Citations

6589 Background: Real-world utilization and comparative effectiveness of direct oral anticoagulants (DOACs), low molecular weight heparin (LMWH) and warfarin for cancer-associated venous thromboembolism (VTE) treatment remains largely unexplored. Methods: De-identified administrative claims data (OptumLabs - Data Warehouse) for adult active cancer patients with acute VTE (1/1/2012-9/30/2019) were assessed for utilization patterns, recurrent VTE, and major bleeding differences between DOACs, LMWH, and warfarin. Patients were followed up till the end of treatment. Patients who crossed over to other anti-coagulants within the follow up period were excluded. Multinomial logistic regression was used to assess predictors of anticoagulant administration. Kaplan-Meier curves were used to evaluate the differences in time to medication discontinuation among the three groups. Propensity score (PS) and inverse probability of treatment weighting were used to balance baseline differences between groups. Standardized difference (SD) was used to assess the balance of covariates after weighting and SD < 10% was considered acceptable. Weighted Cox proportional hazards regression with a robust variance estimator was then used to assess outcomes in PS weighted groups. Results: A total of 5100 patients met the inclusion criteria; 49.3% filled DOACs (n = 2512), 29.2% LMWH (n = 1488), and 28.6% warfarin (n = 1460). Median treatment duration was around 3.2 months for DOACs and warfarin, and 1.8 months for LWMH ( P-value < 0.01). Multinomial regression analysis showed that younger patients were more likely to be prescribed LMWH (OR 0.97 95% CI: 0.97-0.98) as compared to DOACs. Patients with lung (OR 2.07 95% CI: 1.12-3.65; OR 1.87 95% CI: 1.04-3.37), urological (OR: 1.94 95% CI:1.08-3.49; OR: 2.04 95% CI: 1.12-3.73), gynecological (OR 4.25, 95% CI: 2.31-7.82; OR 2.31 95% CI: 1.22-4.39) and colorectal cancer (OR 2.26 95% CI: 1.20-4.32; OR 2.51; 95% CI: 1.32-4.79) were more likely to be prescribed LMWH or warfarin respectively, compared to DOACs. VTE recurrences were more frequent for patients receiving LMWH (HR: 1.47; 95% CI: 1.14-1.90) or warfarin (HR: 1.46; 95% CI: 1.13-1.87) compared to DOACs. LMWH, but not warfarin, was associated with greater major bleeding rates compared to DOACs (HR: 2.27; 95% CI: 1.62-3.20). All-cause mortality rates were also significantly higher for patients receiving LMWH, but not warfarin compared to DOACs (HR: 1.61; 95% CI: 1.15-2.25). Conclusions: Patients with cancer associated VTE remain on anti-coagulation for a remarkably short duration in real-world clinical practice. DOACs and warfarin may offer better compliance than LMWH. Patients receiving DOACs have a lower risk of VTE recurrence, less major bleeding, and improved mortality. Warfarin may still be considered for patients with contraindications to DOACs and non-compliant to LMWH.

TPS6111 Background: Treatment options for recurrent and/or metastatic (R/M) salivary gland cancer (SGC) are limited with response rates to standard cytotoxic chemotherapy (CT) low at 10-30%, and responses to single-agent immune checkpoint inhibition (ICI) <10%. Current therapeutic agents used to treat R/M SGC have an unfavorable toxicity profile including cytotoxic CTs such as cisplatin and doxorubicin and the targeted therapy lenvatinib. Treatments with general applicability and acceptable side effect profile are urgently needed. Pemetrexed (PTX) is a multi-targeted anti-folate CT with an excellent safety and toxicity profile with promising responses reported in a case series of patients (pts) with R/M SGC (Viscuse P and Price K. Marked responses to pemetrexed chemotherapy for metastatic adenocarcinoma of the parotid gland: case series. Head Neck 2019;41(6):E99-103.). As the combination of PTX and pembrolizumab (PMB) showed enhanced responses and survival in pts with lung cancer, we hypothesize that PTX and PMB will have efficacy in pts with R/M SGC and that the combination will have improved anti-cancer activity compared with historical controls. Correlative studies on archived tissues include methylthioadenosine phosphorylase loss, PDL1 expression, and thymidylate synthase expression as potential biomarkers of response. Methods: MC200708 is a single institution (3-site), open-label, single arm phase II study of PTX and PMB in patients with R/M SGC. Pts will be treated in two cohorts: one for pts with adenoid cystic carcinoma (ACC) and the other for pts with all other types of SGC (non-ACC cohort). Eligible pts must be ≥18 years old, have a pathologically confirmed SGC that is not amenable to curative-intent therapy, ECOG 0-2, adequate organ function, and at least 1 measurable lesion by RECIST 1.1. Any number of lines of prior therapy is allowed; prior treatment with checkpoint inhibitors and/or PTX is allowed. Key exclusion criteria: serious medical co-morbidity or autoimmune disease, prior grade 3-4 adverse event (AE) or grade 2-4 lung AE with ICI, and uncontrolled brain metastases. Simon’s two-stage design will be used for each cohort separately given the expected difference in responses in pts with ACC and non-ACC. Primary endpoint is overall response rate. Secondary endpoints are progression free and overall survival and toxicity. All patients will receive the same treatment of PTX 500 mg/m2 IV + PMB 200 mg IV every 3 weeks until disease progression or treatment intolerance. Response assessments will occur every 3 cycles. Enrollment began July 2021 and 16 of the planned 45 patients (ACC cohort 9 of 20 pts, non-ACC 7 of 25) have been accrued. Clinical trial information: NCT04895735.

