Citations

e14531 Background: Afami-cel is an autologous, T-cell receptor T-cell therapy engineered to target melanoma-associated antigen A4 (MAGE-A4) in human leukocyte antigen (HLA) A*02–eligible patients (pts) with advanced solid tumors. SPEARHEAD-1 (NCT04044768) is a Phase 2, two cohort, open-label trial to evaluate the efficacy and safety of afami-cel in pretreated pts with advanced/metastatic synovial sarcoma or myxoid/round cell liposarcoma. Here we report data on cytokine release syndrome (CRS) in the pts with advanced synovial sarcoma treated with afami-cel across Cohort 1 and Cohort 2. Methods: Eligible pts had advanced synovial sarcoma and were HLA-A*02 positive with MAGE-A4–positive tumors. Pts received afami-cel after lymphodepleting chemotherapy containing fludarabine and cyclophosphamide. Tocilizumab administration was permitted for Grade 1 CRS if symptoms persisted for ≥ 24 hours or if the pt had co-morbidities, and for Grade ≥2 CRS. Results: As of August 29, 2022, 72 pts with synovial sarcoma received afami-cel (n = 44 Cohort 1; n = 28 Cohort 2). Afami-cel dose range was 1.92–10.00×109 transduced T-cells. The median age was 39.5 years (range: 16–73 years), 47.2% of pts were female, 88.3% of pts were white, and tumor MAGE-A4 expression H-score was 244.5 (range: 66–300). CRS occurred in 72.2% of the pts with synovial sarcoma receiving afami-cel, including Grade 1 in 50% (36/72), Grade 2 in 20.8% (15/72), and Grade 3 in 1.4% (1/72) of pts as per American Society for Transplantation and Cellular Therapy grading. The median time to onset was 2.5 days (range: 1–5 days), and the median time to resolution was 3 days (range: 1 to 14 days). Twenty-seven of 72 (37.5%) pts received at least one dose of tocilizumab. Consistent with expectations, higher serum IL-6 levels were associated with CRS events and the indicated use of tocilizumab for management. RECIST v1.1 responses were observed in pts with and without CRS. Correlation of clinical factors and CRS with response will be presented. Conclusions: CRS was common after afami-cel administration but was mostly low grade. Administration of tocilizumab in SPEARHEAD-1 was effective in the management of CRS. Clinical trial information: NCT04044768 .

11536 Background: Ripretinib is a switch-control tyrosine kinase inhibitor approved for patients (pts) with gastrointestinal stromal tumor (GIST) who received prior treatment with ≥3 kinase inhibitors, including imatinib. Exploratory baseline circulating tumor DNA (ctDNA) next-generation sequencing (NGS) analysis from INTRIGUE showed pts with second-line advanced GIST with primary KIT exon 11 mutations and secondary resistance mutations exclusively in KIT exons 17/18 derived clinical benefit from ripretinib but not sunitinib (Bauer S et al. J Clin Oncol. 2023; Abs 397784). Outcomes in pts with advanced GIST with ctDNA not detected (ctDNA-ND) had not been evaluated. Here, we present exploratory data from INTRIGUE in pts who had baseline ctDNA-ND vs ctDNA detected (ctDNA-D). Methods: INTRIGUE is an open-label, phase 3 study that enrolled pts with advanced GIST who had disease progression on or intolerance to imatinib (NCT03673501). Pts were randomized 1:1 to ripretinib 150 mg once daily (QD) or sunitinib 50 mg QD (4 wks on/2 wks off) and stratified by mutation according to local pathology report. Baseline peripheral whole blood was analyzed by Guardant360, a 74-gene ctDNA NGS-based assay. Pts with ctDNA-D had ≥1 somatic alteration in the 74 genes analyzed. Results: Pts with ctDNA-ND (82/362, 22.7%) were younger (median: 55.5 vs 62.0 years) and had smaller sums of longest diameters of target lesions (median [range]: 57.6 [11–459] vs 108.8 [15–418] mm) vs ctDNA-D (280/362, 77.3%). Progression-free survival (PFS) was longer in pts with ctDNA-ND vs ctDNA-D and numerically higher with ripretinib vs sunitinib in pts with ctDNA-ND (Table). Pts with ctDNA-ND categorized as not having a KIT exon 9 mutation at randomization ( KIT exon 11, other KIT/PDGFRA, or KIT/PDGFRA wild-type; n = 71) had longer PFS with ripretinib vs sunitinib (median not estimable [NE] vs 11 months; HR = 0.56; 95% CI 0.28 to 1.12). Objective response rate (ORR) and overall survival (OS) were higher with ctDNA-ND vs ctDNA-D. Safety was similar between groups and consistent with the primary analysis. Conclusions: Pts with ctDNA-ND had better efficacy outcomes vs pts with ctDNA-D in both treatment arms; PFS was numerically higher with ripretinib vs sunitinib in pts with ctDNA-ND. Although little is known about the biology driving ctDNA in GIST, these data suggest pts may have improved outcomes and different treatment sensitivity based on ctDNA detectability. Clinical trial information: NCT03673501 . [Table: see text]

