Everolimus Research Articles

Everolimus Personalized Therapy: Second Consensus Report by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.

The Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology established the second consensus report to guide Therapeutic Drug Monitoring (TDM) of everolimus (EVR) and its optimal use in clinical practice 7 years after the first version was published in 2016. This version provides information focused on new developments that have arisen in the last 7 years. For the general aspects of the pharmacology and TDM of EVR that have retained their relevance, readers can refer to the 2016 document. This edition includes new evidence from the literature, focusing on the topics updated during the last 7 years, including indirect pharmacological effects of EVR on the mammalian target of rapamycin complex 2 with the major mechanism of direct inhibition of the mammalian target of rapamycin complex 1. In addition, various concepts and technical options to monitor EVR concentrations, improve analytical performance, and increase the number of options available for immunochemical analytical methods have been included. Only limited new pharmacogenetic information regarding EVR has emerged; however, pharmacometrics and model-informed precision dosing have been constructed using physiological parameters as covariates, including pharmacogenetic information. In clinical settings, EVR is combined with a decreased dose of calcineurin inhibitors, such as tacrolimus and cyclosporine, instead of mycophenolic acid. The literature and recommendations for specific organ transplantations, such as that of the kidneys, liver, heart, and lungs, as well as for oncology and pediatrics have been updated. EVR TDM for pancreatic and islet transplantation has been added to this edition. The pharmacodynamic monitoring of EVR in organ transplantation has also been updated. These updates and additions, along with the previous version of this consensus document, will be helpful to clinicians and researchers treating patients receiving EVR.

The different sequences of CDK4/6 inhibitor and mTOR inhibitor in HR+/HER2-advanced breast cancer: A multicenter real-world study

BackgroundCyclin-dependent kinase 4/6 inhibitor (CDK4/6i) and everolimus (EVE) are effective for patients with hormone receptor–positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). However, the efficacy of different sequences of CDK4/6i and EVE are largely unknown. The study aimed to explore the efficacy of different sequences in China. Methods146 patients with HR+/HER2- MBC who received both CDK4/6i and EVE in salvage setting were collected. Objective response rate (ORR), clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS) were investigated. Results56 patients received CDK4/6i prior to EVE (Group A), 90 patients received CDK4/6i subsequent to EVE (Group B). The median PFS of CDK4/6i and EVE in Group A vs Group B were 8.4m and 2.5m vs 4.6m and 6.1m respectively. The total PFS of first-line and second-line endocrine therapy were not different between Group A and Group B [13.1m vs 17.7m (P = 0.330, HR = 0.738, 95%CI: 0.399–1.365)]. The 5y OS of patients in Group A or Group B were 62.0 % vs 57.4 %, P = 0.569. ConclusionsWe found that no matter CDK4/6i or EVE was used first, the survival were not significantly different between Group A and Group B. Both can be clinical options.

Advances in understanding and managing pediatric heart failure and transplant.

This article highlights the most recent advances in a review of the current literature in the field of pediatric heart failure and transplantation. Diagnostically, the identification of new genetic factors has contributed to a deeper understanding of cardiomyopathy in children. Novel medications like sacubitril/valsartan and Sodium-Glucose cotransporter-2 (SGLT2) inhibitors, which are now standard in the adult population are being studied in pediatric population and offer new promise of pediatric heart failure treatment. Ventricular assist devices are more commonly used in cardiomyopathy patients and single ventricle patients as a bridge to transplant. Recent pediatric heart transplant society (PHTS) data demonstrated that waitlist survival improved significantly over the past decades (i) and new treatments such as daratumumab and eculizumab have been used in high-risk populations and demonstrate promising results. TEAMMATE trial is the first multicenter randomized clinical trial (RCT) in pediatric heart transplant (HT) to evaluate the safety and efficacy of everolimus (EVL) and low-dose tacrolimus (TAC) compared to standard-dose TAC and mycophenolate mofetil (MMF). It will provide valuable information about the safety and efficacy of EVL, TAC, and MMF (ii).Donor cell-free DNA has been used more in pediatric transplant recipients and has significantly decreased invasive EMB (iii). This past 5 years have witness dramatic progress in the field of pediatric heart failure and transplantation including more use of mechanical support in heart failure patients with various underlying etiology, especially use of mechanical support in single ventricle patients and the use of sacubitril/valsartan and SGLT2 inhibitors in the pediatric population. The problem of the highly sensitized transplant recipient remains, although novel therapeutics have been added to our toolbox of options to maintain healthy allograft function. Ongoing research aims to further enhance our understanding and management of pediatric heart failure, emphasizing the need for continued innovation in this complex field.

Efficacy of everolimus plus hormonal treatment after cyclin-dependent kinase inhibitor; real-life experience, A TOG study.

