Post-liver transplant complications-cancer, infections, and renal dysfunction-impose substantial clinical and economic impact on recipients. This study evaluated clinical impacts and cost-effectiveness of adding everolimus (EVR) to a calcineurin inhibitor (CNI)-based regimen in liver transplant recipients, aiming to identify how co-occurring major complications affect cost-effectiveness. We conducted a cohort analysis and a cost-utility analysis, dividing recipients into CNI with and without EVR groups. We calculated adjusted hazard ratios (HRs) for the risk of cancer and posttransplant infection with EVR combination therapy using a Cox regression model. A Markov model that captured the co-occurrence of liver disease, infection, and renal dysfunction was constructed to estimate costs and quality-adjusted life years (QALYs) and compare the incremental cost-effectiveness ratio (ICER) of adding EVR to CNI. A hypothetical cohort of 10 000 liver transplant recipients aged 55 y was simulated during 30 y. The addition of EVR significantly reduced the risk of cancer (HR 0.435; 95% confidence interval 0.279-0.678) while increasing the infection risk in subsequent years (HR 1.468; 95% confidence interval 1.053-2.045). Cost-utility analysis demonstrated the CNI with EVR strategy was cost-effective, with an ICER of US$5298/QALY, well below the $25 000/QALY threshold. In analyses quantifying how co-occurring events shift value, the ICER was $9307/QALY when limited to liver disease, decreased to $4363/QALY with renal dysfunction included, and increased to $10 464/QALY when infection was added. Overall, CNI with EVR regimen in liver transplant remained cost-effective across co-occurring outcomes and perspectives, supporting risk-benefit balancing across cancer, posttransplant infection, and renal function.

Deferiprone mitigates imidacloprid-induced neurotoxicity: Roles of iron chelation, ferroptosis, and ferritinophagy.

Abstract Background: ESR1 mutations (e.g.Y537S and D538G) drive ligand-independent ER activation and resistance in ER-positive breast cancer. (Z)-Endoxifen, the active tamoxifen metabolite, inhibits ER signaling, but its impact on ESR1-mutant signaling and therapy-resistant disease is not yet fully defined. Methods: HEK293T cells were transfected with ESR1-WT or mutant plasmids together with an ERE-luciferase reporter and Renilla control. After 24 h, cells were treated with endoxifen, elacestrant (10 µM-0.01 nM), or 0.1% DMSO for an additional 24 h. Firefly luciferase activity was normalized to Renilla, and mean ± SD values from three independent experiments were used to generate dose-response curves. Transcriptomic analyses of 166 ESR1 Y537S and 45 ESR1-WT MCF-7 samples from PandaOmics were performed, and differential expression after endoxifen treatment was assessed using 27 treated and 25 untreated samples processed with limma and gseapy. Plasma and tumor samples were extracted by methanol precipitation with deuterated endoxifen-d5 and quantified by UPLC-MRM on a Poroshell 120 EC-C18 column using a six-point calibration curve. Results: (Z)-Endoxifen (ENDO) and elacestrant (ELAC) both produced dose-dependent inhibition of ER signaling in wild-type and mutant ESR1 constructs. At 100 nM, ENDO and ELAC showed comparable suppression of WT and three common ESR1 mutants, consistent with the ∼80 nM steady-state ENDO plasma level in women taking 20 mg tamoxifen. At higher doses, ENDO more effectively inhibited Y537S and D538G than ELAC. Transcriptomic analyses revealed that ENDO reversed key mutant-associated transcriptional programs in MCF-7 cells. ENDO significantly downregulated estrogen response, apoptosis, E2F-target, and Myc-target pathways while restoring oxidative phosphorylation, xenobiotic and fatty acid metabolism, p53 signaling, and DNA repair (FDR < 0.05). Transcription factor enrichment showed suppression of resistance-associated POU5F1 and SOX11, and reactivation of FOXA1, ELF3, and SPDEF. ENDO also reduced expression of three genes (MTMR7, IL20, CA12) from a six-gene poor-prognosis ESR1-mutant signature. In the ongoing EVANGELINE phase 2 trial (NCT05607004), mean (Z)-endoxifen plasma levels at 40 mg/day reached 278.5 ng/mL (≈746 nM). Conclusion: In summary, (Z)-endoxifen and elacestrant both suppress ER-dependent transcription in ESR1-WT and mutant models, and clinically relevant (Z)-endoxifen concentrations are sufficient to inhibit mutant ESR1 activity. Endoxifen additionally reprograms key transcriptional and metabolic pathways associated with ESR1-mutant resistance and metastasis. These results support further evaluation of (Z)-endoxifen’s pathway-level effects in ESR1-mutant breast cancer, and ongoing studies are testing its ability to block mutant ESR1-driven proliferation in preclinical models. Citation Format: Sandra Suarez Hammer, Alina Ustiugova, Anastasia Shneyderman, Alexander Veviorskiy, Khadija M. Alawi, Mikhail Korzinkin, Lucia Beaulieu, Hayley Erickson, Scott M. Blackburn, H. Lawrence Remmel, Steven Quay. Mechanistic characterization of (Z)-endoxifen in ESR1-mutant and endocrine-resistant breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1784.