11524 Background: Ripretinib is a switch-control tyrosine kinase inhibitor approved for patients (pts) with gastrointestinal stromal tumor (GIST) who received prior treatment with ≥3 kinase inhibitors, including imatinib. Sunitinib is approved for advanced GIST after imatinib failure. In the first interim analysis (IA) for overall survival (OS) in the INTRIGUE trial, data were immature (OS event rate, 22.3%), and median OS was not reached in either arm for the KIT exon 11 intent-to-treat (ITT) and all-patient (AP) ITT populations (S Bauer, et al. J Clin Oncol. 2022). Additionally, ripretinib had a more favorable safety profile with fewer grade 3/4 treatment-emergent adverse events (TEAEs) than sunitinib. Here, we present the second IA of OS and updated safety from INTRIGUE. Methods: INTRIGUE is a global, open-label, phase 3 study that enrolled adult pts with advanced GIST who had disease progression on or intolerance to imatinib (NCT03673501). Randomization was 1:1 to ripretinib 150 mg once daily (QD) or sunitinib 50 mg QD (4 wks on/2 wks off) and was stratified by KIT mutational status and imatinib intolerance. OS was a key secondary endpoint; data cutoff for the second IA was Sept 1, 2022. Results: Of 453 pts in the AP ITT population, 444 received treatment; 51 remain on treatment (33/223 [14.8%] with ripretinib and 18/221 [8.1%] with sunitinib). Common reasons for treatment discontinuation were progressive disease (PD) assessed by independent radiologic review (55.4%), PD assessed by investigator (10.6%), clinical PD (5.9%), withdrawal of consent (5.4%), and adverse event (AE; 4.5%); fewer pts discontinued due to an AE for ripretinib vs sunitinib (2.7% vs 6.3%). Following study treatment discontinuation, 58 pts (25.6%) from the sunitinib arm received ripretinib; 139 pts (61.5%) from the ripretinib arm later received sunitinib. There were 185 OS events (40.8%) in the AP ITT population; median duration of follow-up was 28.7 and 28.5 months for ripretinib and sunitinib, respectively. OS was similar with ripretinib vs sunitinib in the AP ITT (median 35.5 vs 30.9 months; HR 0.88, 95% CI 0.66 to 1.18; nominal P = 0.39) and KIT exon 11 ITT populations (median 34.0 vs 31.5 months; HR 1.05, 95% CI 0.75 to 1.48; nominal P = 0.77). The updated safety profile was consistent with the primary analysis; fewer pts had grade 3/4 TEAEs with ripretinib vs sunitinib (95 [42.6%] vs 149 [67.4%]). Dose interruptions and reductions were lower with ripretinib vs sunitinib. The median (range) treatment duration was 7.9 (0.2–38.2) months for ripretinib and 6.5 (0.2–38.3) months for sunitinib. Conclusions: In the second IA from INTRIGUE, OS was similar between treatment arms. The safety profile remained consistent with additional data, and results demonstrate favorable safety with ripretinib in pts with advanced GIST previously treated with imatinib. Clinical trial information: NCT03673501 .

Abstract Background and purpose A heart age biomarker has been developed using deep neural networks applied to electrocardiograms. Whether this biomarker is associated with cognitive function was investigated. Methods Using 12‐lead electrocardiograms, heart age was estimated for a population‐based sample ( N = 7779, age 40–85 years, 45.3% men). Associations between heart delta age (HDA) and cognitive test scores were studied adjusted for cardiovascular risk factors. In addition, the relationship between HDA, brain delta age (BDA) and cognitive test scores was investigated in mediation analysis. Results Significant associations between HDA and the Word test, Digit Symbol Coding Test and tapping test scores were found. HDA was correlated with BDA (Pearson's r = 0.12, p = 0.0001). Moreover, 13% (95% confidence interval 3–36) of the HDA effect on the tapping test score was mediated through BDA. Discussion Heart delta age, representing the cumulative effects of life‐long exposures, was associated with brain age. HDA was associated with cognitive function that was minimally explained through BDA.