In advanced breast cancer, endocrine therapy is preferred in the absence of visceral crisis. Cyclin-dependent kinase inhibitors (CDKi) are the gold standards. The selection of subsequent treatments after CDKi treatment is still controversial, and the efficacy of everolimus (EVE) combinations is unknown. In this study, we aimed to investigate the efficacy of EVE after CDKi administration in real-life experiences. The study received data from 208 patients from 26 cancer centers. Demographic and histologic features, diagnosis, progression, last visit dates, and toxicities were recorded. This study was a retrospective case series. One hundred and seven patients received palbociclib, while 101 patients received ribociclib as a CDKi. The overall response and disease control rates of EVE combinations were 60% and 88%, respectively. In univariate analysis, the absence of liver metastasis, age > 40years, better type of response, and immediate treatment after CDKi were related to increased progression-free survival. Liver metastasis and response type were significantly associated with overall survival. In the multivariate analysis, response remained significant in terms of progression-free survival, while response type, liver metastatic disease, and hematologic toxicity were prognostic in terms of overall survival. This study provides evidence of the benefits of EVE combinations after CDKi treatment. EVE combinations may be more appropriate for patients with non-liver metastasis, and the first treatment response shows the benefit of treatment. In addition, immediate treatment after CDKi treatment is more beneficial than later lines of treatment.

22 Association of a germline single nucleotide polymorphism (SNP) in the interleukin-7 (IL7) gene with immune-related adverse events (irAEs)

Abstract Background Adverse events (AEs) can limit treatment immune checkpoint inhibitors (ICI) efficacy and worsen patient outcomes. Our group recently identified a germline IL7 SNP as a potential biomarker for prediction of irAEs (Groha, Nat Med 2022). In the current study, we sought to replicate the association between this IL7 SNP (rs16906115) and AEs in two clinical trials of patients with cancer treated with ICI regimens. Methods In the CheckMate-025 (CM025) trial (NCT01668784), involving patients with metastatic renal cell carcinoma (mRCC) randomized to either nivolumab (NIVO) or everolimus (EVE), whole-exome sequencing (WES) data from tumor and peripheral blood samples were analyzed. The Cancer Genome Analysis pipeline was utilized to identify somatic alterations, and the STITCH pipeline was employed to determine SNP carrier status. In the BinTA-0037 (BTA-0037) trial (NCT03631706), focusing on patients with metastatic non-small cell lung cancer (mNSCLC), the carrier status of a surrogate SNP rs16906062 (R2=0.66) was determined from tumor WES in the pembrolizumab (PEMBRO) arm. Within each treatment arm, time to incident AEs were compared between carriers (SNP+) and non-carriers (SNP-) via multivariable Cox regression, controlling for age, sex, race, ECOG and sample purity. A SNP´treatment interaction term was also included in the entire CM025 cohort. Censoring for AEs occurred at death or last follow-up. A recurrent event analysis for AEs was conducted using the Andersen-Gill model, controlling for the same variables. Additionally, overall survival (OS) and progression-free survival (PFS) were also assessed. Results In total, 534 pts were included (NIVO: n=189, PEMBRO: n=152, EVE: n=193), among which 82 (15.4%) were SNP+. There were no differences in clinical and pathological characteristics between SNP+ and SNP-, except for sex (SNP+ 16.1% vs. SNP- 30.1% in females, P=0.046). Similarly, no differences in somatic alterations, including single nucleotide and copy number variants were seen between SNP+ and SNP- in CM025. SNP carrier status had no effect on OS nor PFS in all treatment arms (all P≥0.22). The rate of grade 2+ AEs was significantly higher in SNP+ vs. SNP- in the NIVO arm (Figure A, HR=2.91[1.48-5.72]), but not in the EVE (Figure B, control, non-ICI) arm (HR=0.63[0.3-1.29], SNP´treatment Pinteraction=0.002). Similarly, the rate of all grade AEs in the PEMBRO arm of BTA-0037 was higher in SNP+ vs. SNP- (Figure C, HR=2.30[1.60-4.60]). The rate of recurrent grade 2+ AEs was also significantly higher in SNP+ vs. SNP- in the NIVO arm (HR=3.43[1.83-6.43]), whereas a trend for fewer recurrent grade 2+ AEs was seen in SNP+ vs. SNP- in the EVE arm (HR=0.46[0.17-1.25], SNP´treatment Pinteraction=0.0005). Figure: Kaplan-Meier curves showing the cumulative rate of adverse events in the NIVO (A) and EVE (B) arms of CM025, as well as the PEMBRO arm of BTA0037 (C), in SNP- and SNP+. Conclusions The IL7 SNP (rs16906115) is associated with significantly higher rates of grade 2+ AEs, including recurrent events, in pts with mRCC or mNSCLC treated with single agent PD-1 inhibitors but not with non-ICI regimens, with no effect on survival and efficacy outcomes. These results confirm the SNP’s predictive potential as a biomarker for irAEs to guide therapeutic decisions in pts treated with ICIs.

