Real-world use of immune checkpoint inhibitors in advanced or recurrent endometrial cancer.

OBJECTIVE: The aim of this study was to describe real-world use of immune checkpoint inhibitors for women with advanced or recurrent endometrial cancer. METHODS: Adult women with advanced or recurrent endometrial cancer who received at least one line of systemic treatment between January 1, 2014 and November 1, 2020, then followed to May 31, 2021 in a nationwide electronic health record-derived de-identified database. Chi-Squared test or Welch's 2-sample t-tests were used to compare patient and clinical factors associated with immune checkpoint inhibitor treatment. Time to next treatment analyses were performed based on the treatment line of the immune checkpoint inhibitor. Sankey plots depicted patient-level temporal systemic treatment. RESULTS: During our study period, 326 women received their first immune checkpoint inhibitor treatment, increasing from 12 patients in 2016 to 148 in 2020. Factors associated with ever receiving immune checkpoint inhibitors included disease stage (p=0.002), mismatch repair (MMR)/microsatellite instability (MSI) status (p<0.001), performance status (p=0.001), and prior radiation receipt (p<0.001) and modality (p=0.003). The most common immune checkpoint inhibitor regimen was pembrolizumab (47.9%) followed by pembrolizumab and lenvatinib (34.7%). Immune checkpoint inhibitors were given as first, second, and third or greater lines of therapy in 24.5%, 41.7%, and 46.1% of evaluable patients. The median time to next treatment was significantly longer if given as an earlier line of treatment (p=0.008). There were significant differences in treatment line of immune checkpoint inhibitor by region (p=0.004), stage (p<0.001), and prior radiation receipt (p=0.014) and modality (p=0.009). Among 326 patients who received immune checkpoint inhibitors, 114 (34.9%) received subsequent treatment including chemotherapy (43.9%), additional immune checkpoint inhibitors (29.8%), and other (26.3%) with no differences in demographic or clinical characteristics based on the type of post-immune checkpoint inhibitor treatment. CONCLUSION: In an observational retrospective real-world database study, immune checkpoint inhibitors were used in 14.7% of patients with advanced or recurrent endometrial cancer across multiple lines of treatment, including after initial immune checkpoint inhibitor treatment.

Pharmacokinetics of Ipatasertib in Subjects With Hepatic Impairment Using 2 Methods of Classification of Hepatic Function.

Ipatasertib is a highly selective small-molecule pan-Akt inhibitor in clinical development. Ipatasertib is predominantly eliminated by the liver, and therefore, the effect of hepatic impairment on ipatasertib pharmacokinetics (PK) was evaluated. In this phase 1 open-label, parallel group study, the PK of ipatasertib were evaluated in subjects with hepatic impairment based on both the Child-Pugh and the National Cancer Institute Organ Dysfunction Working Group classification for hepatic impairment. A single dose of ipatasertib at 100 mg was administered and the PK was characterized in healthy subjects with normal hepatic function or mild, moderate, and severe hepatic impairment. Based on Child-Pugh classification, subjects with moderate and severe hepatic impairment had an ≈2- and 3-fold increase in systemic exposure (area under the plasma concentration-time curve from time 0 to infinity [AUC0-∞ ]) to ipatasertib, respectively, compared to subjects with normal hepatic function. Systemic exposure (AUC0-∞ ) to ipatasertib in subjects with mild hepatic impairment was comparable to that in subjects with normal hepatic function. In accordance with reduced clearance capacity, subjects with mild to severe hepatic impairment showed lower systemic exposure (AUC0-∞ ) of ipatasertib metabolite M1 (G-037720). Overall results were comparable between Child-Pugh and National Cancer Institute Organ Dysfunction Working Group classification criteria. Based on the results from this study, no dosage adjustment is required for ipatasertib when treating patients with mild hepatic impairment, whereas a dose reduction would be recommended for subjects with moderate or severe hepatic impairment. Based on real-world data analysis, ≈2% of the intended patient population is expected to need a modified dose due to moderate or severe hepatic impairment.

Predictors of change differ for moderate and vigorous intensity physical activity and for weekdays and weekends: a longitudinal analysis.