Abstract Objective The factors that influence seizure timing are poorly understood, and seizure unpredictability remains a major cause of disability. Work in chronobiology has shown that cyclical physiological phenomena are ubiquitous, with daily and multiday cycles evident in immune, endocrine, metabolic, neurological, and cardiovascular function. Additionally, work with chronic brain recordings has identified that seizure risk is linked to daily and multiday cycles in brain activity. Here, we provide the first characterization of the relationships between the cyclical modulation of a diverse set of physiological signals, brain activity, and seizure timing. Methods In this cohort study, 14 subjects underwent chronic ambulatory monitoring with a multimodal wrist‐worn sensor (recording heart rate, accelerometry, electrodermal activity, and temperature) and an implanted responsive neurostimulation system (recording interictal epileptiform abnormalities and electrographic seizures). Wavelet and filter–Hilbert spectral analyses characterized circadian and multiday cycles in brain and wearable recordings. Circular statistics assessed electrographic seizure timing and cycles in physiology. Results Ten subjects met inclusion criteria. The mean recording duration was 232 days. Seven subjects had reliable electroencephalographic seizure detections (mean = 76 seizures). Multiday cycles were present in all wearable device signals across all subjects. Seizure timing was phase locked to multiday cycles in five (temperature), four (heart rate, phasic electrodermal activity), and three (accelerometry, heart rate variability, tonic electrodermal activity) subjects. Notably, after regression of behavioral covariates from heart rate, six of seven subjects had seizure phase locking to the residual heart rate signal. Significance Seizure timing is associated with daily and multiday cycles in multiple physiological processes. Chronic multimodal wearable device recordings can situate rare paroxysmal events, like seizures, within a broader chronobiology context of the individual. Wearable devices may advance the understanding of factors that influence seizure risk and enable personalized time‐varying approaches to epilepsy care.

Abstract Surgical resection of early stage soft-tissue sarcomas (STS) is a potentially curative treatment; however, many STS tumors will recur. Predicting recurrence and survival outcomes for patients with early stage STS remains a challenge. In this study, we identify prognostic biomarkers from clinical and transcriptomic data form a large set of early stage STS. Primary tumor samples from 69 subjects with STS were sequenced using the Tempus xT targeted DNA and whole transcriptome next-generation sequencing platforms. The most common histologies included were liposarcoma (n=22), gastrointestinal stromal tumor (n=19), and leiomyosarcoma (n=12). As expected, high-grade tumors were associated with decreased DFS and OS times while tumor histology was only correlated with OS. Single sample gene set enrichment analysis (ssGSEA) values for seven Hallmark genesets were correlated with both DFS and OS; including pro-tumor survival pathways (p53, Apoptosis, TNF-α via NF-κB), tumor proliferation pathways (MTORC1, MYC Targets, Mitotic Spindle), and UV Response signaling. These pathways are associated with tumor proliferation as well as an immunosuppressive tumor microenvironment (TME). To assess the TME of these tumors we estimated immune cell infiltration using CIBERSORTx. Of the 22 cell types accounted for by CIBERSORTx, only elevated infiltration of M2 Macrophages were associated with poor DFS and OS. To further determine TME activation we assessed the expression of 74 known immune response associated genes. Only PDCD1 (PD-1) was associated with reduced DFS and OS times. Clustering on the nine variables identified here to correlate with both DFS and OS revealed two distinct clusters demonstrating similar histologies. While histologies were similar across clusters, cluster 2 exclusively included high-grade tumors while cluster 1 was made up of 57.4% high-grade tumors. Sub-classifying cluster 1 into low and high-grade subgroups demonstrated a stepped biomarker expression pattern associated with both tumor grade and cluster membership. Using established TME genesets, high-grade tumors demonstrated higher tumor proliferative scores than low-grade tumors, while cluster 2 tumors demonstrated increased tumor associated macrophage signaling. In a multivariable model, cluster membership outperformed tumor grade and histology as the only significant predictor of DFS or OS. Taken together, while tumor grade is a strong predictor of clinical outcomes following surgical resection in STS, immunosuppressive signaling patters may help to identify patients at the highest risk. Citation Format: Nathan David Seligson, Yan W. Asmann, Tariq Almerey, Steven Attia, Sanjay P. Bagaria. Immune-suppressive tumor microenvironment leads to poor survival following curative intent surgical resection in soft-tissue sarcomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 990.