Dried Blood Spot Sampling for Monitoring Children With Immune-Mediated Glomerulopathies and After Kidney Transplantation

BackgroundMonitoring kidney function and immunosuppressant levels in children post-kidney transplantation or those with glomerulopathies is challenging due to frequent venipunctures and clinic visits. Capillary dried blood spot sampling (DBS) offers a potential alternative. MethodsIn this prospective single-center study, 89 children (38 % female, 62 % male) requiring therapeutic drug monitoring (TDM) and kidney function assessment were enrolled. 79 % of the patients were kidney transplant recipients, and 21 % suffered from immune-mediated glomerulopathies. The mean age was 13.4 years (range 5.7-18.0). DBS and standard venous serum samples were collected simultaneously for tacrolimus (TAC), cyclosporine A (CsA), everolimus (EVR), and creatinine levels. Further, patient feedback on pain perception and feasibility was collected via questionnaire. ResultsNo significant differences in parameter values between DBS and standard methods were found (creatinine -1.7±14.5 μmol/l; EVR 0.1±1.2 μg/L; TAC 0.3±1.1μg/L; CsA 2.8±9.8 μg/L). DBS demonstrated sufficient accuracy compared to standard methods. Patients favored DBS and telehealth consultations, especially due to less travel and school absences. Patients preferred finger pricking over ear pricking. ConclusionsCapillary DBS proves reliable for TDM and kidney function assessment in pediatric kidney disease. It reduces patient and family burden compared to venous blood collection, while also enabling telehealth consultations.

Early Conversion to Everolimus Within 180 Days of Living Donor Liver Transplantation.

Early conversion to Everolimus (EVR) post deceased donor liver transplant has been associated with improved renal function but increased rejection. Early EVR conversion has not been evaluated after living donor liver transplant (LDLT). A retrospective cohort study was conducted to compare the rate of rejection and renal function in patients converted to EVR early post-LDLT to patients on calcineurin inhibitors (CNIs). This was a single center retrospective cohort study of adult LDLT recipients between January 2012 and July 2019. Patients converted to EVR within 180 days of transplant were compared to patients on CNIs. The primary endpoint was biopsy proven acute rejection (BPAR) at 24 months posttransplant. Key secondary endpoints included eGFR at 24 months, change in eGFR, adverse events, and all-cause mortality. From a total of 173 patients involved in the study: 58 were included in the EVR group and 115 in the CNI group. Median conversion to EVR was 26 days post-LDLT. At 24 months, there was no difference in BPAR (22.7% EVR vs. 19.1% CNI, p = 0.63). Median eGFR at 24 months posttransplant was not significantly different (68.6 [24.8 to 112.4] mL/min EVR vs. 75.9 [35.6-116.2] mL/min CNI, p = 0.103). Change in eGFR from baseline was worse in the EVR group (-13.0 [-39.9 to 13.9] mL/min EVR vs. -5.0 [-31.2 to 21.2] mL/min CNI, p = 0.047). Median change from conversion to 24 months posttransplant (EVR group only) was -3.43mL/min/1.73 m2 (-21.0 to 9.6). Early EVR conversion was not associated with increased risk of rejection among LDLT recipients. Renal function was not impacted. EVR may be considered as an alternative after LDLT in patients intolerant of CNIs.

A Dual-Targeting, Multi-Faceted Biocompatible Nanodrug Optimizes the Microenvironment to Ameliorate Abdominal Aortic Aneurysm.

Abdominal aortic aneurysm (AAA) is a highly lethal cardiovascular disease that currently lacks effective pharmacological treatment given the complex pathophysiology of the disease. Here, single-cell RNA-sequencing data from patients with AAA and a mouse model are analyzed, which reveals pivotal pathological changes, including the M1-like polarization of macrophages and the loss of contractile function in smooth muscle cells (SMCs). Both cell types express the integrin αvβ3, allowing for their dual targeting with a single rationally designed molecule. To this end, a biocompatible nanodrug, which is termed EVMS@R-HNC, that consists of the multifunctional drug everolimus (EVMS) encapsulated by the hepatitis B virus core protein modifies to contain the RGD sequence to specifically bind to integrin αvβ3 is designed. Both in vitro and in vivo results show that EVMS@R-HNC can target macrophages as well as SMCs. Upon binding of the nanodrug, the EVMS is released intracellularly where it exhibits multiple functions, including inhibiting M1 macrophage polarization, thereby suppressing the self-propagating inflammatory cascade and immune microenvironment imbalance, while preserving the normal contractile function of SMCs. Collectively, these results suggest that EVMS@R-HNC presents a highly promising therapeutic approach for the management of AAA.