Immunosuppressive therapies increase the risk of infection, but there is little information regarding their effects on cellular antimycobacterial activity. In this context, the aim was to evaluate in vitro the impact of commonly used immunosuppressive drugs on the ability of peripheral blood mononuclear cells (PBMCs), neutrophils (polymorphonuclear cells, PMNs), and monocyte-derived macrophages (MDMs) to control Mycobacterium abscessus. Biofilm formation was assessed by quantifying bacterial colonies in cellular cultures (BCCCs) and bacterial viability by colony-forming units (CFUs). BCCCs showed significant differences among treatment conditions in PBMCs. The median (interquartile range) BCCC values for tacrolimus (TAC) 16.5 (41), everolimus (EVE) 11 (33), methotrexate (MTX) 12.5 (22) and leflunomide (LEF) 11 (29) were all significantly higher than the negative control (DMSO) 5 (14), indicating that these immunosuppressants impaired the ability of PBMCs to restrict BCCC formation. Log-transformed CFUs also varied across treatments in PMNs. Mycophenolic acid (MPA) 5.98 (2.61) and EVE 5.85 (2.77) increased LogCFU recovery compared with DMSO 5.58 (2.63), whereas MTX 5.18 (2.74) decreased it. In contrast, immunosuppressants had no significant overall effect in MDM cultures. Interestingly, 6-mercaptopurine (6MP) affected the size of colonies. Prednisolone, as expected, but also MTX and LEF, inhibited the expression in infected PBMCs of IL-1β, IL-1Ra, IL-6, CCL3, CCL5, CXCL8 and TIMP-2, whereas IL-10, CCL2 and CXCL7 expression remained essentially unchanged. Unexpectedly, methotrexate promoted CXCL8 expression, a chemokine for PMNs. These results show that commonly used immunosuppressive drugs can differentially modulate the antimycobacterial activity of PBMCs and innate immune cells, affecting both mycobacterial viability and biofilm formation.

