Everolimus In Patients Research Articles

The Efficacy of a Lower Dose of Everolimus in Patients with Advanced Neuroendocrine Tumors

Background: Everolimus at 10 mg daily is approved to treat patients with advanced grade 1/2 neuroendocrine tumors (NETs), although it may lead to significant toxicity. Grade 3 or higher drug-related adverse events and drug discontinuation occur in approximately one-fourth of cases. However, phase I trials have demonstrated that doses from 5 mg daily efficiently inhibit NET cell signaling. Objectives and Methods: This multicenter retrospective study compared the time to treatment failure (TTF) in patients with NETs who received a mean daily dose of 7–10 mg (higher dose [HD]) or ≤6 mg (lower dose [LD]) of everolimus. Results: Ninety-two patients were included: 74 (80%) in the HD group and 18 (20%) in the LD group. At a median follow-up of 4.2 years, the median time to treatment failure (TTF) was 9.2 months for the HD and 7.2 months for the LD groups (p = 0.85). The TTF did not significantly differ between the LD and the HD groups (HR: 1.24; 95% CI: 0.68–2.25; p = 0.47), even after adjusting for age at treatment initiation, the NET grade, and the treatment line. Conclusion: Everolimus doses from 5 to 6 mg/day seem to be equally as effective as higher doses, but lower doses are potentially associated with less toxicity and lower costs. These findings support validation through a randomized clinical trial.

1150P Search for biomarkers to personalize treatment with streptozotocin plus 5-fluorouracil or everolimus in patients with advanced pancreatic neuroendocrine tumors: The randomized phase III SEQTOR trial (GETNE-1206)

1150P Search for biomarkers to personalize treatment with streptozotocin plus 5-fluorouracil or everolimus in patients with advanced pancreatic neuroendocrine tumors: The randomized phase III SEQTOR trial (GETNE-1206)

1156P The efficacy of lower doses of everolimus in patients with advanced neuroendocrine tumors

1156P The efficacy of lower doses of everolimus in patients with advanced neuroendocrine tumors

Pharmacokinetic variability of everolimus and impact of concomitant antiseizure medications in patients with tuberous sclerosis complex: A retrospective study of therapeutic drug monitoring data in Denmark and Norway.

The mTOR-inhibitor everolimus is a precision drug with antiepileptogenic properties approved for treatment of epilepsy in persons with tuberous sclerosis complex (TSC) in combination with other antiseizure medications (ASMs). However, the pharmacokinetic variability of everolimus is scarcely described, and the available information on pharmacokinetic interactions is scarce. The purpose of this study was to investigate pharmacokinetic variability of everolimus in patients with TSC, and the impact of age, sex and comedication. In this retrospective observational study we used anonymized data from medical records of patients with TSC using everolimus in Norway and Denmark, 2012 to 2020. Long-term therapeutic drug monitoring (TDM) identified inter-patient and intra-patient variability. The study included 59 patients, (36 females (61%)), median age 22 (range 3-59 years). Polytherapy was used in 50 patients (85%). The most frequently used ASMs were lamotrigine (n = 21), valproate (n = 17), and levetiracetam (n = 13). Blood concentrations of everolimus were measured in all patients. Pharmacokinetic variability of everolimus between patients was extensive, as demonstrated by a 24-fold variability from minimum-maximum concentration/dose (C/D)-ratios. The coefficient of variation (CV) for intra-patient (n = 59) and inter-patient variability (n = 47, ≥3 measurements) was 40% and 43%, respectively. The C/D-ratio of everolimus was 50% lower in 13 patients (22%) using enzyme-inducing ASMs compared to the 30 patients who did not (0.7 vs 1.4 ng/mL mg, P < .05). Age and sex were not significantly associated with changes in C/D-ratios of everolimus. Long-term TDM identified extensive variability in concentrations over time for everolimus both within and between patients, where comedication with enzyme-inducing ASMs was an important contributing factor. The findings suggest a need for TDM in patients with TSC treated with everolimus.

Everolimus in patients with severe liver allograft rejection: An invaluable rescuer

Everolimus in patients with severe liver allograft rejection: An invaluable rescuer

Phase III Randomized, Placebo-Controlled Trial of Endocrine Therapy ± 1 Year of Everolimus in Patients With High-Risk, Hormone Receptor-Positive, Early-Stage Breast Cancer.