BACKGROUND: Predictors of physical activity (PA) change are rarely investigated separately for different PA intensities and for weekdays/weekends. We investigated whether individual-level predictors of one-year change in objectively-measured physical activity differ for moderate PA (MPA) and vigorous PA (VPA) and for weekends and weekdays. METHODS: Accelerometer-assessed PA (mins) was obtained at baseline and +1 year (n = 875, 41.5% male, Mean ± SD baseline age: 9.8 ± 0.4 years-old). Potential predictors (n = 38) were assessed at baseline from psychological (e.g., self-efficacy), socio-cultural (e.g., parent support) and environmental domains (e.g., land use). Associations between predictors and change in MPA (2000-3999 counts/minute (cpm)) and VPA (≥4000 cpm) separately for weekdays and weekends were studied using multi-level linear regression. Analyses were adjusted for school clustering, sex and baseline PA. RESULTS: Weekend PA declined (MPA decline 4.6 ± 21.8 mins/day; VPA decline: 2.1 ± 20.1 mins/day; both p < 0.001) whereas weekday PA did not significantly change. Higher baseline PA and being a girl were associated with greater PA declines in all four outcomes; remaining predictors differed for MPA and VPA and/or weekdays and weekends. Family logistic support was associated with less of a decline in weekend MPA (CI 95%) 0.15 (0.05, 0.25) and VPA 0.19 (0.09, 0.29), and peer support with less of a decline in weekday MPA 0.18 (0.02, 0.34) and VPA 0.22 (0.06, 0.38). CONCLUSIONS: Results highlight the relevance of investigating predictors of PA change separately for different PA intensities and for weekdays/weekends. In addition to continued focus on school PA promotion, more effort to target interventions during weekends, such as in the family and community appears important. Encouraging peer support to increase weekday PA and targeting parent support for weekend PA may be health promotion priorities.

Do children's individual correlates of physical activity differ by home setting?

We investigated whether physical activity (PA) correlates differed for 9-10 year-old British children living in urban, suburban and rural settings. We analysed cross-sectional data on 1653 children (SPEEDY study). Exposure variables were self-reported, whilst PA was measured using Actigraph accelerometers. Data were analysed using multilevel hierarchical regression models, stratified by home setting. PA levels did not differ by home setting. Boys, those of normal weight and those having a preference for PA had higher PA levels in all strata, but additional correlates were identified within each setting. These results highlight the potential importance of tailoring interventions to specific environmental and population strata.

Determinants of change in physical activity in children and adolescents: a systematic review.

CONTEXT: Data are available on correlates of physical activity in children and adolescents, less is known about the determinants of change. This review aims to systematically review the published evidence regarding determinants of change in physical activity in children and adolescents. EVIDENCE ACQUISITION: Prospective quantitative studies investigating change in physical activity in children and adolescents aged 4-18 years were identified from seven databases (to November 2010): PubMed, SCOPUS, PsycINFO, Ovid MEDLINE, SPORTDdiscus, Embase, and Web of Knowledge. Study inclusion, quality assessment, and data extraction were independently validated by two researchers. Semi-quantitative results were stratified by age (4-9 years, 10-13 years, and 14-18 years). EVIDENCE SYNTHESIS: Of the 46 studies that were included, 31 used self-reported physical activity; average methodologic quality was 3.2 (SD=1.2), scored 0-5. Of 62 potential determinants identified, 30 were studied more than three times and 14 reported consistent findings (66% of the reported associations were in the same direction). For children aged 4-9 years, girls reported larger declines than boys. Among those aged 10-13 years, higher levels of previous physical activity and self-efficacy resulted in smaller declines. Among adolescents (aged 14-18 years), higher perceived behavioral control, support for physical activity, and self-efficacy were associated with smaller declines in physical activity. CONCLUSIONS: Few of the variables studied were consistently associated with changes in physical activity, although some were similar to those identified in cross-sectional studies. The heterogeneity in study samples, exposure and outcome variables, and the reliance on self-reported physical activity limit conclusions and highlight the need for further research to inform development and targeting of interventions.