BOLERO-5: a phase II study of everolimus and exemestane combination in Chinese post-menopausal women with ER + /HER2- advanced breast cancer

BackgroundThe global BOLERO-2 trial established the efficacy and safety of combination everolimus (EVE) and exemestane (EXE) in the treatment of estrogen receptor positive (ER +), HER2-, advanced breast cancer (ABC). BOLERO-5 investigated this combination in a Chinese population (NCT03312738).MethodsBOLERO-5 is a randomized, double-blind, multicenter, placebo controlled, phase II trial comparing EVE (10 mg/day) or placebo (PBO) in combination with EXE (25 mg/day). The primary endpoint was progression-free survival (PFS) per investigator assessment. Secondary endpoints included PFS per blinded independent review committee (BIRC), overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR), pharmacokinetics, and safety.ResultsA total of 159 patients were randomized to EVE + EXE (n = 80) or PBO + EXE (n = 79). By investigator assessment, treatment with EVE + EXE prolonged median PFS by 5.4 months (HR 0.52; 90% CI 0.38, 0.71), from 2.0 months (PBO + EXE; 90% CI 1.9, 3.6) to 7.4 months (EVE + EXE; 90% CI 5.5, 9.0). Similar results were observed following assessment by BIRC, with median PFS prolonged by 4.3 months. Treatment with EVE + EXE was also associated with improvements in ORR and CBR. No new safety signals were identified in BOLERO-5, with the incidence of adverse events in Chinese patients consistent with the safety profile of both drugs.ConclusionThe efficacy and safety results of BOLERO-5 validate the findings from BOLERO-2, and further support the use of EVE + EXE in Chinese post-menopausal women with ER + , HER2- ABC. NCT03312738, registered 18 October 2017.

Relevance of timing intake of everolimus (EVE) combined with adjuvant endocrine therapy (ET) in patients (pts) with high-risk early breast cancer: Results of a sub-study of the UCBG-UNIRAD trial.

542 Background: We reported the benefit of taking evening tamoxifen compared to morning/afternoon as adjuvant treatment for high-risk breast cancers in the UNIRAD phase III trial (NCT01805271) (1). Here, we examine the relevance of EVE timing intake in this trial. Methods: 1,277 pts with high-risk HR+/ HER2- primary BC were randomly assigned to adjuvant ET with placebo or EVE (1). Patients prospectively reported in a diary the daily timing for ET and EVE intake among four 6-h slots (06:00 to 11:59 (morning), 12:00 to 17:59 (afternoon), 18:00 to 23:59 (evening), or 24:00 to 05:59 (night). The association between EVE, ET timing and disease-free survival (DFS) was a prespecified secondary endpoint of the trial. Results: EVE timing was recorded by 513 of 632 patients (81.2%). Patients declaring EVE intake in the morning (n= 248, 48 %) or in the afternoon (n=52, 10%) were older than those declaring evening (n=207, 40 %) or night (n=6,1%) intakes ( p<0.001). They were more likely to be postmenopausal (p=0.001) and to take AI rather than tamoxifen (p = 0.03). Only 17 patients (3%) changed EVE intake timing throughout the study. EVE intake dialy times were binned into 2 categories for analyses: morning/afternoon group (n=300) and evening/night group (n = 213). The patients who took morning/afternoon EVE chose another timing for ET in 38% of the cases compared to 17.1% in evening/Night EVE group (p<0.01). The timing of EVE intake was not significantly associated with definitive EVE withdrawal ( p=0.62) in the whole population. Time to EVE withdrawal was significantly longer in the patients taking tamoxifen rather than AI (17.2 vs 10.9 months, p = 0.0047). Prolonged duration of EVE treatment was associated with evening/night intakes of both EVE and tamoxifen, compared to other drug timing modalities (p = 0.04). With a median follow-up of 85months, 15 patients relapsed locally (3%), 55 developed metastases (11%), 36 patients died (7%). Overall, EVE intake timing was not associated with DFS (HR=0.84 [95% CI, 0.53 - 1.35], p=0.4). There was a significant interaction between EVE timing intake and ET type ( P interaction= 0.001). Patients on evening/night EVE combined with tamoxifen had a reduced likelihood of relapse compared to those taking morning/afternoon EVE (HR = 0.17 [0.05- 0.59], p = 0.005). In contrast, no significant EVE effect was found in the AI group (HR = 1.56 [0.92 2.64], p = 0.1). Evening/Night intake of EVE plus tamoxifen was independently associated with DFS (HR 0.13 [0.03-0.6], p = 0.002) after adjustment for age, nodal status, tumor size, ET timing intake, and EVE dose (2.5, 5 or 10 mg). Conclusions: These exploratory results are consistent with a role of circadian rhythm in the efficacy of EVE when given with tamoxifen in pts with high risk early breast cancer. 1. S. Giacchetti et al, Abst 546, ASCO 2023. Clinical trial information: NCT01805271 .