Phosphatidylinositol 3-kinase/AKT-serine threonine kinase/mammalian target of rapamycin (mTOR) pathway abnormalities contribute to endocrine resistance. Everolimus, an mTOR inhibitor, improved progression-free survival in hormone receptor-positive metastatic breast cancer (BC) when combined with endocrine therapy (ET). In this phase III randomized, placebo-controlled trial, we assessed the efficacy of everolimus + ET as adjuvant therapy in high-risk, hormone receptor-positive, human epidermal growth factor receptor 2-negative BC after adjuvant/neoadjuvant chemotherapy. Patients were randomly assigned 1:1 to physician's choice ET and 1 year of everolimus (10 mg orally once daily) or placebo stratified by risk group. The primary end point was invasive disease-free survival (IDFS) evaluated by a stratified log-rank test with the hazard ratio (HR) estimated by Cox regression. Subset analyses included preplanned evaluation by risk group and exploratory analyses by menopausal status and age. Secondary end points included overall survival (OS) and safety. Everolimus did not improve IDFS/OS when added to ET in patients with early-stage high-risk, hormone receptor-positive BC. One thousand and nine hundred thirty-nine patients were randomly assigned with 1,792 eligible for analysis. Overall, no benefit of everolimus was seen for IDFS (HR, 0.94 [95% CI, 0.77 to 1.14]) or OS (HR, 0.97 [95% CI, 0.75 to 1.26]). The assumption of proportional hazards was not met suggesting significant variability in the HR over time since the start of treatment. In an unplanned subgroup analysis among postmenopausal patients (N = 1,221), no difference in IDFS (HR, 1.08 [95% CI, 0.86 to 1.36]) or OS (HR, 1.19 [95% CI, 0.89 to 1.60]) was seen. In premenopausal patients (N = 571), everolimus improved both IDFS (HR, 0.64 [95% CI, 0.44 to 0.94]) and OS (HR, 0.49 [95% CI, 0.28 to 0.86]). Treatment completion rates were lower in the everolimus arm compared with placebo (48% v 73%) with higher grade 3 and 4 adverse events (35% v 7%). One year of adjuvant everolimus + ET did not improve overall outcomes. Subset analysis suggests mTOR inhibition as a possible target for patients who remain premenopausal after chemotherapy.

Expression of the receptor tyrosine kinase AXL and clinical outcomes to cabozantinib and everolimus in patients with metastatic renal cell carcinoma enrolled in the METEOR trial.

4543 Background: High expression of the receptor tyrosine kinase AXL has been associated with resistance to targeted agents and anti-PD-1 therapy in multiple tumor types, including metastatic clear cell Renal Cell Carcinoma (mccRCC). Cabozantinib (cabo), a multitargeted tyrosine kinase inhibitor (TKI) active against VEGFR, MET, and AXL, is approved for the treatment of mccRCC, but no predictive biomarkers are available. Here, we analyzed tumor samples from the METEOR trial to assess whether AXL expression predicts improved clinical outcomes with cabo relative to everolimus (evero, mTOR inhibitor) in patients (pts) with mccRCC. Methods: Double immunohistochemistry staining for AXL and CD45/CD163 (immune cell/ macrophage markers) was performed on 278 pretreatment tumor tissues from the METEOR trial (cabo=147; evero=131). Image analysis algorithms were used to assess the % of AXL+ tumor cells (TC), % of AXL+ immune cells (IC), and combined % of AXL+ TC and IC (TC/IC). Optimal cutoffs, based on the minimum p-value approach, were determined at the 17th, 30th, and 22nd percentile for TC, IC, and TC/IC, respectively. The association with progression-free survival (PFS) was assessed using Cox regression adjusted for IMDC risk groups, the presence of bone metastases, and the number of previous VEGFR TKI treatments. The association with objective response rate (ORR) (cabo arm only due to low response rate in evero arm) was reported descriptively. Results: We observed a strong correlation between % AXL+ TC and % AXL+ IC (Spearman correlation coefficient 0.85; p-value &lt;0.001). In the evero arm, high % AXL+ TC and high % AXL+ TC/IC were significantly associated with shorter PFS (median 1.9 vs. 4.1 months and 1.9 vs 4.2 months, respectively); a similar trend was observed for % AXL+ IC. In the cabo arm, % AXL+ TC, % AXL+ IC, and % AXL+ TC/IC were not associated with PFS or ORR (Table). The magnitude of increase in PFS for pts receiving cabo versus evero was larger in pts with high % AXL+ TC compared to pts with low % AXL+ TC (HR: 0.30 vs. 0.51, p-interaction=0.18) and in pts with high % AXL+ TC/IC compared to pts with low % AXL+ TC/IC (HR: 0.30 vs 0.53, p-interaction=0.12). Conclusions: Our finding that the improvement in outcome with cabo relative to evero is more evident in pts with high levels of AXL expression supports that the antitumor activity of cabo in mccRCC is mediated, in part, by AXL inhibition. Our work identifies AXL expression as a potential predictive biomarker for cabo-based therapies in mccRCC. [Table: see text]

177Lu-edotreotide versus everolimus in patients with advanced neuroendocrine tumors of lung or thymic origin: The phase 3 randomized LEVEL, GETNE-T2217 trial.