4146 Background: Targeting focal adhesion kinase (FAK) renders checkpoint immunotherapy effective in pancreatic ductal adenocarcinoma (PDAC) mouse models. Defactinib is a highly potent oral FAK inhibitor shown to have a tolerable safety profile. We evaluated the safety and recommended phase 2 dose (RP2D) of defactinib in combination with pembrolizumab and gemcitabine for PDAC patients. Methods: We conducted a multicenter, open-label, phase I study with dose escalation and expansion phases. In 3x3 dose escalation, patients with refractory solid tumors were treated at five escalating dose levels of defactinib and gemcitabine to identify a RP2D. In expansion phase, patients with metastatic PDAC who progressed on frontline treatment (refractory cohort) or had treatment response or stable disease (SD) on standard gemcitabine/nab-paclitaxel (maintenance cohort) were treated at RP2D. Pre- and post-treatment tumor biopsies were performed to evaluate changes in tumor immunity. Results: The triple drug combination was well-tolerated with no dose-limiting toxicities. Among 17 treated patients with refractory PDAC, the disease control rate (DCR) was 58.8% with one partial response (PR) and nine SDs and the median progression-free survival (PFS) and overall survival (OS) were 4.2 months and 9.1 months, respectively. Among the evaluable patients in the maintenance cohort, DCR was 63.6% with one PR and six SD. Three patients with SD came off study due to treatment- or disease-related complications. The median PFS and OS were 5.0 months and 8.3 months, respectively. Conclusions: The combination of defactinib, pembrolizumab, and gemcitabine was well-tolerated, had promising preliminary efficacy, and showed increased infiltrative T lymphocytes in post-treatment tumor biopsies. Incorporation of a more potent chemotherapy backbone should be considered to achieve better clinical response in future trial design. Clinical trial information: NCT02546531.

e15118 Background: Melanoma, non-small cell lung cancer (NSCLC), colorectal adenocarcinoma and thyroid tumors frequently harbor BRAF mutations and are tumor types eligible for treatment with FDA-approved BRAF inhibitors. Although there are many ongoing clinical trials with BRAF inhibitors in various advanced tumor types, currently eligibility requires both tumor type identification and BRAF mutation confirmation. The 92-gene assay (CancerTYPE ID) is a gene expression-based classifier of 50 tumor types and subtypes for metastatic patients with diagnostic ambiguity. Multimodal biomarker testing, including NGS, IHC and FISH, enables identification of actionable biomarkers to guide targeted therapy selection. Here, a database of metastatic cases integrating tumor type with biomarker analysis was used to identify patients eligible for BRAF inhibitor treatment. Methods: MOSAIC (Molecular Synergy to Advance Individualized Cancer Care) is an IRB-approved, de-identified database of diagnostically ambiguous cases submitted for CancerTYPE ID testing with tumor type-guided multimodal biomarker testing (Neogenomics). In this study, metastatic cancers of various tumor types with BRAF mutations were identified. Results: CancerTYPE ID determined 27 different tumor types in 2929 (92.5%) of 3168 cases. BRAF mutations were identified in 87 cases across 18 tumor types and subtypes. Out of the 87 cases, 22 (25.3%) had BRAF mutations in a tumor type eligible for FDA-approved BRAF inhibitor treatment, including melanoma, NSCLC, colorectal adenocarcinoma and thyroid cancer. Another 26 (29.9%) BRAF-mutated cases were detected in a tumor type with ongoing BRAF inhibitor clinical trials, including lymphoma, pancreaticobiliary and ovarian cancer (Table). Conclusions: This analysis identified patients with metastatic cancer with actionable BRAF mutations eligible for FDA-approved therapy, and patients who may be eligible for investigational BRAF inhibitors based on tumor type and mutation status. Notably, cancer type identification is critical given that FDA-approved BRAF inhibitor treatment regimens vary based on the tumor-specific indication. These findings support the clinical utility of molecular tumor type classification by CancerTYPE ID combined with biomarker profiling to identify additional treatment options for patients with metastatic cancer.[Table: see text]