Antitumor activity of nab-sirolimus versus mTOR inhibitors temsirolimus, sirolimus, and everolimus in A549 NSCLC xenografts.

e15096 Background: The mTORC1 pathway, often activated by mutations in genes like TSC1, TSC2, PIK3CA, PTEN, STK11, and KEAP1, plays a pivotal role in cancer progression; in some settings, alterations in STK11 and KEAP1 may be associated with treatment resistance and poor prognosis. Despite the broad importance of the mTORC1 pathway in cancer cell growth and survival, mTOR inhibitors (mTORis) temsirolimus (TEM), sirolimus (SIRO), and everolimus (EVE) have limited clinical application in the cancer setting. nab-Sirolimus, an injectable form of albumin-bound SIRO that leverages unique transport properties of albumin known to increase tumor drug accumulation, is approved for treatment of malignant PEComa. Here, we report the antitumor activity of nab-sirolimus in comparison to other mTORis in A549 NSCLC ( KRAS G12S, STK11 Q37*, and KEAP1 G333C) xenografts, and the correlation of antitumor activity, tumor PK profile, and mTOR pathway suppression. Methods: Athymic mice bearing subcutaneous A549 NSCLC xenografts were treated with either saline or equal weekly doses of nab-sirolimus (administered intravenously [IV]; 5 or 15 mg/kg/week), TEM (IV; 5 mg/kg/week), or SIRO or EVE (both oral; 15 mg/kg/week). Tumors were harvested at different time points after mTORi treatment and analyzed for tumor drug levels (LC-MS/MS) and mTOR pathway biomarkers (pS6 and p4EBP1) via western blot (WB). Results: In A549 xenografts, nab-sirolimus (IV) treatment resulted in significantly greater suppression of tumor growth compared with TEM (IV), SIRO (oral), and EVE (oral) (Table). Average intratumoral drug concentrations 24 hours after IV mTORi treatment were significantly higher with nab-sirolimus (420-539 ng/g) compared with TEM (TEM [parent] 34.9 ng/g; SIRO [active metabolite measured from TEM] 13.2 ng/g) and compared with 7-day steady-state concentrations for oral SIRO (17 ng/g) and EVE (10 ng/g). WB confirmed that nab-sirolimus consistently inhibited mTOR targets pS6 and p4EBP1, whereas TEM, SIRO, and EVE were less effective. Conclusions: nab-Sirolimus resulted in significantly higher intratumoral drug concentration, stronger inhibition of mTOR targets, and greater antitumor activity compared to other IV and oral mTORis in a KRAS/STK11/KEAP1 mutated NSCLC xenograft model. These results support further clinical evaluation of nab-sirolimus as a single agent or in combination with other therapeutic agents in oncology. [Table: see text]

Association of a germline single nucleotide polymorphism (SNP) in the interleukin-7 (IL7) gene with immune-related adverse events (irAEs) in the CheckMate 025 trial.

12140 Background: Immune checkpoint inhibitors (ICIs) have dramatically improved outcomes of patients (pts) with metastatic renal cell carcinoma (mRCC). Unfortunately, adverse events (AEs) can limit treatment efficacy and worsen patient outcomes. Recently, a germline IL7 SNP (rs16906115) was identified as a potential biomarker for prediction of irAEs. We aimed to characterize the association between a germline IL7 SNP (rs16906115) and AEs in a prospective clinical trial of patients with mRCC treated with nivolumab (NIVO) or everolimus (EVE). Methods: Whole-exome sequencing (WES) data of tumor and peripheral blood samples from CheckMate 025 (NCT01668784) were used to infer somatic alterations using the Cancer Genome Analysis pipeline, as well as SNP carrier status using the STITCH pipeline. Within each treatment arm, time to incident adverse events (AEs) were compared between carriers (SNP+) and non-carriers (SNP-) via multivariable Cox regression, controlling for age, sex and sample purity, followed by a SNP´treatment interaction term in the whole cohort. Overall survival (OS) and progression-free survival (PFS) were also assessed. Finally, a recurrent event analysis for AEs was conducted using the Andersen-Gill model, controlling for the same variables. Results: In total, 382 pts were included (NIVO: n=189, EVE: n=193), among which 56 (14.7%) were SNP+. There were no differences in clinical and pathological characteristics between SNP+ and SNP-, except for sex (SNP+ 16.1% vs. SNP- 30.1% females, P=0.046). Similarly, no differences in somatic alterations, including single nucleotide and copy number variants were seen between SNP+ and SNP-. SNP carrier status had no effect on OS nor PFS in both treatment arms (all P≥0.47). Regarding AEs, 63 pts (33.3%) in the NIVO arm experienced at least 1 grade 2+ AE, compared to 78 pts (40.4%) in the EVE arm. The most common types of grade 2+ AEs were cutaneous (21.0%), hepatobiliary (16.8%) and endocrine (15.8%) in the NIVO arm, and respiratory (30.1%), cutaneous (22.3%) and gastrointestinal (19.4%) in the EVE arm. The rate of grade 2+ AEs was significantly higher in SNP+ vs. SNP- in the NIVO arm (HR=2.91[1.48-5.72]), but not in the EVE arm (HR=0.63[0.3-1.29], SNP´treatment Pinteraction=0.002). The rate of recurrent grade 2+ AEs was also significantly higher in SNP+ vs. SNP- in the NIVO arm (HR=3.43[1.83-6.43]), whereas a trend for fewer recurrent grade 2+ AEs was seen in SNP+ vs. SNP- in the EVE arm (HR=0.46[0.17-1.25], SNP´treatment Pinteraction=0.0005). Conclusions: The IL7 SNP (rs16906115) is associated with significantly higher rates of grade 2+ AEs, including recurrent events, in pts with mRCC treated with NIVO but not with EVE, with no effect on survival outcomes. These results affirm the SNP’s predictive potential as a biomarker for irAEs to guide therapeutic decisions in pts treated with ICIs.