TPS3177 Background: Everolimus is the only approved drug for the treatment of patients with neuroendocrine tumors (NETs) of lung and thymic origin, showing a median progression-free survival (PFS) of 11 months. Retrospective data for peptide receptor radionuclide therapy (PRRT) have demonstrated promising activity in somatostatin receptor (SSTR)-positive lung NETs. This study aims to compare the efficacy, safety, and patient-reported outcomes of 177Lu-edotreotide versus the standard of care everolimus in patients with advanced lung and thymic NETs. Methods: The LEVEL trial is a randomized, open-label, phase 3 international trial of 177Lu-edotreotide versus everolimus in patients with progressive, advanced, and well/moderately differentiated NETs of lung (typical/atypical) or thymic origin. Patients could be treatment naïve or have progressed (PD) on somatostatin analogues or ≤2 additional systemic treatments. Prior PRRT or mTOR inhibitors are not permitted. Eligible patients are randomly assigned 3:2 to 6 cycles of 177Lu-edotreotide (7.5±0.7 GBq / cycle) or to oral everolimus 10 mg once daily until PD or unacceptable toxicity. Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) scans are performed every 12 weeks until PD. Blood samples are analyzed at baseline, at 1st tumor assessment, and at PD for pharmacodynamic endpoints. Archival tumor tissue samples will be analyzed for ancillary studies. The primary endpoint is PFS according to RECIST v1.1. Secondary endpoints include overall response rate, duration of response, overall survival, safety, and quality of life (assessed through EORTC QLQ-C30). The expected sample size is 120 patients using a two-sided group sequential Lan-DeMets with O’Brien-Fleming-like boundaries test to demonstrate statistically significant risk reduction of 46.4% (HR= 0.536) in PFS between arms (α=0.05, β=0.2). The study has received institutional review board/ethics committee approval. Recruitment started in Oct 2023. Thirteen patients are already included. Clinical trial information: NCT05918302 .

Sequential use of PI3K/AKT/mTOR pathway inhibitors alpelisib and everolimus in patients with hormone receptor-positive (HR+) metastatic breast cancer.

1057 Background: Alpelisib (A), a PI3K inhibitor, is FDA-approved with fulvestrant for patients with PIK3CA-mutated HR+/HER2- MBC. Everolimus (E), an mTOR inhibitor, is FDA-approved with endocrine therapy (ET) regardless of PI3K/AKT/mTOR pathway mutation status. The efficacy and safety of sequential treatment with these pathway inhibitors is not well described. Methods: This single-center retrospective cohort study identified patients with HR+/HER2- MBC treated with both A and E sequentially, each in combination with ET, in either order from 2012-2023. We collected information on patient demographics, clinical and pathologic characteristics, treatment history, treatment adverse effects, and dates of disease progression (defined as radiographic or clinical progression leading to treatment change) from medical records. Patients treated first with E then A were categorized as Group 1 and those first with A then E as Group 2. Rates of prior CDK4/6i use were compared between groups with the chi-square test; differences in prior lines of therapy were assessed with the Wilcoxon rank sum test. Median PFS1 (PFS on 1st pathway inhibitor) and PFS2 (PFS on 2nd pathway inhibitor) were computed using the Kaplan-Meier method and the impact of prior treatment on PFS2 between groups was compared using Cox proportional hazards analysis. Results: 115 patients with HR+/HER2- MBC were included in this study. There were 62 (54%) patients in Group 1 and 53 (46%) patients in Group 2. Median prior lines of therapy in the metastatic setting for Group 1 was 4 (range 1-13) and for Group 2 was 3 (range 1-8; p=0.08). Median number of intervening therapies between E and A in Group 1 was 2 (range 0-8) and between A and E in Group 2 was 0 (range 0-4; p&lt;0.001). 34/62 (55%) patients in Group 1 and 45/53 (85%) in Group 2 received prior CDK4/6i ( p&lt;0.001). In Group 1, 49/62 (79%) of patients discontinued E for progression and 13 (21%) discontinued for toxicity. Median PFS1 was 9.2 months (95%CI 5.5-13.0) and PFS2 was 5.0 months (95%CI 4.6-7.9). In Group 2, 34/53 (64%) of patients discontinued A for progression and 19 (36%) discontinued for toxicity. Median PFS1 was 9.3 months (95%CI 7.0-14.0) and PFS2 was 3.5 months (95%CI 3.0-4.1). After adjusting for prior CDK4/6i use and prior lines of therapy (total and intervening), PFS2 was not significantly different between the groups. Genomic information will be included at the time of presentation. Conclusions: This is the largest retrospective study to-date of patients treated sequentially with PI3K/AKT/mTOR pathway inhibitors. PFS was longer with the 1st pathway inhibitor than with the 2nd regardless of sequence. This has implications for optimal integration of capivasertib, an AKT inhibitor, into HR+ MBC treatment. Prospective studies testing optimal sequencing are needed.

