Citations

Abstract INTRODUCTION Robust plasma-based biomarkers to distinguish Lewy body disease (LBD) and Alzheimer’s disease (AD) are currently lacking. We applied track-etch magnetic nanopore (TENPO) sorting for enrichment of brain-derived extracellular vesicle (EV) signatures as potential biomarkers to address this gap. METHODS We analyzed plasma from 137 autopsy-confirmed patients [30 LBD, 31 AD, 30 AD/LBD, 19 AD with amygdala Lewy bodies (AD/ALB), and 27 controls], sequencing miRNAs from TENPO-isolated GluR2-positive (neuron-enriched) and GLAST-positive (astrocyte-enriched) EVs, and measuring plasma proteins (Aβ40, Aβ42, tau, p-Tau181, p-Tau231) via SIMOA. RESULTS We identified 16 GluR2+, 8 GLAST+, and 4 protein biomarkers with differential expression (false discovery rate-corrected P value < .1) between LBD and AD. A multimodal 15-feature panel classified LBD versus AD with 10-fold cross-validated accuracy = 0.95 and area under the curve (AUC) = 0.96. DISCUSSION Brain-derived EVs offer accurate and accessible miRNA biomarkers for the differential diagnosis of LBD and AD.

Abstract Femtech, a sector dedicated to the development of technologies addressing women's health issues, holds significant potential to revolutionize healthcare for women. This study provides an overview of current Femtech solutions tailored to meet the unique needs of women. It analyzes the present landscape, highlighting key areas where artificial intelligence (AI) and generative technologies have made substantial impacts. Furthermore, the study explores strategies to foster future growth and broader adoption of Femtech within the healthcare sector with a glance at Artificial Intelligence. The ultimate objective is to advance the development of more effective, personalized, accessible, and equitable healthcare solutions for women. The study will review and categorize 56 women’s health-related applications and devices currently available on the US market, identifying existing gaps and areas for potential improvement.

Abstract Background: mTOR activation is associated with chronic inflammation in ME/CFS. Previous studies have shown that sustained mTOR activation can cause chronic muscle fatigue by inhibiting ATG13-mediated autophagy. This highlights the pivotal role of mTOR in the pathogenesis of ME/CFS. Methods: We conducted a decentralized, uncontrolled trial of rapamycin in 86 patients with ME/CFS to evaluate its safety and efficacy. Low-dose rapamycin (6 mg/week) was administered, and core ME/CFS symptoms were assessed on days 30 (T1), 60 (T2), and 90 (T3). Plasma levels of autophagy metabolites, such as pSer258-ATG13 and BECLIN-1, were measured and correlated with clinical outcomes, specifically MFI. Results: Rapamycin (6 mg/week) was tolerated without any SAEs. Of the 40 patients, 29 (72.5%) showed strong recovery in PEM, fatigue, and OI, along with improvements in MFI fatigue domains and SF-36 aspects. High levels of BECLIN-1 were detected in T3. Plasma pSer258-ATG13 levels were strongly downregulated at T1. Spearman’s correlation analysis indicated an association between autophagy impairment and reduced activity. Conclusions: Low-dose rapamycin effectively reduced PEM and other key symptoms in patients with ME/CFS, as measured by BAS, SSS, MFI, and SF-36. Future studies should encompass dose optimization and develop a diagnostic tool to identify responders with mTOR-mediated autophagy disruption.