Safety and Efficacy of Mycophenolate Mofetil Associated With Tacrolimus for Kidney-pancreas and Kidney Transplantation: A Systematic Review and Meta-Analysis of Randomized Studies

IntroductionThis study evaluated the efficacy and safety of mycophenolate mofetil (MMF) associated with tacrolimus (TAC) in patients undergoing kidney-pancreas and kidney transplants, in comparison with cyclosporine (CyA), azathioprine (AZA), everolimus (EVL), sirolimus (SRL), manitimus (MAN), mizoribine (MZR), and enteric-coated mycophenolate sodium (ECMPS) in combination or monotherapy. MethodsA systematic review and meta-analysis of randomized clinical trials was performed. The outcomes comprised acute rejection, graft loss, and adverse events. ResultsThirty studies were included. The main adverse events related to the TAC+MMF scheme were infection (36%; 95%CI: 26%-46%), including cytomegalovirus (CMV) (14%; 95%CI: 8%-20%); anemia (20%; 95%CI: 2%-37%); leukopenia (18%; 95%CI: 3%-33%); nausea (20%; 95%CI: 1%-39%); and diarrhea (26%; 95%CI:13%-40%). TAC+MMF was compared to the schemes AZA+TAC, CyA+AZA, CyA+MMF, CyA+SRL, ECMPS, EVL, MAN+TAC, MMF+SRL, MZR, TAC+AZA, TAC+EVR, TAC+MZR, TAC +SRL and TAC. TAC+MMF was associated with a lower risk of rejection than MMF monotherapy (RD: -0.24; 95%CI -0.46; -0.02). Comparing TAC+MMF with the other regimens, no significant difference was found for graft loss. TAC+MMF was associated with a higher risk of infections than MZR (RD: 0.174; 95%CI: 0.25; 0.323) and TAC monotherapy (RD: 0.07; 95%CI 0.003; 0.138). ConclusionGastrointestinal and hematological adverse events and infections are the most common with TAC+MMF for kidney-pancreas and kidney. TAC+MMF effectively prevents acute cellular rejection, and alternatives with AZA, CyA, SRL, ECMPS, EVL, MAN, and MSR have similar efficacy and safety profiles. TAC monotherapy and MZR may be associated with a lower risk of infections.

#1996 Identification of the biological bases associated with the mTOR-I-related podocytopathy through high-resolution mass spectrometry

Abstract Background and Aims mTOR inhibitors (mTOR-I) often cause podocytopathy with the development of proteinuria (sometimes in the nephrotic range) in kidney transplant patients, but the biological mechanisms underlying this effect have been only partially defined. Method Immortalized human podocytes were treated in vitro with different everolimus (EVE) doses (10, 100, 200, 500 nM) for 24 h. Total cell lysates and supernatants were subjected to high-resolution mass spectrometry (Proteomics analysis). Innovative tests were used for bioinformatics analysis, including the Support Vector machine (SVM) and partial least squares discriminant analysis (PLS-DA). The results were validated in vitro and in human urine samples from 30 patients treated with EVE-based immunosuppressive treatment, using various molecular biology techniques (western blot, ELISA). Results Proteomic evaluation identified more than 7000 differentially expressed proteins. Among these, after a conservative statistical analysis, 78 showed an expression level significantly and directly correlated with EVE dosage. Functional analysis of the selected proteins showed a biological interconnection that involved several pathways, including kinases, cell cycle regulation, epithelial–mesenchymal transition, and protein synthesis. Osteopontin (SPP1) and Polo Like Kinase 2 (PLK2) were two of the most significantly correlated proteins (p < 0.00001, FDR<0.5%). The data were then confirmed through biomolecular experiments in vitro and in vivo in urine samples from kidney transplant recipients who received immunosuppressive treatment with EVE. Conclusion This study, for the first time, analyzed the biological impact of mTOR-I on podocytes, helping to understand not only the molecular basis of its therapeutic effect but also the biological reasons underlying their adverse events (particularly proteinuria). Validation of our data on larger cohorts of patients treated with this category of drugs will help identify new therapeutic targets to minimize adverse effects.