Abstract Background: Everolimus (EV) and alpelisib (AL), both approved for treating HR+/HER2- Metastatic Breast Cancer (MBC), inhibit different steps of the PI3K/AKT/mTOR (PAM) pathway. They share unique side effects (SE), many of which are considered class effects (e.g., hyperglycemia). It is unclear if the emergence of an SE during a PAM inhibitor (PAMi) treatment predicts the risk of the same SE during subsequent PAMi treatment. Such cross-incidence (CrIn) of SEs across PAMi is understudied and could help predict and prevent SEs. Similarly, the efficacy of a PAMi on a tumor resistant to a different PAMi hasn’t been well established, as these tumors are excluded from new PAMi clinical trials. Methods: The objectives of the study were to assess 1. CrIn of important AEs between AL and EV; 2. efficacies of AL after treatment with EV and vice versa, among patients with HR+/HER2- MBC. A retrospective study was conducted in 3 U.S. cancer institutes (Wilmot, Roswell Park, Duke). Patients with HR+/HER2-MBC with PIK3CA mutation who received both drugs were included. Groups (grps) were defined based on the PAMi sequence: EV followed by AL (EV-AL) or reverse, AL-EV. Progression-free survival (PFS) and Overall Survival (OS) were estimated using Kaplan-Meier method and compared between grps using log-rank test. Survival analyses were conducted for the 2nd PAMi in the sequence. Multivariable analyses were done using Cox Models. Results: Of 55 pts screened, 46 were eligible: 30 in EV-AL and 16 in AL-EV grp. Baseline (at start of 2nd PAMi) variables were similar between the grps. Median age (years) was 64 in EV-AL grp, 65 in AL-EV grp. 70% of EV-AL grp and 81% of AL-EV grp were white. 47% of EV-AL grp and 56% of AL-EV grp had visceral disease. 77% of EV-AL grp and 79% of AL-EV grp had ECOG performance status 0-1. 97% of EV-AL and 100% of AL-EV grp had prior CDK4/6 inhibitors. 23% of EV-AL grp and 12% of AL-EV grp had >2 lines of prior chemotherapy for MBC. Median AL use was 5.3 months (m) in EV-AL grp vs 4.5m in AL-EV grp (p= 0.15); Median EV use was 6.3m in EV-AL grp vs 3.8m in AL-EV grp (p=0.76). Fulvestrant was the most common endocrine therapy with AL (90% in EV-AL, 94% in AL-EV) vs exemestane with EV (67% in EV-AL, 75% in AL-EV). Overall, hyperglycemia (hypG) was the most common SE with AL (65%), followed by diarrhea (38%), rash (20%), and stomatitis (20%). On EV, patients had diarrhea (16%), stomatitis (16%), rash (14%) and hypG (11%). In EV-AL grp, among the 3 pts who had developed hypG on EV, all 3 developed hypG on AL (100% CrIn). CrIn of rash, diarrhea & stomatitis on AL after developing them on EV were 50%, 20% and 33% respectively. In AL-EV, CrIn of hypG, rash, diarrhea, & stomatitis on EV after having them on AL were 10%, 0%, 25%, & 33% respectively. Comparing the efficacy of 2nd PAMi among the grps, median PFS on AL was 6.9m (95% CI 4.2–10.8) in EV-AL grp vs 7.4m (95% CI 3.5–23.1) on EV in AL-EV grp (p=0.64). In multivariable analysis, risks of PFS event on 2nd PAMi were not significantly different between grps [Hazard ratio (HR) 0.95 (95% CI 0.37-2.4) p=0.91]. Median OS on AL was 15.9m (12.4-34.2) in EV-AL grp vs that on EV was 20.1m (13.2-46.7) in AL-EV grp (p=0.84). In multivariable analysis, the risks of death after starting 2nd PAMi were not significantly different between grps [HR 0.92 (95%CI 0.39-2.17), p=0.85]. Conclusion: This study has assessed CrIn of SEs across EV and AL use. Notably, all patients who developed hypG and half who developed rash on EV also developed them again on AL. These CrIn results could help clinicians use preemptive strategies (like metformin, topical steroids) while using 2nd PAMi. AL and EV therapy were each associated with mPFS >6m when used as 2nd PAMi, suggesting meaningful activity. No significant differences were observed in PFS or OS between these two drugs when used as the 2nd PAMi. Further validation of efficacy and CrIn of SEs is needed in a larger dataset. Citation Format: A. Dhakal, A. Shrestha, Z. Shah, S. Chinniah, A. Roy, T. Smith, S. Gandhi, H. Moore, A. Van Swearingen, M. Strawderman, D. Peterson, C. Anders, R. O'Regan. Comparing Cross-Toxicities and Efficacy of Everolimus and Alpelisib in Different Sequences in Metastatic Breast Cancer Patients [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-06-05.

Abstract Background: Premenopausal women represent nearly 30% of patients (pts) with ER+/HER2- early breast cancer (EBC). Ovarian function suppression (OFS) in combination with tamoxifen or aromatase inhibitors improves disease-free survival but has limitations such as toxicity, suboptimal estrogen suppression, and poor adherence. Elacestrant (ELA) showed superior efficacy vs standard endocrine therapy (ET) in pretreated pts with ER+/HER2- metastatic breast cancer. Mechanistically, ELA acts as a selective ER degrader while exhibiting agonistic activity in non-breast endocrine-responsive tissues like bone, making it particularly suitable for the adjuvant setting. In the SOLTI-ELIPSE trial, 4-week preoperative ELA in ER+/HER2- EBC postmenopausal pts led to a 53% reduction in Ki67 and complete cell cycle arrest (CCCA) rate of 27%. We hypothesize that ELA may serve as an effective ET in the premenopausal EBC setting, with or without OFS. Methods: SOLTI-2104-PremiÈRe (NCT05982093) is a phase 2, non-comparative, open-label, randomized, trial assessing ELA ± triptorelin (T) in premenopausal pts with stage I-IIB ER+/HER2- EBC, age ≥35 years, cT>1 cm, and Ki67 10-35% by local assessment. Pts were stratified by PAM50 subtype (Luminal A vs Non-luminal A) and randomized to ELA 345 mg daily until surgery/biopsy at D28, alone or with T 3.75 mg on days 1 and 29. The primary endpoint was CCCA at D28 (central Ki67 ≤2.7%). Secondary endpoints included CCCA by subtype, changes in central Ki67, changes in gene expression from baseline, and safety. Changes in gene expression were evaluated per arm (paired samples), with P-values corrected using false discovery rate (FDR). Estrogen levels were monitored by LC-MS/MS. Results: From SEP 2023 to MAR 2025, 49 pts were randomly assigned to receive ELA (n=23) and ELA+T (n=26). Baseline characteristics: median age 47; caucasian 92%; cT1-T2 96%, N1 6%; grade 1-2 94%; central Ki67 median 20% in the ELA arm and 16% in ELA+T. PAM50 subtypes were 75.5% Luminal A and 24.5% Luminal B. CCCA was achieved in 28.6% and 26.9% in ELA and ELA+T, arm respectively and in a higher rate in Luminal A tumors. Ki67 was significantly reduced in both arms. Both arms exhibited a shift to a less proliferative phenotype after treatment (Table 1). PAM50 Risk of Recurrence (ROR)-high/medium switched to ROR- low, and PAM50 Luminal B subtype switched to Luminal A/Normal-like. Treatment showed a toxicity profile consistent with previous data. Conclusions: This study provides the first evidence that ELA ± OFS elicits antiproliferative and molecular responses in premenopausal women with ER+/HER2- EBC. Both regimens had comparable and significant reductions in Ki67, CCCA, ROR-P scores, and proliferation gene expression. PremiÈRe trial support the potential role of ELA as a novel ET in this population, potentially sparing the need for OFS. Citation Format: M. Bellet, P. Tolosa, C. Hernando, M. Vidal, V. Ortega, M. Tapia, S. González-Santiago, P. Sánchez, Y. Fernández, M. Cruellas, M. Alva, E. Mension, M. Espinosa-Bravo, T. Cortadellas, S. Aragón, M. Gaudio, E. Sanfeliu, P. Galván, R. Olivera, G. Villacampa, M. Bergamino, N. Santos, S. Cano-Crespo, X. González-Farré, A. Prat, J. M. Ferrero-Cafiero, A. Hurtado, T. Pascual. Elacestrant alone or in combination with triptorelin in premenopausal women with ER+/HER2- early breast cancer: primary analysis from the phase 2 SOLTI-2104- PremiÈRe trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PD10-01.