Abstract PO2-06-07: A Randomized Phase II Comparison of Single-Agent Carboplatin versus the Combination of Carboplatin and Everolimus for the Treatment of Advanced Triple Negative Breast Cancer

Abstract Background: Both TNBC and BRCA-1 associated breast cancers are sensitive to DNA cross-linking agents such as platinum compounds due to defective DNA repair by homologous recombination. TNBCs are also associated with a high frequency of PTEN loss, which can lead to activation of the mTOR pathway resulting in tumor cell growth and proliferation. mTOR activation can confer resistance to platinum agents, and this phenomenon may be reversible by the addition of an mTOR inhibitor, such as everolimus. A prior phase II single arm trial of carboplatin and everolimus in patients (pts) with advanced TNBC demonstrated good tolerability and preliminary efficacy. Methods: We conducted a phase II, multicenter, randomized trial in pts with advanced TNBC, who had received 0-3 prior lines of therapy. Pts were randomly assigned (in a 2:1 ratio) to carboplatin and everolimus or carboplatin alone. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR), and safety. We planned to enroll 72 pts which would provide &amp;gt; 80% power for a one-sided log-rank test at the 5% level of significance, to detect a 2.5 month improvement in median PFS between treatment groups, assuming a median PFS of 2.5 months in the control group. An interim analysis for futility was planned after 36 events with a stopping boundary of P &amp;lt;0.375 for the comparison of PFS, using an Obrien-Fleming spending function. Of note, the trial was stopped earlier than planned based on a sensitivity/tipping point analysis which indicated that terminating the trial 3 months ahead of schedule would have no substantial impact on the primary endpoint. Results: A total of 56 pts were randomized between 2015 and 2022, of whom 36 received carboplatin/everolimus and 20 carboplatin alone. The median age of the population was 62.8 years (range: 33-87) and about 20% of pts had BRCA-1 or BRCA-2 mutations. In the overall population, pts had received a median of 1 (range 1-3) prior line of therapy in the metastatic setting, with 75% of pts receiving prior chemotherapy and 47% prior carboplatin. The median PFS was significantly improved in pts who received carboplatin and everolimus (4.7 months) versus those who received carboplatin alone (2.1 months; HR: 0.37; 95% CI: 0.19-0.72; p=0.0042). Overall survival was 22.1 months in pts on the combination versus 14.4 months on carboplatin alone (HR: 0.73; 95% CI: 0.30-1.72; p=0.3106). CBR was 61% with the combination vs 50% with carboplatin monotherapy, as shown in Table 1. Most common adverse events (AEs) on carboplatin and everolimus included thrombocytopenia (81%), anemia (69%), leukopenia (67%), fluid retention (64%), and neutropenia (61%). Overall, Grade 3/4 events occurred in 75% of pts (83% of pts on combination vs 60% on carboplatin alone) and were primarily anemia (40% vs 17%), thrombocytopenia (47% vs 0%), and neutropenia (20% vs 0%). Of note, there was an increase in thrombocytopenia with the addition of everolimus (All Grades: 81% vs 35%, Grade 3/4: 39% vs 0%). Conclusions: Treatment options for TNBC are limited due to a lack of targeted therapies. The combination of carboplatin and everolimus in this study was associated with a 63% reduction in risk of progression or death in pts with metastatic TNBC. The regimen was well tolerated and provides a promising treatment option for pts with advanced TNBC. Table 1. Results in Patients on Carboplatin and Everolimus versus Carboplatin Alone NE= Not Estimable; 1Unevaluable patients treated as non-responders in CBR and ORR calculations. Citation Format: Rima Patel, Jami Fukui, Paula Klein, Erin Moshier, Charles Shapiro, Anupama Goel, Julie Fasano, Theresa Shao, Aarti Bhardwaj, Rita Vaccaro, Gargi Atul Joshi, Joseph Sparano, Amy Tiersten. A Randomized Phase II Comparison of Single-Agent Carboplatin versus the Combination of Carboplatin and Everolimus for the Treatment of Advanced Triple Negative 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 PO2-06-07.

Abstract PS15-01: A first-in-human phase 1 study of SIM0270, a brain-penetrant oral selective estrogen receptor degrader (SERD), in patients with ER+/HER2- locally advanced or metastatic breast cancer

