

Abstract Objective The n2c2/UMass Lowell spin-off shared task focused on medical concept normalization (MCN) in clinical records. This task aimed to assess state-of-the-art methods for matching salient medical concepts from clinical records to a controlled vocabulary. We describe the task and the dataset used, compare the participating systems, and identify the strengths and limitations of the current approaches and directions for future research. Materials and Methods Participating teams were asked to link preselected text spans in discharge summaries (henceforth referred to as concept mentions) to the corresponding concepts in the SNOMED CT (Systematized Nomenclature of Medicine Clinical Terms) and RxNorm vocabularies from the Unified Medical Language System. The shared task used the MCN corpus created by the organizers, which maps all mentions of problems, treatments, and tests in the 2010 i2b2/VA challenge data to the Unified Medical Language System concepts. Submitted systems represented 4 broad categories of approaches: cascading dictionary matching, cosine distance, deep learning, and retrieve-and-rank systems. Disambiguation modules were common across all approaches. Results A total of 33 teams participated in the shared task. The best-performing team achieved an accuracy of 0.8526. The median and mean performances among all teams were 0.7733 and 0.7426, respectively. Conclusions Overall performance among the top 10 teams was high. However, particularly challenging for all teams were mentions requiring disambiguation of misspelled words, acronyms, abbreviations, and mentions with more than 1 possible semantic type. Complex mentions of long, multiword terms were also challenging and, in the future, will require better methods for learning contextualized representations of concept mentions and better use of domain knowledge.

Background: Recurrent pericarditis (RP) episodes and conventional treatments result in morbidity, but the impact on patient health-related quality of life (HRQoL) has not been quantified. The Phase 2 trial NCT03980522 of rilonacept (IL-1α/IL-1β inhibitor) evaluated HRQoL. Methods: Patients with active RP who were symptomatic at Baseline (A-RP, n=16) and RP patients who were not currently experiencing a recurrence but were corticosteroid-dependent at Baseline (CSD-RP, n=9) were enrolled. All received rilonacept weekly for 6 weeks to end of base treatment period (TP) plus an optional 18-week extension treatment period (EP). Corticosteroid tapering occurred in the EP. Physical and mental HRQoL (PROMIS Global Health v1.2 Physical and Mental Component Scores [PCS/MCS]) were assessed at baseline and follow-up. Results: Figure 1 presents the PROMIS PCS/MCS and pain scale scores (both patient-reported) as well as C-reactive protein levels over time. Mean PCS/MCS scores at baseline were 39.9/44.5 and 43.3/46.5 for A-RP and CSD-RP groups respectively (versus the norm mean of 50). In A-RP, PCS/MCS scores improved by 11.4/5.6 points by end of base TP, and this improvement was sustained throughout the EP (increase of 11.4/6.0 points from baseline at end of EP). In CSD-RP, PCS/MCS scores increased by 1.8/1.4 points by end of TP and improved by 3.5/4.2 points at end of study, after tapering or discontinuation of corticosteroid without disease recurrence. Conclusion: Impaired baseline HRQoL suggests negative impact of RP. For A-RP, rilonacept rapidly improved pericarditis signs and symptoms which was associated with HRQoL improvements. For CSD-RP, rilonacept supported tapering/withdrawal of corticosteroids without recurrence, with maintained/improved HRQoL. These results suggest rilonacept can improve RP patient HRQoL while providing an alternative to corticosteroids.