Abstract Background: Patients with HR+HER2− advanced/metastatic breast cancer (ABC) who have tumors that progressed after CDK4/6 inhibitor and endocrine therapy (ET) represent a high unmet medical need. Histone lysine acetyltransferases KAT6A and KAT6B regulate lineage-specific gene transcription via H3K23 acetylation. PF-07248144 is a selective inhibitor of KAT6A and KAT6B. PF-07248144 (5 mg QD) in combination with fulvestrant (FUL) has demonstrated encouraging and durable antitumor activity with a manageable safety profile in patients with heavily pretreated HR+HER2− ABC in a phase 1/2 study. The phase 3 study is designed to evaluate and confirm the efficacy and safety of PF-07248144 plus FUL in patients with HR+HER2− ABC after tumor progression on CDK4/6i -based therapy, when compared to standard of care therapy. Methods: This open-label, randomized phase 3 trial is comparing PF-07248144 plus FUL versus everolimus (EVE) plus ET [FUL or exemestane (EXE)]) in patients with HR+HER2− ABC. Key inclusion criteria are: age ≥ 18 years; histologically confirmed HR+HER2− ABC; progression after prior CDK4/6i-based therapy; available tumor tissue; measurable disease or non-measurable bone-predominant disease, defined by RECIST v1.1; Adequate organ function; ECOG PS 0 or 1. Key exclusion criteria are: presence of detectable PIK3CA/AKT1/PTEN alterations; prior chemotherapy or therapy targeting PIK3CA/AKT1/PTEN in ABC; >2 prior lines post-CDK4/6i of systemic anticancer therapy in ABC and no more than one line of chemotherapy; systemic anticancer therapy or radiation within 2 weeks of randomization. Up to 400 patients will be randomized (1:1) to receive either PF-07248144 plus FUL versus EVE plus ET (FUL or EXE). Patients will be stratified by ET (FUL vs EXE), prior systemic lines of therapy in metastatic setting (1 vs 2), and disease site (visceral vs non-visceral). The primary endpoint is progression-free survival by blinded independent central review. Overall survival is a key secondary endpoint; other secondary endpoints include objective response, duration of response, clinical benefit rate, safety, and pharmacokinetics of PF-07248144. Citation Format: K. M. Kalinsky, R. M. Layman, A. Giordano, T. Mukohara, Y. Park, G. J. Lindeman, G. Bianchini, A. Nonneville, V. Diéras, S. Kuemmel, S. Wang, Z. Shao, S. Kent, M. Li, M. Oliveira. Randomized phase 3 trial evaluating KAT6 inhibitor PF-07248144 plus fulvestrant in HR+HER2− advanced/metastatic breast cancer after progression on CDK4/6 inhibitor-based therapy [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-08-19.