PURPOSE Continued improvement in outcomes is needed for advanced cutaneous squamous cell carcinoma (cSCC). Methods Alliance A091802 is a randomized phase II trial of avelumab (800 mg IV once every 2 weeks) plus cetuximab (500 mg/m 2 IV once every 2 weeks) versus avelumab alone once every 2 weeks for up to 2 years. Cetuximab was given for 1 year in the avelumab + cetuximab arm. Crossover at progression to avelumab + cetuximab was allowed. Randomization was 1:1, stratified by PD-L1 and HIV status. Patients had distant metastatic or unresectable locally advanced cSCC, were anti–PD-1/PD-L1 monoclonal antibody–naive, had no previous cetuximab in the advanced setting, had an Eastern Cooperative Oncology Group performance status of 0-2, and could be HIV+ (CD4 >200, viral load <200). Patients with chronic lymphocytic leukemia, immunosuppression, or active autoimmune diseases were excluded. The primary end point was progression-free survival (PFS; null hypothesis: median = 12 months v alternative hypothesis: 21 months or a 75% improvement, power of 80% with one-sided alpha .2, n = 57, 37 PFS events required). Secondary end points were overall survival, objective response rates (ORRs), clinical benefit rate, and toxicity. RESULTS Sixty patients were enrolled; 57 patients were evaluable. The median age was 72 years, all were HIV–; 75.4% was PD-L1+, 84.2% had head/neck origin, 47.4% had distant metastasis, and there were no differences in baseline characteristics by arm. Avelumab + cetuximab significantly improved PFS versus avelumab (median, 11.1 [7.6-not reached (NR)] v 3.0 months [2.7-13.6] hazard ratio, 0.48 [95% CI, 0.23 to 0.97], P = .018). Avelumab patients who crossed over (n = 9) to combination had a median PFS after crossover of 11.3 months (5.8-NR). The confirmed ORR was 27.6% with avelumab + cetuximab and 21.4% with avelumab. Grade 3 treatment-related adverse events occurred in 48.3% and 21.5% of patients with avelumab + cetuximab (most common: rash [20.7%], infusion reaction [20.7%]) and avelumab, respectively. CONCLUSION Avelumab + cetuximab significantly improved PFS versus avelumab alone in patients with advanced cSCC. Alliance A091802 supports a larger confirmatory study with the combination of cetuximab and PD-1:PD-(L)1 blockade.

11507 Background: Advanced uterine leiomyosarcoma (uLMS) is an aggressive malignancy with poor prognosis. Standard-of-care treatments, including trabectedin (Tb) or pazopanib (P), provide median progression-free survival (PFS) of 3-4 months (mo) and objective response rates (ORR) of ~11%. Homologous recombination deficiency (HRD) in a subset of uLMS supports the use of PARP inhibitors combined with DNA-damaging agents. Preclinical studies demonstrated synergistic activity of olaparib and temozolomide (T+O), and a prior single-arm Phase II study of T+O showed promising efficacy independent of an established biomarker, warranting further investigation in a randomized setting. Methods: Alliance A092104 is a Phase II/III trial evaluating olaparib (200 mg BID) plus temozolomide (75 mg/m² daily, days 1-7, every 21 days) versus investigator’s choice of Tb or P in patients (pts) with advanced uLMS who progressed on ≥2 prior systemic therapies. Stratification factors included ECOG (0-1 vs. 2) and prior lines (2 vs. ≥3). The Phase II (Phase III) primary endpoint was PFS (OS), with a planned suspension of accrual at the end of Phase II. A total of 70 evaluable pts (58 PFS events) were needed to detect an improvement in PFS from 4 vs. 8 mo with power of 90% and 1-sided type I error of 10%, with futility assessed after 29 PFS events. Upon meeting the Phase II futility threshold for PFS, the trial was permanently closed. Data were released from the data and safety monitoring board. Pts continue to be followed for outcomes. Results: 74 pts enrolled (Arm 1: T+O, n = 37; Arm 2: investigator’s choice, n = 37 (Tb, 18; P, 13; 6 pts did not start treatment). The arms were balanced for baseline demographics except race, with the T+O arm having a higher proportion of black/African American (29.7% vs. 16.2%). 21 pts remain on treatment. Hematologic adverse events (AEs) were more frequent in the T+O arm, with Grade 4 neutropenia (19.5%) and thrombocytopenia (8.3%) both managed by dose reductions. Non-hematologic Grade 3 AEs were higher in the investigator’s choice arm (45.2% vs. 13.9%). No Grade 5 AEs were reported. In the first 70 pts, with a median follow-up of 5.9 mo, and 39 total PFS events, the median PFS was 3.2 mo (95% CI: 2.0-NE) for T+O versus 5.6 mo (95% CI: 2.8-NE) for investigator’s choice (HR = 1.00; 95% CI: 0.60-2.17; 1-sided stratified log rank p = 0.50). Within Arm 2, the median PFS for Tb and P were respectively 5.6 (95% CI: 3.1-NE) and 3.8 (95% CI: 1.5-NE) mo. 3 pts in the T+0 arm and 1 patient in the investigator’s choice arm (Tb) had a confirmed partial response. Conclusions: The trial did not meet its primary endpoint of PFS in Phase II. This suggests that a biomarker may be needed before there is further exploration of PARP inhibitor-based regimens in uLMS. Overall survival and analysis of tissue-based biomarkers will be presented. Clinical trial information: NCT05432791 .