Abstract Background: ER+/HER2- breast cancer is the most prevalent subtype, and endocrine-based therapy is the standard treatment. SIM0270 is a brain-penetrant and highly potent oral SERD that has demonstrated ER degradation and robust antitumor activity across various preclinical models, including those with intracranial xenograft tumors. Methods: This Phase 1 study evaluates the safety, pharmacokinetics and preliminary anti-tumor activity of SIM0270 as monotherapy and/or in combination with palbociclib or everolimus in patients with HR+/HER2- advanced or metastatic breast cancer. The primary objective of the phase 1a study, which consisted of the dose escalation stage and the dose expansion stage, is to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of SIM0270 as monotherapy. A Bayesian Optimal Interval design (BOIN) was adopted. SIM0270 was administered orally daily in 28-day cycles. Here we report preliminary monotherapy data. Results: As of May 22nd 2023, 45 female patients were enrolled, receiving SIM0270 at dose levels of 10 mg (n=4), 30 mg (n=4), 60 mg (n=9), 90 mg (n=6), 120 mg (n=11), 200 mg (n=5), or 300 mg (n=6). The median age was 56 years (range, 40-73) and ECOG performance status was 0 (18%) or 1 (82%). Most patients were heavily pretreated, with a median of 2 prior endocrine-based therapies (range, 0-5) and a median of 2 prior chemotherapies (range, 0-8). Thirty-one patients (69%) received prior fulvestrant, 42 (93%) received prior aromatase inhibitors, and 28 (62%) received prior CDK4/6 inhibitors. Visceral metastases were present in 33 patients (72%), and brain metastases in 7 patients (16%). The most common TEAEs were sinus bradycardia (51%), anemia (38%), hypalbuminaemia (31%), hypercholesterolaemia (24%), urinary tract infection (24%), asthenia (24%), electrocardiogram (ECG) QT prolonged (24%), and dizziness (22%). Most of the TEAEs were Grade 1-2. Grade 3 TRAEs were ECG QT prolonged, gamma-glutamyltransferase(γ-GT) increased and dizziness in 2 patients each. All AEs were manageable with dose interruption or reduction, except only 1 patient discontinued treatment of SIM0270 due to TRAE (Grade 3 γ-GT increased). Four patients experienced dose-limiting toxicities (DLTs): 1 with Grade 3 ECG QT prolonged at 200mg dose level, 1 with Grade 3 ECG QT prolonged and 2 with Grade 3 dizziness at 300mg dose level. All DLTs were resolved with dose interruption then reduction. The MTD of single-agent SIM0270 was established as 200mg QD. Pharmacokinetic analysis revealed a T1/2 of approximately 70 hours, and the AUC and Cmax increased in an approximately linear manner with dose escalation. Concentration in cerebrospinal fluid was measured in 1 patient after 41 days treatment of SIM0270, which is consistent with preclinical data and suggested high concentration of SIM0270 in the brain of patients. Among 31 response evaluable patients (per RECIST 1.1 criteria), 4 PRs (3 unconfirmed) were observed, yielding an ORR of 12.9%. Brain lesions were all stable in 4 evaluable patients per RANO-BM criteria. In patients with ESR1 mutations at baseline and samples available for analysis, 4/6(67%) exhibited a reduction or loss of mutant ESR1 upon SIM0270 treatment. Conclusions: Single-agent SIM0270 was well tolerated and showed favorable antitumor activity in heavily pretreated advanced or metastatic ER+/HER2- breast cancer patients, including those previously treated with CDK4/6 inhibitors and fulvestrant. Phase 1a dose expansion with single-agent SIM0270 is ongoing, and the RP2D will be determined based on further accumulative data of tolerability and efficacy. (NCT05293964) Citation Format: Jiong Wu, Jian Zhang, Qingyuan Zhang, Yuping Sun, Hongtao Li, Yongmei Yin, Yehui Shi, Wenfeng Li, Yunjiang Liu, Min Yan, Chen Yang, Lili Zhu, Yang Yang, Liting Xue. A first-in-human phase 1 study of SIM0270, a brain-penetrant oral selective estrogen receptor degrader (SERD), in patients with ER+/HER2- locally advanced or metastatic 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 PS15-01.

Everolimus Mitigates the Risk of Hepatocellular Carcinoma Recurrence after Liver Transplantation.

To obtain long-term data on the use of everolimus in patients who underwent liver transplantation for hepatocellular carcinoma, we conducted a retrospective, single-center analysis of adult recipients transplanted between 2013 and 2021. Patients on everolimus-incorporating immunosuppression were matched with those on tacrolimus using an inverse probability of treatment weighting methodology. Two propensity-matched groups of patients were thus compared: 233 (45.6%) receiving everolimus versus 278 (54.4%) on tacrolimus. At a median (interquartile range) follow-up of 4.4 (3.8) years after transplantation, everolimus patients showed a reduced risk of recurrence versus tacrolimus (7.7% versus 16.9%; RR = 0.45; p = 0.002). At multivariable analysis, microvascular infiltration (HR = 1.22; p < 0.04) and a higher tumor grading (HR = 1.27; p < 0.04) were associated with higher recurrence rate while being within Milan criteria at transplant (HR = 0.56; p < 0.001), a successful pre-transplant downstaging (HR = 0.63; p = 0.01) and use of everolimus (HR = 0.46; p < 0.001) had a positive impact on the risk of post-transplant recurrence. EVR patients with earlier drug introduction (≤30 days; p < 0.001), longer treatment duration (p < 0.001), and higher drug exposure (≥5.9 ng/mL; p < 0.001) showed lower recurrence rates versus TAC. Based on our experience, everolimus provides a reduction in the relative risk of hepatocellular carcinoma recurrence, especially for advanced-stage patients and those with earlier drug administration, higher drug exposure, and longer time on treatment. These data advocate for early everolimus introduction after liver transplantation to reduce the attrition rate consequent to chronic immunosuppression.