627 Background: GEP-NETs arise from neuroendocrine cells of the digestive tract (88%) or pancreas (12%). Therapies for progressive GEP-NETs include surgery, somatostatin analogs (SSA), chemotherapy, targeted therapy, and radioligand therapy. 177 Lu-DOTATATE is a radiolabeled SSA approved for progressive GEP-NETs based on NETTER-1 and shown to be an effective first-line therapy for Grade 2 and 3 GEP-NETs in NETTER-2. Prior to 177 Lu-DOTATATE approval, EVE, a mammalian target of rapamycin inhibitor, was the recommended therapy for progressive GEP-NETs. Here we describe pt characteristics and real-world outcomes of 177 Lu-DOTATATE vs EVE in pts with GEP-NETs. Methods: This was a retrospective, non-interventional, cohort study of pts treated with 177 Lu-DOTATATE or EVE using data from the open-source IQVIA Longitudinal Prescription and Pt Centric Medical Claims databases between Jul 1, 2017–Feb 28, 2025, representing the largest analysis of real-world GEP-NET data to date. Pt characteristics were assessed using descriptive statistics from 6 months prior to the index date (date of earliest evidence of 177 Lu-DOTATATE or EVE initiation). Following propensity-score matching of cohorts, overall survival (OS) and time to next systemic treatment (TTNT) were assessed with Kaplan–Meier and Cox models from index date to the end of follow-up. Results: The study included 5367 pts treated with 177 Lu-DOTATATE (n=3410) or EVE (n=1957). Prior to matching, pt characteristics were comparable between 177 Lu-DOTATATE and EVE groups, with a median (range) age of 67 (18–85) vs 65 (18–85) years. Prior exposure to systemic therapies was higher with 177 Lu-DOTATATE (68%) vs EVE (59%), with only 5% prior EVE exposure in the 177 Lu-DOTATATE group. The most common comorbidities in pts included hypertension (38% vs 37%); liver, gallbladder, and pancreatic diseases (29% vs 28%); and diabetes (24% vs 26%) for 177 Lu-DOTATATE vs EVE, respectively. Post-matching, the median (95% CI) TTNT was not reached (NR) (70.2 months–NR) with 177 Lu-DOTATATE (n=1559) vs 29.0 (25.2–34.6) months with EVE (n=1559) (p<0.0001). In pts who initiated a subsequent therapy (16% vs 38%) during the study, the median (range) TTNT was 20.5 (2.1–74.0) vs 8.0 (0.7–73.5) months with 177 Lu-DOTATATE vs EVE, respectively. Overall, 76% vs 73% of pts treated with 177 Lu-DOTATATE vs EVE were still alive at the end of follow-up. Cox proportional hazard and sensitivity analyses showed a robust, significant survival benefit for 177 Lu-DOTATATE vs EVE, with a hazard ratio (95% CI) of 0.74 (0.59–0.92) for OS (p=0.007). Conclusions: OS benefit and lower and less frequent treatment initiation after 177 Lu-DOTATATE vs EVE treatment, suggests a clinical benefit of 177 Lu-DOTATATE vs EVE with lower therapy burden in pts with GEP-NETs.

Everolimus ameliorates cognitive deficits and synaptic dysfunction in mice with prefrontal cortical ADNP knockdown.

Purpose:VE-cadherin is a key component of endothelial adherens junctions, and its disorganization contributes to vascular dysfunction. While rapamycin analogs like everolimus (EVL) are clinically linked to endothelial barrier dysfunction (EBD), the underlying molecular mechanisms remain poorly defined. This study investigates how EVL alters VE-cadherin organization, trafficking, cytoskeletal architecture, and barrier function in endothelial cells.Methods:Human umbilical vein endothelial cells (HUVECs) were treated with 500 nM EVL for 4 or 24 h. Junctional VE-cadherin organization was quantified using confocal microscopy and the Junction Analyzer Program. Cytoskeletal changes were assessed via F-actin anisotropy, and pharmacologic inhibitors (chlorpromazine, chloroquine, and brefeldin A) were used to block clathrin-mediated endocytosis, lysosomal degradation, and Golgi trafficking, respectively. Barrier function was evaluated using TEER and 4 kDa FITC-dextran transwell assays.Results:EVL reduced continuous VE-cadherin and increased punctate junctions in a time-dependent but partially reversible manner. Inhibiting endocytosis or lysosomal degradation preserved VE-cadherin continuity, while Golgi disruption blocked recovery. EVL also increased F-actin anisotropy, reflecting enhanced stress-fiber alignment within individual cells, but transiently uncoupled intracellular actin organization from coordinated cytoskeletal alignment across the monolayer. Functionally, EVL decreased TEER and increased dextran permeability by 2.24–2.63-fold, indicating significant barrier disruption.Conclusions:EVL compromises endothelial barrier integrity by promoting VE-cadherin internalization and lysosomal degradation, accompanied by cytoskeletal remodeling and a Golgi-dependent, partial restoration of junctional VE-cadherin. These findings highlight endocytic, degradative, and Golgi-mediated trafficking pathways as key modulators of EVL-induced endothelial barrier dysfunction and provide mechanistic insight into the vascular effects of rapalog-based mTOR inhibition.