1114 Background: While treatment and management of TNBC has improved, there is a need for novel prognostic biomarkers to better inform outcomes and guide therapeutic options. ILF2 is a poorly characterized protein with pleiotropic functions that is highly expressed in TNBC. Here we evaluated the associations of ILF2 with 1) genomic and transcriptomic data, 2) tumor microenvironment (TME), and 3) clinical outcomes in TNBC. Methods: 15,544 breast cancer (BC) samples, including 3,038 TNBC, were tested by NGS (592, NextSeq; WES, NovaSeq) and WTS (NovaSeq; Caris Life Sciences, Phoenix, AZ). ILF2 -high (H) and ILF2 -low(L) TNBC were defined by respective quartiles. Immune cell fractions were estimated by WTS deconvolution (Quantiseq). Real world overall survival (OS) was obtained from insurance claims and calculated from tissue collection to last contact using Kaplan-Meier estimates. Statistical significance was determined by chi-square, Fisher’s exact, and Mann-Whitney U test with p-values adjustments (q < .05). Results: ILF2 expression (median Log2(TPM+1) was higher (all q < .05) in key subgroups: ductal compared to lobular carcinoma (6.4 vs 6.0); primary compared to metastatic BC (6.4 vs 6.3); African American compared to White (6.4 vs 6.3); basal compared to luminal A, luminal B, HER2 PAM50 subtypes (6.9 vs 5.8, 6.3, 6.3); and TNBC compared to HR+HER2+, HR-HER2+, HR+HER2- subtypes (6.7 vs 6.3, 6.4, 6.2). Biopsied tissues from primary TNBC (pTNBC) and metastatic TNBC (mTNBC) patients were stratified into ILF2- H and ILF2- L groups. In both mTNBC and pTNBC, ILF2- H groups had 1) higher percentage of young patients (age < 50) (pTNBC: 35.5% vs 19.8%; mTNBC: 28.1% vs 17.3%; all q < .05); 2) higher mutation frequency of TP53 (pTNBC: 94.5% vs 79.6%; mTNBC: 92.4% vs 74.4%), but lower frequencies for PIK3CA ( pTNBC: 5.1% vs 23.4% , mTNBC: 8.8% vs 27.4%), CDH1 ( pTNBC: 0.8% vs 6.1%; mTNBC: 2.8% vs 12.2%; all q < .05); 3) higher infiltration of NK cells (pTNBC: 3% vs 2.6%; mTNBC: 2.8% vs 2.6%), but lower infiltration of M2 Mφ (pTNBC: 2.5% vs 3.3%; mTNBC: 2.6% vs 3.2%) and Tregs (pTNBC: 1.5% vs 1.9%; mTNBC: 1.4% vs 1.7%; all q < .05); 4) higher expression levels of immune checkpoint ( CD274, PDCD1LG2, CTLA4, LAG3, HAVCR2, FOXP3, IDO1, CD276 , FC: 1.2-3.1; all q < .05), stem cell genes (C D44, NANOG, POU5F1, KLF4, ALDH1A1 , FC: 1.4-2.4; all q < .05), and drug efflux genes ( ABCC3, ABCC11, ABCC2, ABCB1, ABCG2, ABCC1 , FC: 1.1-4.5; all q < .05) compared to ILF2- L group. In pTNBC, ILF2- H had significantly shorter OS vs ILF2- L group (22.3 vs 28.9 months, HR 1.2 [95% CI 1-1.5], p = .03), but no significant differences were observed between mTNBC ILF2 groups (HR 1.1 [95% CI 0.93-1.3], p = .2). Conclusions: ILF2 -H TNBC patients showed differential genomic and transcriptomic alterations that relate to therapy resistance, immune suppressive TME, and shorter OS. Further studies are warranted to validate the effects of ILF2 upregulation on therapeutic efficacy.