2538 Background: Claudin 18.2 (CLDN18.2) is a highly selective cell lineage marker with limited expression in normal gastric tissues and significantly higher expression in primary gastric, pancreatic tumors and their metastases. Anti-CLDN18.2-targeted CAR T cells, termed CT041, were developed to evaluate tumor response and patient-reported outcomes in the gastric and pancreatic cancer. Preliminary results of the trial (NCT03874897) showed an objective response rate (ORR) of about 60% in gastric cancer from a non-Western population. Here we report the results of CT041 for metastatic gastric cancer after ≥ 2 prior lines of systemic therapy or pancreatic cancer ≥ 1 prior line from six centers in the United States. Methods: This single-arm, open-label, phase Ib study (NCT04404595) investigated autologous CT041 CAR T cells in patients with CLDN18.2 positive advanced gastric (including diffuse, signet-ring) or pancreatic adenocarcinoma. All patients completed a conditioning regimen consisting of fludarabine, cyclophosphamide, and nab-paclitaxel prior to CT041 CAR T cells. The primary objective was to assess the safety, efficacy and cytokinetic profile of CT041. Adverse Events (AEs) were graded according to CTCAE 5.0, and tumor response was assessed per RECIST 1.1. Results: As of February 15, 2022, 11 patients (5 gastric and 6 pancreatic) with a median of 2 prior lines of therapy (range 1- 4) were treated with CT041 at a dose between 2.5 and 4 x 108 cells. There were no dose limiting toxicities, treatment-related deaths, severe cytokine release syndrome (CRS), immune effector cell-associated neurologic syndrome (ICANS), or severe gastrointestinal (GI) related AEs. All CRS were grade 1 or 2. Only one patient received tocilizumab. No grade 4 AEs were observed except for hematologic toxicities related to conditioning. The first eight patients were evaluable for response by the date of data cut-off: 1 patient achieved a complete response after two CT041 doses (gastric), 2 had partial response (gastric), 2 had stable disease with tumor shrinkage (pancreatic) and 3 (pancreatic) had progression of disease after an initial biochemical response. ORR was 37.5% (3/8) in all patients including 100% (3/3) in the gastric subgroup (all ≥ 3 prior lines). The last three patients had not reached the time for response assessment. CAR T cell expansion correlated with ctDNA reduction. The median duration of response and the progression-free survival had not been reached. Conclusions: These preliminary results indicate that CT041 therapy was safe and had therapeutic efficacy in patients with advanced GI cancers. In heavily pre-treated gastric cancer, CT041 may have significantly improved anti-tumor activity compared to historical treatment regimens. Clinical trial information: NCT04404595.

Abstract Purpose: This phase Ib/2 trial investigated pembrolizumab-containing trimodality therapy in patients with gastroesophageal junction (GEJ) adenocarcinoma. Patients and Methods: Patients with GEJ adenocarcinoma (cT1–3NanyM0) received neoadjuvant pembrolizumab-containing chemoradiation (CROSS regimen) followed by surgical resection and adjuvant pembrolizumab. The primary endpoints were tolerability in the first 16 patients and pathologic complete response [pCR (ypT0N0)]. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). An independent propensity-score-matched cohort (treated with CROSS without immunotherapy) was used for comparison. Exploratory analyses included immune biomarkers in the tumor microenvironment (TME) and plasma. Results: We enrolled 31 eligible patients, of whom 29 received all expected doses of neoadjuvant pembrolizumab and 28 underwent R0 resection. Safety endpoints were met. The primary efficacy endpoint was not met [7/31 (22.6%) achieved pCR]. Patients with high [i.e., combined positive score (CPS) ≥ 10] baseline expression of programmed death (PD)-L1 in the TME had a significantly higher pCR rate than those with low expression [50.0% (4/8) vs. 13.6% (3/22); P = 0.046]. Patients with high PD-L1 expression also experienced longer PFS and OS than propensity-score-matched patients. Among trial patients with PD-L1 CPS &lt; 10, unprespecified analysis explored whether extracellular vesicles (EV) could identify further responders: an elevated plasma level of PD-L1–expressing EVs was significantly associated with higher pCR. Conclusions: Adding pembrolizumab to trimodality therapy showed acceptable tolerability but did not meet the pre-specified pCR endpoint. Exploratory analyses suggested that high PD-L1 expression in the TME and/or on EVs may identify patients most likely to achieve tumor response.