Efficacy and safety of everolimus with reduced tacrolimus versus standard tacrolimus in liver transplant recipients: A systematic review and meta-analysis of randomized controlled trials.

Coronary artery disease (CAD) remains a leading cause of mortality worldwide, while conventional drug-eluting stents (DES) face limitations in long-term safety and controlled drug release. Here, we developed a poly (L-lactic acid) (PLLA)-based biodegradable vascular scaffold (BVS) with a three-layer coating using distinct technologies for spatiotemporal drug delivery. The luminal surface was selectively coated via electrospraying with alpha-lipoic acid (ALA) to promote endothelialization. The abluminal surface was treated using ultrasonic spray coating with magnesium hydroxide (MH) and everolimus (EVL) to suppress smooth muscle cell proliferation and inflammation. Finally, a precision dot-printing method was employed to deliver doxorubicin (DOX) for early inhibition of restenosis. This strategy enabled time- and site-specific drug release, achieving antioxidant, anti-inflammatory, and anti-restenotic effects while facilitating re-endothelialization. In vivo studies in a porcine model confirmed that the BVS-AEMD significantly reduced thrombosis and inflammation, underscoring its potential as a next-generation cardiovascular therapeutic platform.

9 Background: In January 2025 data reported from the STARTER-NET trial (JCOG1901) demonstrated a significant progression-free survival (PFS) benefit with everolimus plus lanreotide (EV-LAN) versus everolimus (EV) alone in patients with non-functioning aggressive (Ki-67 5-20% or diffuse liver metastases) gastroenteropancreatic neuroendocrine tumors (GEP-NETs). We analyzed the cost-effectiveness and adverse reactions (AEs) of this upfront combination treatment compared to monotherapy. Methods: We performed direct cost analysis using available U.S. drug pricing and AE management estimates. The median PFS from the STARTER-NET trial was used as a proxy for treatment duration. Incremental cost-effectiveness was estimated per month of PFS. Reported preliminary AEs from the STARTER-NET trial were compared to the EVELAR study to assess the estimates. Results: The total estimated cost of EV therapy is $177,500 over a median duration of 11.5 months. In comparison, the EV-LAN incurred a total cost of $698,100 over 29.7 months. The costs associated with managing adverse events were estimated at $5,000 for monotherapy and $15,000 for combination therapy. The incremental cost of PFS per additional month was approximately $28,555. No significant improvement in overall survival (OS) or quality of life was observed in the trial. Preliminary data on AEs from STARTER-NET reported diarrhea in 36.8% and mucositis in 62.1% of patients. The EVERLAR phase 2 study reported diarrhea in 70.9% and mucositis in 65.9 % of patients with EV-LAN. Interestingly STARTER-NET reported significantly higher hyperglycemia in 62.1% compared to 15.9 % in the EVERLAR study. Conclusions: Although EV-LAN showed significantly improved PFS in the STARTER-NET trial it incurs substantially higher costs with uncertain impact on quality-adjusted outcomes. The combination may not be cost-effective under typical willingness-to-pay thresholds, raising concerns about affordability and value, particularly lacking OS. These findings underscore the need to integrate cost analyses into treatment decision-making. Analysis of AEs confirms significantly lower diarrhea and higher occurrence of hyperglycemia compared to previous observations. The difference in side effect profile could be explained by patient demographics which also mandates confirmation of treatment response in patients with different demographics.

Breast cancer recurrence may arise from dormant disseminated tumor cells (DTCs) that persist in bone marrow and other sites. Clinically, DTCs are independently associated with breast cancer recurrence and death. Preclinical studies in mouse models identified autophagy and mammalian target of rapamycin (mTOR) signaling as critical mechanisms of tumor dormancy and escape. We subsequently tested the effects of transient versus chronic inhibition of autophagy with chloroquine or hydroxychloroquine (HCQ) and mTOR signaling with rapamycin (RAPA) or everolimus (EVE) on residual tumor cell (RTC) burden and recurrence-free survival (RFS). In mice harboring dormant RTCs, inhibition of mTOR alone or in combination with autophagy inhibition decreased RTC burden and improved RFS in a duration-dependent manner. RTC number was strongly and inversely correlated with RFS, suggesting that RTC reduction mediated an improvement in RFS. To translate findings clinically, we performed a randomized phase 2 trial (CLEVER) of HCQ, EVE or their combination in breast cancer survivors within 5 years of diagnosis who had detectable DTCs on bone marrow aspirate. Primary endpoints were feasibility and safety; secondary endpoints included DTC reduction/clearance and RFS. In total, 51 DTC+ patients initiated HCQ (n = 15), EVE (n = 15) or HCQ + EVE (n = 21). Treatment was feasible and tolerable; only one patient discontinued early for grade 3 toxicity. At 42 months median follow-up, landmark 3-year RFS for HCQ, EVE and HCQ + EVE was 91.7%, 92.9% and 100%, respectively, and was greater in those who cleared DTCs versus those who did not (hazard ratio (HR) = 0.21 (95% confidence interval 0.01-3.4)). Posterior probabilities were 98-99.9% that three cycles of HCQ, EVE or HCQ + EVE led to reduced or undetectable DTCs compared to observation alone, with estimated DTC reductions of 80%, 78% and 87%, respectively. These findings provide proof-of-concept that targeting dormant RTCs with HCQ, EVE or their combination in breast cancer survivors or mouse models depletes minimal residual disease, warranting a definitive human randomized controlled trial. ClinicalTrials.gov registration: NCT03032406 .