The treatment of sarcoma necessitates a collaborative approach, given its rarity and complex management. At a single institution, multidisciplinary teams of specialists determine and execute treatment plans involving surgical, radiation, and medical management. Treatment guidelines for systemic therapies in advanced or nonresectable soft tissue sarcoma have advanced in recent years as new immunotherapies and targeted therapies become available. Collaboration between institutions is necessary to facilitate accrual to clinical trials. Here, we describe the success of the Midwest Sarcoma Trials Partnership (MWSTP) in creating a network encompassing large academic centers and local community sites. We propose a new model utilizing online platforms to expand the reach of clinical expertise for the treatment of advanced soft tissue sarcoma.

Background: We developed a deep learning algorithm that detects coronary artery calcium (CAC) score using 12-lead electrocardiograms (CAC- ECG). We tested the hypothesis that the output from the CAC-ECG algorithm would be associated with incident atherosclerotic cardiovascular disease (ASCVD) events and that the CAC- ECG would refine the AHA/ACC Pooled Cohort Equation’s (PCE) predictive capabilities. Methods: A community-based cohort of consecutive patients seeking primary care in Olmsted County, MN, between 1998-2000 with passive follow-up via record linkage. Inclusion was identical to the PCE. The original CAC-ECG was developed in 43,210 subjects yielding an AUC of 0.83. Herein, we used the CAC-ECG output to predict a high CAC (≥ 300). Primary outcome was ASCVD defined as fatal and non-fatal myocardial infarction and ischemic stroke, secondary outcome was Major Adverse Cardiovascular Events (MACE) further including PCI, CABG, and mortality. Events were validated in duplicate. Cox proportional hazard models adjusted for variables included in the PCE and were stratified to evaluate the effect of the CAC-ECG on PCE-predicted risk. Follow-up was truncated at 10 years for PCE analyses. Results: We included 24,793 subjects, mean ± SD age 53.9 ± 12.1, 52% women, 95% white. After 16.7±3.7 yrs follow-up, 2,366 (9.5%) had ASCVD and 3,401 (13.7%) had MACE. Risk of ASCVD and MACE increased with CAC-ECG probability quintiles, independent of risk factors, p for trend <0.001 ( Fig. A-B ). The CAC-ECG enhanced the predicted capabilities of the PCE across all ASCVD risk groups ( Fig. C ). Net reclassification improved 13.7% with comparable C-statistic from 0.77 vs. 0.78 for PCE and CAC-ECG. Conclusions: CAC-ECG was associated with ASCVD and MACE and improved PCE predicted risk. The CAC-ECG algorithm could identify individuals at risk in primary prevention; Unlike the PCE, the CAC-ECG can be applied without chart review or performing a computer tomography and may be reliably used retrospectively in cohorts with digitally stored ECGs.

Surgical treatment of pelvic sarcoma involving the bone is the standard of care but is associated with several sequelae and reduced functional quality of life (QOL). Treatment with photon and proton radiotherapy is associated with relapse. Carbon ion radiotherapy (CIRT) may reduce both relapse rates and treatment sequelae. The PROSPER study is a tricontinental, nonrandomized, prospective, three-arm, pragmatic trial evaluating treatments of pelvic sarcoma involving the bone. Patients aged at least 15 years are eligible for inclusion. Participants must have an Eastern Cooperative Oncology Group Performance Status score of two or less, newly diagnosed disease, and histopathologic confirmation of pelvic chordoma, chondrosarcoma, osteosarcoma, Ewing sarcoma with bone involvement, rhabdomyosarcoma (RMS) with bone involvement, or non-RMS soft tissue sarcoma with bone involvement. Treatment arms include (1) CIRT (n = 30) delivered in Europe and Asia, (2) surgical treatment with or without adjuvant radiotherapy (n = 30), and (3) proton therapy (n = 30). Arms two and three will be conducted at Mayo Clinic campuses in Arizona, Florida, and Minnesota. The primary end point is to compare the 1-year change in functional QOL between CIRT and surgical treatment. Additional comparisons among the three arms will be made between treatment sequelae, local control, and other QOL measures.