The association between computed tomography attenuation value of renal angiomyolipoma associated with tuberous sclerosis complex and response to everolimus.

The response to everolimus in patients with renal angiomyolipoma associated with tuberous sclerosis complex (TSC-RAML) varies among individuals. This study aims to identify potential factors associated with the response to everolimus. We retrospectively examined data encompassing age, gender, tumor size, computed tomography attenuation value (CT value), CT enhancement, and tumor reduction rate in patients with TSC-RAML undergoing everolimus in two previously registered clinical trials. A total of 33 participants (29.33 ± 6.63years old, 20 females) were included. The correlation analysis conducted separately for tumors located in the left and right kidneys revealed significant negative correlations (P < 0.05) between tumor reduction rate and age, as well as tumor size. While significant positive correlations (P < 0.05) were observed between tumor reduction rate and unenhanced CT value as well as CT enhancement. Nonetheless, based on multiple linear regression analysis, unenhanced CT value emerged as the sole-independent predictor of tumor reduction rate among age, gender, tumor size, unenhanced CT value and CT enhancement for both left (coefficient = 0.00319, P < 0.0001) and right kidneys (coefficient = 0.00315, P = 0.0104). Notable reductions were observed in unenhanced CT value (- 3.81 vs - 24.70HU, P < 0.0001) and CT enhancement (48.16 vs 33.56HU, P < 0.0001) following a 3-month administration of everolimus. The decline in both unenhanced CT value and tumor size predominantly occurred within the initial 3months, subsequently maintaining a relatively stable level throughout the treatment. The unenhanced CT value of TSC-RAML showed an independent correlation with the response to everolimus, suggesting its potential as a predictor of everolimus efficacy in patients with TSC-RAML.

Everolimus treatment in patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative advanced breast cancer and a predictive model for its efficacy: a multicenter real-world study

Background: Everolimus is beneficial for patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2−) advanced breast cancer (ABC). However, some patients developed drug resistance and the well-established predictor for everolimus efficacy was limited. Objectives: The study was designed to evaluate the efficacy of everolimus in different treatment lines and identify several clinicopathological markers to estimate everolimus efficacy in patients with HR+/HER2− ABC. Design: This was a retrospective and multicenter study. Methods: Between 2014 and 2022, more than 2000 patients with tumors who received everolimus were collected from multiple cancer centers in China (National Cancer Center, Chinese PLA General Hospital, Peking University Cancer Hospital &amp; Institute). A training cohort and two validation cohorts were developed. Results: The training cohort included 338 patients. The median progression-free survival (PFS) for everolimus was 5.6 months, with an objective response rate of 25.1% and a clinical benefit rate of 54.4%. PFS was significantly worse from first-line (1L) to second-line (2L) to third-line (3L), with PFS1L for 13.5 months, PFS2L for 6.1 months, and PFS3L for 4.1 months ( p = 2.9e−6, hazard ratio (HR) = 0.70, 95% confidence interval (CI) = 0.61–0.82). The clinicopathological characteristics, including post-1L everolimus treatment, Ki67 index of more than 40%, more than two metastatic sites at first recurrence, and receiving adjuvant chemotherapy, were independent risk factors for PFS. A predictive model for everolimus efficacy was established using these four factors. In the low-risk group, patients achieved a median PFS of 12.6 months, significantly longer compared to 2.7 months for those in the high-risk group ( p = 2.4e−64, HR = 9.41, 95% CI = 7.05–12.56). The area under the curve was 0.96, 0.95, and 0.94 for 6-month, 1-year, and 3-year PFS, respectively. Internal validation cohort (PFS 18.4 vs 3.1 months, p = 3.6e−11, HR = 3.78, 95% CI = 2.49–5.74) and external validation cohort (PFS 13.5 vs 3.1 months, p = 2.9e−10, HR = 11.53, 95% CI = 4.68–28.37) confirmed its power for estimating clinical benefits of everolimus. Conclusion: A predictive model was successfully established to predict survival outcomes for everolimus in patients with HR+/HER2− ABC, which may provide references for the management of everolimus in Chinese patients with HR+/HER2− ABC.