Abstract PO3-14-01: Heterogeneity of tumor immune microenvironment to predict everolimus efficacy in premenopausal women with hormone receptor-positive/human epidermal growth factor receptor 2-negative adavanced breast cancer

Abstract Objective Everolimus (EVE), a mammalian target of rapamycin (mTOR) inhibitor, has been shown to prolong survival of patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-), advanced breast cancer (ABC) with endocrine resistance. Preclinical studies have suggested that mTOR is closely associated with the tumor immune microenvironment (TME). We aimed to explore the tumor heterogeneity of TME between patients with different response to everolimus (EVE), and identify potential markers to predict efficacy of EVE in premenopausal patients with HR+/HER2−, advanced breast cancer (ABC) suffering endocrine resistance. Methods Patients were divided into two groups according to the best response to EVE: the responsive subgroup (RS) and the non-responsive subgroup (NRS). Postoperative tumor tissue from patients who received EVE was collected for whole exome sequencing. Transcript abundance of 126 distinct tumor regions of interest (ROIs) were quantitated using digital spatial profiling, including 42 tumor cell zones (TCZs), 42 immune cell zones (ICZs), and 42 stroma cell zones (SCZs). Based on investigation in multiple discrete areas, differences in cell components, function and pathway, gene expression and immune cell infiltration between RS and NRS were investigated. Results Totally, 93 differentially expressed genes (DEGs) were identified in the ICZs, 174 DEGs in the TCZs, and 197 DEGs in the SCZs, using p< 0.05 and |log2FC >1| as the screening criterion. Among all the subgroup analyses on different ROIs, the statistical significance of PIP gene was the highest (ICZs: p=2.6E-12, TCZs: p=1.25E-20, SCZs: p=2.0E-18) in the comparison of RS and NRS. Moreover, we found that PIP was highly expressed in NRS and patients with a progression-free survival < 1 year. The receptor-legend analysis showed that, the intra-and inter-cellular communication in RS was mainly mediated by interaction between CCL-CCR family, while NRS mainly by COL family complex. Comparing all cell components extracted from each ROI, no statistical differences were found between RS and NRS, only a statistical trend in the SCZs (p=0.098). Further cell classification analysis showed fibroblasts highest in TCZs and SCZs, macrophages in ICZs. Compared to NRS, in TCZs, fibroblasts were significantly increased (p=0.01), and plasma cells (p=0.02) and neutrophils (p=0.03) were decreased in RS. In SCZs, the downregulated fibroblasts (p=0.04) and enhanced plasma cells (p=0.01) were observed in NRS. In ICZs, pDCs (p=0.048) and neutrophils (p=0.006) were significantly elevated in NRS compared with RS. Conclusion The utility of digital spatial gene expression profiling might provide some references to predict the efficacy of EVE in premenopausal patients with HR+/HER2- ABC with endocrine resistance. Citation Format: Yujing Tan, Fei Ma, Jiayu Wang, Pin Zhang, Binghe Xu, Liyan Xue, Ying Fan. Heterogeneity of tumor immune microenvironment to predict everolimus efficacy in premenopausal women with hormone receptor-positive/human epidermal growth factor receptor 2-negative adavanced breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-14-01.

Impact of Everolimus Initiation and Corticosteroid Weaning During Acute Phase After Heart Transplantation on Clinical Outcome: Data from the Korean Organ Transplant Registry (KOTRY).

The effect of changes in immunosuppressive therapy during the acute phase post-heart transplantation (HTx) on clinical outcomes remains unclear. This study aimed to investigate the effects of changes in immunosuppressive therapy by corticosteroid (CS) weaning and everolimus (EVR) initiation during the first year post-HTx on clinical outcomes. We analyzed 622 recipients registered in the Korean Organ Transplant Registry (KOTRY) between January 2014 and December 2021. The median age at HTx was 56years (interquartile range [IQR], 45-62), and the median follow-up time was 3.9years (IQR 2.0-5.1). The early EVR initiation within the first year post-HTx and maintenance during the follow-up is associated with reduced the risk of primary composite outcome (all-cause mortality or re-transplantation) (HR, 0.24; 95% CI 0.09-0.68; p < 0.001) and cardiac allograft vasculopathy (CAV) (HR, 0.39; 95% CI 0.19-0.79; p = 0.009) compared with EVR-free or EVR intermittent treatment regimen, regardless of CS weaning. However, the early EVR initiation tends to increase the risk of acute allograft rejection compared with EVR-free or EVR intermittent treatment.