1107 Background: Chronic stress-mediated β2-adrenergic receptor (β2-AR) signaling promotes tumor growth via immunosuppression in the tumor microenvironment (TME) in preclinical models. Blockade of β2-AR has shown higher survival benefit in patients with TNBC in observational studies compared to other breast cancer (BC) subtypes. However, the molecular and immunological features associated with ADRB2 (gene for β2-AR) gene expression in TNBC are unknown, prompting this investigation. Methods: 3,038 TNBC samples were analyzed via NGS (592-gene panel, NextSeq; WES/WTS, NovaSeq; Caris Life Sciences, Phoenix, AZ). Immune cell fractions were calculated by deconvolution of WTS: Quantiseq. TNBC ADRB2 -high(H) and ADRB2 -low(L) RNA expression were classified as above or below the 50 th percentile, respectively. Real-world overall survival (OS) was obtained from insurance claims and calculated from tissue collection to last contact using Kaplan-Meier estimates. Statistical significance was assessed using chi-square and Mann-Whitney U tests with multiple comparison adjustments (q < 0.05). Results: ADRB2 gene expression was lowest in TNBC (median (TPM: 1.6) compared to N = 453 HR-HER2+ (1.9), N = 629 HR+HER2+ (2.0) and N = 4,918 HR+HER2- (2.2) BC (all q < 0.05). African American or Black patients (N = 670) had lower expression of ADRB2 compared to European American or White (N = 1,412) TNBC patients (1.3 vs 1.7, q < 0.05). ADRB2 -H TNBC had higher mutation frequency of PIK3CA (21% vs 15.4%), CDH1 (7% vs 3.5%), NF1 (8% vs 4%), AKT1 (3.5% vs 2.1%), but lower frequency of TP53 (81.6% vs 87.5%), NOTCH1 (2.5% vs 4.5%) and NOTCH3 (4.4% vs 11.7%) compared to ADRB2 -L, all q < 0.05. ADRB2 -H had greater PD-L1 (22C3) positivity (39.1% vs 30.2%, q < 0.05), higher % of B cells (4.5 vs 3.4), M1 Mφ (3.4 vs 2.8), M2 Mφ (3.9 vs 2.2), Tregs (2.2 vs 1.3), NK cells (3.1 vs 2.6), DC (3.1 vs 2.9), CD8 + T cells (0.9 vs 0.2), all q < 0.05. ADRB2 -H TNBC had higher T-cell inflamed score (95 vs -80), IFN γ score (-0.23 vs -0.37), MAPK activation score (-0.46 vs -1.7), all q < 0.05; and higher expression of immune checkpoint genes ( CD274, PDCD1, PDCD1LG2, CTLA4, LAG3, HAVCR2, FOXP3, IDO1, TNFSF14, TIGIT, BTLA, CEACAM1, CD47, CD274 ; fold change: 1.6-3.7, all q < 0.05). ADRB2 -H tumors had higher expression of genes related to inflammatory response, IFNγ response, IL6-JAK-STAT3 signaling (normalized enrichment score (NES): 1.9 – 2.1), while ADRB2 -L had enrichment of MYC targets V1, MYC targets V2, E2F targets and G2M checkpoint (NES: 2.5 – 4.2), all FDR < 0.01. ADRB2 -H TNBC had better OS (mOS: 23.6 vs 18.6 months; HR 0.81, 95% CI 0.73-0.89, p < 0.0001) compared to ADRB2 -L. Conclusions: High ADRB2 expression in TNBC is associated with better survival and an immune enriched TME, elevated immune checkpoints and other targetable vulnerabilities. Future studies are needed to investigate ADRB2 as a potential stress biomarker and therapeutic target.