Phase 3 LEVEL trial of 177Lu-edotreotide vs everolimus in patients with advanced neuroendocrine tumors of lung or thymic origin (GETNE-T2217)

Phase 3 LEVEL trial of 177Lu-edotreotide vs everolimus in patients with advanced neuroendocrine tumors of lung or thymic origin (GETNE-T2217)

Population pharmacokinetics of everolimus in patients with seizures associated with focal cortical dysplasia

Background: Everolimus is an inhibitor of mammalian target of rapamycin complex 1. As mutations in TSC1 and TSC2, which cause partial-onset seizures associated with TSC, were found in focal cortical dysplasia type Ⅱ (FCD Ⅱ) patients, a clinical trial has been performed to explore the efficacy and safety of everolimus in FCD patients. However, no dosage regimen was determined to treat FCD II. To recommend an optimal dose regimen for FCD patients, a population pharmacokinetic model of everolimus in FCD patients was developed.Methods: The data of everolimus were collected from September 2017 to May 2020 in a tertiary-level hospital in Korea. The model was developed using NONMEM® software version 7.4.1 (Icon Development Solutions, Ellicott City, MD, United States).Results: The population pharmacokinetics of everolimus was described as the one-compartment model with first-order absorption, with the effect of BSA on clearance. The final model was built as follows: TVCL = 12.5 + 9.71 × (BSA/1.5), TVV = 293, and TVKA = 0.585. As a result of simulation, a dose higher than 7 mg/m2 is needed in patients with BSA 0.5 m2, and a dose higher than 6 mg/m2 is needed in patients with BSA 0.7 m2. A dose of 4.5 mg/m2 is enough in the population with BSA higher than 1.5 m2 to meet the target trough range of 5–15 ng/mL.Conclusion: Based on the developed pharmacokinetics model, the optimal dose of everolimus in practice was recommended by considering the available strengths of Afinitor disperz®, 2 mg, 3 mg, and 5 mg.

Everolimus precision therapy for the GATOR1-related epilepsies: a case series.

Pathogenic variants in the GAP activity towards RAGs 1 (GATOR1) complex genes (DEPDC5, NPRL2, NPRL3) cause focal epilepsy through hyperactivation of the mechanistic target of rapamycin pathway. We report our experience using everolimus in patients with refractory GATOR1-related epilepsy. We performed an open-label observational study of everolimus for drug-resistant epilepsy caused by variants in DEPDC5, NPRL2 and NPRL3. Everolimus was titrated to a target serum concentration (5-15ng/mL). The primary outcome measure was change in mean monthly seizure frequency compared with baseline. Five patients were treated with everolimus. All had highly active (median baseline seizure frequency, 18/month) and refractory focal epilepsy (failed 5-16 prior anti-seizure medications). Four had DEPDC5 variants (three loss-of-function, one missense) and one had a NPRL3 splice-site variant. All patients with DEPDC5 loss-of-function variants had significantly reduced seizures (74.3-86.1%), although one stopped everolimus after 12 months due to psychiatric symptoms. Everolimus was less effective in the patient with a DEPDC5 missense variant (43.9% seizure frequency reduction). The patient with NPRL3-related epilepsy had seizure worsening. The most common adverse event was stomatitis. Our study provides the first human data on the potential benefit of everolimus precision therapy for epilepsy caused by DEPDC5 loss-of-function variants. Further studies are needed to support our findings.

Does the dose matter? Antiproliferative efficacy and toxicity of everolimus in patients with neuroendocrine tumors - Experiences from a tertiary referral center.

The mTOR-inhibitor everolimus has been approved for the treatment of advanced neuroendocrine tumors (NETs) but is associated with relevant toxicities in clinical practice. Hence, optimal treatment sequencing and the impact of dose reductions have yet to be clarified. This retrospective analysis assessed patients with advanced, well-differentiated NET treated with everolimus at the Medical University of Vienna. The primary objective was to evaluate the efficacy of everolimus in a real-world cohort. A total of 52 patients treated with everolimus for advanced NET grade 1 (G1) or G2 (or typical or atypical carcinoid) 2010-2021 were included in this analysis. The most common sites of origin were pancreas (44%) and lung (29%). The initial dose was decided by the treating physician based on clinical assessment and 25 patients (48%) each were started at 10 mg/day and 5 mg/day. Median progression-free survival (PFS) following everolimus in the overall cohort was 9.8 months (95% CI: 4.3-15.3), with a statistically significant PFS difference (p = .03) between NET G1/typical carcinoids (42.9 months) and NET G2/atypical carcinoids (8.9 months). PFS was numerically but not significantly shorter in patients treated with a reduced dose (7.5 months vs. 12.4 months, p = .359). Even in this mixed full/half dose cohort, 93% developed treatment-related side effects (mostly grade I, no grade IV), 63% had dose reductions or interruptions, and five stopped due to toxicity. Median survival following treatment was 40.9 months (95% CI: 21.5-60.3) and no difference with regard to dosing was observed (p = .517). These data from an unselected patient cohort show long-term outcomes similar to those reported in the pivotal studies. Comparing everolimus starting dose, median PFS did not significantly differ for patients treated at a lower dose. While this finding is limited by the sample size and warrants prospective verification, initiating therapy at a reduced dose might be practicable and safe in a distinct subset of patients.

Adjuvant everolimus in patients (Pts) with localized non-clear cell renal cell carcinoma (RCC): Subgroup analysis from the Everest trial (SWOG S0931).