Objective Hyperinsulinemia elicits an increase sympathetic nervous system activity directed toward skeletal muscle (muscle sympathetic nerve activity, MSNA). The insulin‐mediated increase in MSNA is primarily attributed to its effect within the central nervous system. In addition to direct central effects, insulin also elicits peripheral vasodilation, which may further increase MSNA via arterial baroreflex‐mediated mechanisms in order to maintain blood pressure (BP). Herein we examined the contribution of insulin‐induced peripheral vasodilation and role for the arterial baroreflex in the MSNA response to hyperinsulinemia. We hypothesized that rescuing peripheral resistance with co‐infusion of the vasoconstrictor phenylephrine would attenuate the MSNA response to hyperinsulinemia. We further hypothesized the insulin‐mediated increase in MSNA would be recapitulated with another vasodilator (sodium nitroprusside, SNP). Methods In 33 healthy adults (28M/5F, 28±1 yrs, BMI 25.0±0.5 kg/m 2 ) MSNA (microneurography) and BP (Finometer/brachial catheter) were measured, and total peripheral resistance (TPR, ModelFlow) was calculated at rest and during intravenous insulin (n=20) or SNP (n=13) infusion. A subset of participants receiving insulin (n=7) were co‐infused with phenylephrine. Spontaneous arterial baroreflex sensitivity was determined over 5‐min at baseline and during pharmacological intervention(s). Results Insulin infusion increased MSNA (p=0.05) and decreased TPR (p<0.05), with no effects on arterial baroreflex sensitivity or BP (p>0.05). Co‐infusion with phenylephrine returned MSNA and TPR to baseline, with no effect on baroreflex sensitivity (p>0.05). Similar to insulin, SNP increased MSNA (p<0.01) and decreased TPR (p<0.05), with no effect on baroreflex sensitivity (p>0.05). Conclusions Present findings reveal that acute hyperinsulinemia increases MSNA without a change in arterial baroreflex sensitivity in healthy men and women. Insulin‐mediated increases in MSNA are lost with co‐infusion of phenylephrine and can be recapitulated with infusion of SNP. Results support a dynamic interplay between central and peripheral mechanisms during hyperinsulinemia to increase MSNA and maintain BP.

OBJECTIVES: To describe the prevalence, associated risk factors, and outcomes of serious neurologic manifestations (encephalopathy, stroke, seizure, and meningitis/encephalitis) among patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. DESIGN: Prospective observational study. SETTING: One hundred seventy-nine hospitals in 24 countries within the Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study COVID-19 Registry. PATIENTS: Hospitalized adults with laboratory-confirmed SARS-CoV-2 infection. INTERVENTIONS: None. RESULTS: Of 16,225 patients enrolled in the registry with hospital discharge status available, 2,092 (12.9%) developed serious neurologic manifestations including 1,656 (10.2%) with encephalopathy at admission, 331 (2.0%) with stroke, 243 (1.5%) with seizure, and 73 (0.5%) with meningitis/encephalitis at admission or during hospitalization. Patients with serious neurologic manifestations of COVID-19 were older with median (interquartile range) age 72 years (61.0–81.0 yr) versus 61 years (48.0–72.0 yr) and had higher prevalence of chronic medical conditions, including vascular risk factors. Adjusting for age, sex, and time since the onset of the pandemic, serious neurologic manifestations were associated with more severe disease (odds ratio [OR], 1.49; p < 0.001) as defined by the World Health Organization ordinal disease severity scale for COVID-19 infection. Patients with neurologic manifestations were more likely to be admitted to the ICU (OR, 1.45; p < 0.001) and require critical care interventions (extracorporeal membrane oxygenation: OR, 1.78; p = 0.009 and renal replacement therapy: OR, 1.99; p < 0.001). Hospital, ICU, and 28-day mortality for patients with neurologic manifestations was higher (OR, 1.51, 1.37, and 1.58; p < 0.001), and patients had fewer ICU-free, hospital-free, and ventilator-free days (estimated difference in days, –0.84, –1.34, and –0.84; p < 0.001). CONCLUSIONS: Encephalopathy at admission is common in hospitalized patients with SARS-CoV-2 infection and is associated with worse outcomes. While serious neurologic manifestations including stroke, seizure, and meningitis/encephalitis were less common, all were associated with increased ICU support utilization, more severe disease, and worse outcomes.

A Carotid web (CaW) is defined as a focal shelf-like projection of non-atheromatous, fibrous tissue along the posterior wall of the carotid bulb. CaW are rare and commonly overlooked lesions increasingly recognized as a cause of stroke in otherwise healthy patients. Intravascular imaging modalities such as intravascular ultrasound and optical coherence tomography (OCT) have been proposed as an adjunct to digital subtraction angiography for the evaluation of CaW. However, the use of OCT in CaW has yet to be described. This report investigated the utility of OCT as an adjunct imaging modality in the evaluation of CaW morphology in a young patient with recurrent ischemic strokes.