6002 Background: There is a need for continued improvement in outcomes with systemic therapy for advanced cSCC. Pre-clinical data suggest immunologic synergy between IgG1 mAb therapy targeting EGFR and PD-1:PD-(L)1 blockade. Methods: Alliance A091802 is a randomized phase II trial of avelumab (AV) (800 mg) plus cetuximab (C) (500 mg/m2) vs. AV alone every 2 weeks for up to 2 years (yrs). C was given for 1 yr in the AV+C arm. Crossover at progression to AV+C was allowed in the AV arm. Randomization was 1:1 and stratified by PD-L1 [+(>1%) vs. -] and HIV status (+ vs. -). Eligible patients (pts) had distant metastatic or unresectable locally advanced cSCC, anti-PD-1/PD-L1 mAb naive, no prior cetuximab in the advanced setting, ECOG PS 0-2, HIV+ if CD4 >200 and VL <200. Pts with CLL, immunosuppression, or active autoimmune diseases were excluded. The primary endpoint was progression-free survival (PFS) (Ho: Median=12 mo vs Ha: 21 mo or a 75% improvement, power of 80% with one-sided alpha 0.2, n=57, 37 PFS events required). Secondary endpoints were overall survival (OS), confirmed response rate (ORR), clinical benefit rate, and toxicity. After 31/37 events, an early unplanned analysis (along with sensitivity analyses) was performed because it became apparent that 37 events would not be reached. These results were submitted to the Alliance Data and Safety Monitoring Board, which recommended releasing the data. Data cutoff was 1/16/25. Results: 60 pts were enrolled between 2019-2023; 57 pts were evaluable. Median age was 72 yrs (41‒93), 96.5% were white, 91.2% male, all HIV-; 75.4% PD-L1+. 84.2% were head/neck origin, 47.1% had distant metastasis, and there were no differences in baseline characteristics by arm. AV+C significantly improved PFS compared to AV [median 11.1 months (mo) (7.6‒not reached (NR)) vs. 4.8 mo (2.8‒NR) hazard ratio (HR) 0.53 95% CI (0.26‒1.09), one-sided p=0.041]. The median OS of AV+C vs. AV was NR (25.2‒NR) vs. 35.8 mo (18.6‒NR) HR 0.77 (0.33‒1.78) p=0.267. ORR was 31.0% in the AV+C arm and 21.4% in the AV arm. Treatment-related adverse events (TRAE) of any grade (G) occurred in 93% and 78.6%, respectively, and were G>3 in 48.3% and 21.5% of pts in the AV+C [most common G3 TRAEs were rash (20.7%) and infusion-related reaction (20.7%)] and AV arms, respectively. There were no G5 events. Outcomes after crossover and by PD-L1 status will be presented subsequently. Conclusions: Avelumab plus cetuximab significantly improved PFS vs. avelumab alone in advanced cSCC pts, without unexpected toxicity. Alliance A091802 supports a larger confirmatory study with combination cetuximab and PD-1:PD-(L)1 blockade. Support: U10CA180821, U10CA180882, U24CA196171; U10CA180868 (NRG Oncology); U10CA180888 (SWOG); https://acknowledgments.alliancefound.org . EMD Serono CrossRef Funder ID: 10.13039/100004755. Clinical trial information: NCT03944941 .

e15024 Background: Anetumab ravtansine (AR) is an antibody-drug conjugate (ADC) containing the microtubule inhibitor DM4. ADC drugs have high interpatient variability in pharmacokinetics and pharmacodynamics (PK/PD), which raises concerns whether current dosing based on body weight (mg/kg) is optimal. Thus, we evaluated the effects of patient characteristics, including novel biomarkers of the innate immune system (IIS), on the PK/PD of AR. Methods: Studies were performed in patients in three clinical trials of different cancers with AR as part of treatment: 1) platinum-resistant or refractory high-grade ovarian cancer treated with AR at 2.2mg/kg IV weekly plus bevacizumab(N = 19); 2) pleural mesothelioma treated with AR at 6.5 mg/kg IV every 3 weeks plus pembrolizumab(N = 28); and 3) mesothelin-positive advanced pancreatic adenocarcinoma treated with AR at 5.5-6.5 mg/kg IV every 3 weeks plus nivolumab (and ipilimumab or gemcitabine, N = 27). Intensive plasma PK sampling was performed after the first dose to calculate clearance (CL), volume of distribution (Vd), and area-under-the-plasma-concentration-time curve (AUC 0-inf ). The relationship between biomarkers of FcɣRs (CD64, CD32, CD16) on IIS blood cells, total body weight (TBW), body surface area (BSA), lean body mass (LBM), and sex with PK parameters and clinical outcomes were evaluated by pearson correlation, t-test and multivariate regression analysis. Population PK (popPK) methods further evaluated patient covariates and variability in PK. Results: Patients with higher IIS FcγR CD64 and/or higher TBW or higher BSA had higher AR ADC CL (p < 0.05). AR ADC CL was lower in females (0.030 ± 0.007 L/h) versus males (0.042 ± 0.006 L/h) (p < 0.05). Patients with stable disease and partial response had higher AR ADC AUC 0-inf versus patients with progressive disease AR ADC disposition was described by linear CL with two pathways for the release of the payload DM4, hydrolysis and the IIS. A time-varying drug-to-antibody ratio predicted the release of the DM4 payload. In the PopPK model, LBM and albumin were associated with CL of the AR ADC, LBM and IIS FcγR CD64 were associated with the Vd of the AR ADC, and LBM and age were associated with the CL of the released DM4. Conclusions: These results suggest that TBW-based dosing of AR ADC is not optimal, whereas precision dosing of antibodies and ADCs based on the use of novel metrics of body habitus, IIS biomarkers, and sex may be more appropriate to reduce PK variability and improve response.