4546 Background: In S0931, adjuvant treatment with the mTOR inhibitor everolimus respectively yielded disease-free survival (DFS) and overall survival (OS) hazard ratios (HR) of 0.85 (95% CI 0.71-1.00) and 0.90 (95% CI 0.71-1.13) in pts with resected, localized RCC. Previously, everolimus had been shown to be active in chromophobe RCC (chRCC; Tannir et al Eur Urol 2016) and papillary RCC (papRCC; Escudier et al Eur J Cancer 2016). We sought to evaluate the efficacy of everolimus within these non-clear cell subsets of EVEREST. Methods: 1545 adult pts with treatment-naïve, non-metastatic, fully-resected RCC at intermediate high- (pT1 G3-4 N0 to pT3a G1-2 N0) or very high-risk (pT3a G3-4 to pT4 G-any or N+) for recurrence were randomized 1:1 to 54 weeks of everolimus 10 mg PO daily or placebo within 12 weeks of radical or partial nephrectomy. Exploratory analyses of RFS and OS chromophobe and papillary subgroups were performed. Results: A total of 99 eligible pts had chRCC; 109 had papRCC (16 type I; 37 type II; 56 NOS). Median follow-up is 6.3 years. Pt characteristics were balanced between the 2 arms in each histological group. Thirty-four (34%) pts in the chRCC subgroup and 50 (46%) pts in the papRCC subgroup had very high-risk disease. Fewer pts completed all 54 weeks of everolimus in each subgroup compared to placebo (49% vs. 74% in the ChRCC subgroup and 46% vs. 71% in the papillary subgroup). DFS and OS for each subgroup are shown. Conclusions: Non-clear cell histology accounted for a considerable proportion (~13%) of S0931 pts. The estimated everolimus HRs for DFS and OS in the chRCC subset are consistent with the overall trial result, but those same modest HRs were not seen in papRCC, in contrast to prior reports of mTOR inhibitor activity in this subtype. Although inferences are limited by sample size and wide CIs, this is the largest experience in chRCC or papRCC among any adjuvant trials presented to date. Clinical trial information: NCT01120249 . [Table: see text]

EvERA Breast Cancer (BC): Phase III study of giredestrant + everolimus vs exemestane + everolimus in patients (pts) with estrogen receptor-positive, HER2-negative locally advanced or metastatic BC (ER+, HER2– LA/mBC).

TPS1119 Background: Endocrine therapy (ET) + a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) is the standard of care in pts with ER+, HER2– mBC in the first-line setting. Fulvestrant ± a CDK4/6i, and everolimus + exemestane are the current approved second-line regimens. However, therapeutic resistance to some ETs, such as aromatase inhibitors, can arise from ESR1 mutations (m) driving estrogen-independent transcription and proliferation. Current post-CDK4/6i treatment options are suboptimal. New therapy options are therefore needed to reduce this risk and to improve outcomes, tolerability, quality of life, and adherence to treatment. Giredestrant is a highly potent, nonsteroidal oral selective ER antagonist and degrader (SERD) that achieves robust ER occupancy and is active regardless of ESR1-mut status. While Phase I SERD combination data in the post-CDK4/6i setting are encouraging, there are no randomized combination data. Combining giredestrant and everolimus may improve outcomes after CDK4/6is and in pts with ESR1m tumors. Methods: evERA BC (NCT05306340), a Phase III, global, randomized, open-label, multicenter study will evaluate the efficacy and safety of giredestrant + everolimus vs. exemestane + everolimus in pts with ER+, HER2– LA/mBC who had previous treatment with a CDK4/6i and ET in the LA/mBC or adjuvant setting. Pts will be randomized to either giredestrant (30 mg) + everolimus (10 mg) by mouth (PO) every day (QD), or exemestane (25 mg) + everolimus (10 mg) PO QD. Pts will receive treatment until disease progression or unacceptable toxicity. Pts will use a dexamethasone mouth rinse 4 times QD for 8 weeks concurrently with study treatment. Eligibility: Female/male pts ≥ 18 years with ER+, HER2– LA/mBC and disease progression ≥ 6 months (mo) after initiating ET + CDK4/6i in the LA/mBC setting (and ≥ 4 mo on most recent ET, if ET + CDK4/6i was not the most recent therapy received), or relapsed either while taking or within 12 mo of exposure to combination adjuvant ET (≥ 12 mo) + CDK4/6i (≥ 6 mo), and available blood sample for circulating tumor DNA central testing for ESR1m status. Men and pre-/perimenopausal women will receive a LHRH. Co-primary endpoints: Investigator-assessed progression-free survival (per RECIST v1.1) in the intent-to-treat and ESR1m populations. Secondary endpoints: Overall survival; objective response rate; duration of response; clinical benefit rate; pt-reported outcomes; safety; pharmacokinetics. Co-primary endpoint analyses will use a two-sided stratified log-rank test at an overall 0.05 significance level. An independent data monitoring committee will be in place for safety. Target enrollment is 320 pts, and this study is currently recruiting. Encore from SABCS 2022 (OT2-01-07). Clinical trial information: NCT05306340 .