2592MO Fruquintinib (FRUQ) plus sintilimab (SIN) versus axitinib (AXI) or everolimus (EVE) monotherapy as 2L treatment in pts with locally advanced or metastatic renal cell carcinoma (RCC): Results from phase III part of a randomized, open-label, active-controlled phase II/III study (FRUSICA-2)

Drug-induced interstitial lung disease (DILD) is an adverse event associated with the use of various anticancer drugs. Although DILD is rare, it is a serious complication that can lead to treatment interruption and, in some cases, life-threatening outcomes. The early detection of DILD requires careful monitoring of subjective symptoms, regular computed tomography (CT) scans, and biomarker assessments. We present two cases in which electronic patient-reported monitoring by a pharmacist, utilizing an electronic patient-reported outcome (ePRO) application, enabled the early detection of DILD in patients with breast cancer undergoing anthracycline-based adjuvant therapy and treatment for recurrence with everolimus (EVL) and exemestane (EXE). In the first case, a woman in her 50s with early stage breast cancer received dose-dense epirubicin and cyclophosphamide (EC) therapy as adjuvant treatment following surgery. On day 14 of the second cycle, the ePRO flagged cough and fever symptoms. The following day, the patient's fever subsided, and chest X-rays showed no abnormal findings. The third cycle of dose-dense EC therapy was discontinued, and the patient was followed up. Monitoring with ePROs was continued, and on day 18, the patient developed a fever again and experienced worsening dyspnea, prompting a medical consultation. Chest CT confirmed the diagnosis of DILD, and steroid pulse therapy was initiated. In the second case, a woman in her 60s with recurrent breast cancer underwent EVL + EXE. Between days 86 and 89, ePROs identified fever, fatigue, and cough, prompting the patient to consult a physician. A chest CT scan revealed grade 1 DILD, which led to the discontinuation of EVL therapy. These cases suggest that the application of ePRO is valuable for the early detection of DILD, potentially improving patient outcomes by allowing timely intervention.

Everolimus (EVE), an mTOR inhibitor, is widely used in solid organ transplantation (SOT) because of its immunosuppressive properties. Due to its narrow therapeutic window and significant pharmacokinetic variability, therapeutic drug monitoring (TDM) is essential for achieving optimal outcomes. We developed and thoroughly validated a robust LC-MS/MS method to measure EVE levels in venous whole blood (WB) and capillary blood collected using two microsampling devices: Mitra™ (volumetric absorptive microsampling, VAMS) and Capitainer® (quantitative dried blood spot, qDBS). The validation followed EMA and IATDMCT guidelines, assessing linearity (1.27–64.80 ng/mL for WB and 0.50–60 ng/mL for VAMS/qDBS), as well as selectivity, accuracy, precision, matrix effects, recovery, stability, and incurred sample reanalysis. Clinical validation involved 66 matched samples from 33 adult SOT recipients. The method demonstrated high accuracy and precision across all matrices, with no significant carryover or matrix interference. Statistical analysis using Passing–Bablok regression and Bland–Altman plots showed excellent agreement between the microsampling methods and the venous reference. Hematocrit effects were tested both in laboratory conditions and on clinical samples and were found to be negligible. This study provides the first comprehensive analytical and clinical validation of the Mitra and Capitainer devices for EVE monitoring. The validated LC-MS/MS microsampling method supports decentralized, patient-centred TDM, offering a reliable alternative to conventional blood sampling in transplant care.