Conversion from twice-daily everolimus to once-daily sirolimus in long-term stable liver transplant recipients

BackgroundAfter organ transplantation, strategies for simplifying the therapeutic regimen may improve adherence and prevent acute organ rejection and/or late graft loss. The present study aimed to evaluate the safety and efficacy of conversion from everolimus (EVR) twice daily to sirolimus (SIR) once daily in a large cohort of liver transplantation (LT) patients. MethodsWe included 108 LT patients with at least 12 months of post-transplant follow-up and no rejection episodes in the last year. Conversion was based on a 1:1 ratio (but eventually adapted to available formulations of SIR). ResultsThe median age at the time of conversion was 68.9 years (range: 26.1–83.6); 75.0% were men. The main indications for mTOR inhibitor use were renal failure (38.9%) and/or a history of malignancy (37.0%). Median conversion time after LT was 14.8 years (range: 2.3–31.5). The median dose of EVR and SIR (initially) was 1.50 mg/day (range: 0.5–4.5). The mean follow-up after conversion was 15.8±4.4 months. Median serum EVR/SIR trough levels before/after conversion were 3.85 ng/mL vs. 6.32 ng/mL (p < 0.05), i.e. a 1:1.64 ratio. At the end of follow-up after conversion, the median dose of SIR was 1.25 mg/day (range: 0.5–3.5), and the mean serum SIR trough level was 5.23 ng/mL; 9 patients (8.3%) had returned to EVR, because of side effects (mainly digestive), that resolved thereafter. No biopsy-proven acute rejection episode was observed. Finally, 87.1% of patients considered the conversion beneficial and the cost was reduced by 50.3%. ConclusionThe results of our study indicate that conversion from once-daily EVR to once-daily SIR in stable LT patients is safe, but needs dose adaptations and careful monitoring.

Preclinical multi-physiologic monitoring of immediate-early responses to diverse treatment strategies in breast cancer by optoacoustic imaging.

Optoacoustic imaging enables the measurement of tissue oxygen saturation (sO2) and blood perfusion while being utilized for detecting tumor microenvironments. Our aim was to employ multispectral optoacoustic tomography (MSOT) to assess immediate-early changes of hemoglobin level and sO2 within breast tumors during diverse treatments. Mouse breast cancer models were allocated into four groups: control, everolimus (EVE), paclitaxel (PTX), and photodynamic therapy (PDT). Hemoglobin was quantified daily, as well as sO2 and blood perfusion were verified by immunohistochemical (IHC) staining. MSOT showed a temporal window of enhanced oxygenation and improved perfusion in EVE and PTX groups, while sO2 consistently remained below baseline in PDT. The same results were obtained for the IHC. Therefore, MSOT can monitor tumor hypoxia and indirectly reflect blood perfusion in a non-invasive and non-labeled way, which has the potential to monitor breast cancer progression early and enable individualized treatment in clinical practice.

Everolimus-encapsulation in Pluronic P123 self-assembled micelles as drug delivery systems for drug-coated balloons

Drug-coated balloons (DCBs) are effective tools for cardiovascular interventions, ensuring uniform drug delivery to occluded arteries. This research investigates the potential of Pluronic P123 (P123), a micelle-forming polymer, to solubilize and release Everolimus (EVE) from DCBs. Furthermore, it seeks to understand how the ratio of P123 to EVE affects release rates and micelle formation under physiological conditions. We tested three P123 to EVE ratios: 90:10, 75:25, and 50:50. Microscopy revealed that increasing EVE proportions resulted in more uniform coatings. Fourier-transform infrared spectroscopy (FTIR) analysis confirmed the successful incorporation of EVE into the P123 matrix without altering its chemical properties. Differential scanning calorimetry (DSC) studies showed that EVE incorporation affected the crystalline structure of P123, leading to more uniform coatings. In vitro release studies showed that all formulations had <1% drug loss in the first minute (the tracking phase); furthermore, the 90:10 ratio exhibited optimal drug release in the following 3 min, corresponding to the deployment phase in DCB angioplasty. Analysis of micelle loading capacity (LC), encapsulation efficiency (EE), size, and structure indicated an increase in both LC and EE with higher EVE content and a corresponding enlargement in micelle size. Given these findings, the optimized formula provided a consistent coating on commercial balloons, highlighting the potential of using P123 for DCB drug coating and release.

Cost-effectiveness analysis of elacestrant versus standard endocrine therapy for second-/third-line treatment of patients with HR+/HER2- advanced or metastatic breast cancer: a US payer perspective.

This study evaluated the cost-effectiveness of elacestrant (ELA) and standard-of-care (SOC) as second-/third-line treatment for pretreated estrogen receptor (ER)- positive/human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer (A/MBC) in the US. The 3 health states partitioned survival model (PSM) was conducted from the perspective of the US third-party payers. The time horizon for the model lasted 10 years. Effectiveness and safety data were derived from the EMERALD trial (NCT03778931). Costs were derived from the pricing files of Medicare and Medicaid Services, and utility values were derived from published studies. One-way sensitivity analysis as well as probabilistic sensitivity analysis were performed to observe model stability. ELA led to an incremental cost-effectiveness ratio (ICER) of $8,672,360/quality-adjusted life year (QALY) gained compared with SOC in the overall population and $2,900,560/QALY gained compared with fulvestrant (FUL) in the ESR1(estrogen receptor 1) mutation subgroup. The two ICERs of ELA were significantly higher than the willingness-to-pay (WTP) threshold values of $150,000/QALY. ELA was not cost-effective for the second-/third-line treatment of patients with ER+/HER2-A/MBC compared with SOC in the US.