4516 Background: Ipilimumab/nivolumab (ipi/nivo) is a standard of care first-line treatment (tx) for patients (pts) with mccRCC; however, ideal timing of subsequent immunotherapy txs are not well defined. We performed an analysis of patients initially treated with ipi/nivo and subsequent cohort assignments on PDIGREE (A031704). Methods: The PDIGREE trial treated pts with IMDC intermediate/poor risk mccRCC with first-line ipi/nivo (Step 1) at NCTN sites (categorized as academic (A), academic regional (R), and community (C)). Subsequent management was based on iRECIST responses at 12 weeks: pts with complete response (CR) received 1-year nivo maintenance; pts with progressive disease (PD) received cabozantinib (cabo) monotherapy, pts with non-CR/non-PD were randomized to nivo with or without cabo (for primary endpoint of overall survival [OS], target sample size was 1175). Enrollment was held when the randomized sample target was reached. Pts with unresolved toxicity at week 22 were managed off protocol. Step 1 pt demographics, assignments into Step 2, and adverse event (AE) data are presented. Descriptive statistics were used, and cohorts were compared using a chi-square test. These data were released with DSMB approval and do not inform the primary OS endpoint (1EP). Results: From May 2019 to May 2024, 1111 pts were enrolled and treated with ipi/nivo. Pt characteristics included median age 64.0 years (range 29.0-86.0); 819 (73.7%) males; White (85.1%), Hispanic (10.4%), Black (4.2%), and American Indian/Native Hawaiian (1.3%); 849 (76.8%) intermediate risk/257 (23.2%) poor risk; 458 (41.2%) at Academic, 113 (10.2%) at Regional, and 540 (48.6%) at Community centers; and 603 (54.3%) with de novo metastases. 364 pts (33%) stopped tx in Step 1: 160 (44%) for AEs, 46 (13%) for PD/clinical PD/suspected PD, 42 (12%) withdrawals, 39 (11%) alternative txs, 37 (10%) deaths on the study, 12 (3%) other complicating disease, 8 (2%) MD decision and 19 (5%) other reasons. Of the 37 deaths, 15 (1.4%) grade 5 SAEs were reported, 6 of which were due to PD. Of 747 (67%) pts registered to Step 2 at 3 months, 9 (1.2%) achieved CR, and 141 (18.9%) pts were assigned to the PD cohort. 597 pts (80%) were randomized for the 1EP, notable with fewer pts with poor risk [(21 vs 27%, p = 0.01] and bone metastases [24.5% vs 34.2%, p = 0.0007] compared to Step 1 pts who discontinued tx. Gr 3/4 tx-related AEs in 314/1093 (29%) evaluable pts included diarrhea/colitis (8%), transaminase elevation (3%), rash (2%), adrenal insufficiency (2%), fatigue (2%), and hypophysitis (1%). Conclusions: The PDIGREE trial enrolled a representative US-based population with mccRCC. Step 1 pt characteristics and associated outcomes with induction ipi/nivo reveal new insights into the tolerability and tx response of 1L ipi/nivo. Clinical trial information: NCT03793166 .