Nonalcoholic steatohepatitis (NASH) is a strong risk factor for end-stage liver disease. Trigonelline (TG) is a plant alkaloid with anti-oxidant, anti-dyslipidemic, and anti-insulin resistance activities. Everolimus (EV), a conventional drug and an mTOR inhibitor, has been demonstrated to improve metabolic outcomes. The synergistic effect of the co-treatment of TG and EV against NASH conditions remains unknown. We have developed a fast food (FF)-diet and thioacetamide-induced chronic steatohepatitis in a C57BL/6J mice model of 24 weeks duration. We have evaluated the synergistic protective effect of TG and EV at reduced doses to avoid any undesired toxic manifestations of the FF and thioacetamide. The study was demonstrated by comparative analysis across different groups after 24 weeks. Co-exposure to FF diet and thioacetamide resulted in chronic steatohepatitis, evident by focal necrosis, bridging fibrosis, loss of liver architecture, and excessive collagen deposition. Protein and gene analysis revealed enhanced de novo lipogenesis (SREBP-1, PPAR-Ƴ, CD36), inflammation (interleukin-6, tumor necrosis factor, CYP2E1), fibrosis (transforming growth factor beta, alpha-smooth muscle actin, tissue inhibitors of metalloproteinases-1), and extracellular matrix deposition (MMP-1, Col1A1). TG + EV at reduced doses showed marked synergistic effects in preventing inflammation, fibrosis, and lipogenesis markers. This study provides a novel 24-week FF diet and thioacetamide-induced murine NASH model for possible preclinical drug discovery studies. Furthermore, our treatment regimen discovered the synergistic effect of TG and EV at reduced doses in preventing chronic steatohepatitis.

TPS1129 Background: ET+CDK4/6i is standard-of-care (SOC) in 1L ER+/HER2- aBC; however, tumors eventually develop resistance. Constitutive activation in the PI3K/AKT/mTOR pathway can contribute to endocrine resistance in breast cancer. ESR1 mutations are a common type of acquired resistance that emerges in 40-50% of patients in the metastatic setting after prolonged aromatase inhibitor exposure. There is an unmet need for novel therapeutic approaches to overcome resistance mechanisms and improve outcomes in patients with ER+/HER2- aBC with ESR1 -mutated tumors progressing after ET+CDK4/6i. ELA is a next-generation oral SERD that binds to ER-alpha, inducing its degradation. In EMERALD, ELA improved PFS vs SOC ET in patients with ESR1 -mutated tumors (HR 0.55; 95% CI 0.39-0.77; P=0.0005) [Bidard 2022]. Differences were notable among patients who received prior ET+CDK4/6i ≥12 mo; median PFS with ELA was 8.6 mo vs 1.9 mo with SOC ET (HR 0.41; 95% CI 0.26-0.63) [Bardia 2024]. Crosstalk between ER and PI3K/AKT/mTOR pathways provides a rationale for evaluating ELA+EVE (a mTORC1 inhibitor). In ELEVATE phase 1b (NCT05563220), ELA+EVE demonstrated ORR 22% and CBR at 24 weeks 72% in patients with ER+/HER2- aBC progressing after ET+CDK4/6i; ELA 345 mg + EVE 7.5 mg was identified as the RP2D [Rugo ESMO 2024]. Safety was consistent with the known profile of EVE+SOC ET. ADELA compares ELA+EVE vs ELA+PBO in ER+/HER2- aBC patients with ESR1- mutated tumors progressing on ET+CDK4/6i. Methods: ADELA (NCT06382948) is an international, multicenter, double-blind, placebo-controlled phase 3 trial. Eligible patients are adults (≥18 yrs) with ER+/HER2- aBC and ESR1 -mutated tumors, previously treated with 1-2 lines of ET for aBC, and evidence of disease progression on prior ET+CDK4/6i for aBC after ≥6 mo. Patients receiving CDK4/6i-based adjuvant therapy are eligible (disease progression must be confirmed after ≥12 mo of treatment but <12 mo following CDK4/6i completion). Other criteria include adequate organ function and ECOG PS 0-1. Exclusion criteria include prior chemotherapy for aBC and active uncontrolled/symptomatic brain metastasis. Patients will be randomized 1:1 to 28-d cycles of ELA 345 mg + EVE 7.5 mg QD or ELA 345 mg + PBO QD until disease progression or unacceptable toxicity. Patients will receive dexamethasone mouthwash during the first 8 wks. Stratification factors are presence of visceral metastases (yes vs no) and duration of prior CDK4/6i (≥12 mo vs <12 mo). The primary objective will be to evaluate PFS based on blinded independent review committee. Secondary endpoints include investigator-assessed PFS, OS, ORR, CBR, DoR, TTR, best percentage change in tumor burden, safety, and HRQoL. Status: Planned enrollment is 240 patients; recruitment is ongoing. Clinical trial information: NCT06382948 .

Association between everolimus combination therapy and cancer risk after liver transplantation: A nationwide population-based quasi-cohort study.