Association between treatment-emergent hypertension and survival with lenvatinib treatment for patients with hepatocellular carcinoma in the REFLECT study.

BACKGROUND: Lenvatinib is approved as a first-line treatment for patients with unresectable and/or recurrent hepatocellular carcinoma (HCC). Lenvatinib achieved promising clinical benefits in REFLECT but was associated with clinically significant treatment-emergent hypertension (CSTE-HTN, a grouped term), a common class effect of tyrosine kinase inhibitors. This post hoc analysis assessed the impact of CSTE-HTN on the efficacy and safety of lenvatinib in HCC. METHODS: Patients from REFLECT who received lenvatinib (n = 476) were stratified according to CSTE-HTN. Tumors were assessed by mRECIST. Overall survival (OS) and progression-free survival (PFS) were evaluated using landmark analyses at 4 and 8 weeks. RESULTS: A total of 212 patients in the lenvatinib arm developed CSTE-HTN, and 264 did not. CSTE-HTN first occurred at 3.7 weeks (median); the worst grade CSTE-HTN occurred at 4.1 weeks (median). No patients had life-threatening CSTE-HTN and/or died due to CSTE-HTN. Median OS was numerically longer in patients with versus without CSTE-HTN (at 4 weeks: 16.3 vs. 11.6 months; hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.621-1.004; at 8 weeks: 13.5 vs. 11.6 months; HR, 0.87; 95% CI, 0.696-1.089). Median PFS was similar between patients with and without CSTE-HTN (at 4 weeks: 6.6 vs. 6.4 months; HR, 0.887; 95% CI, 0.680-1.157; at 8 weeks: 5.7 vs. 6.4 months; HR, 1.09; 95% CI, 0.84-1.41). Objective response rate was numerically higher in patients with (48.6%) versus without CSTE-HTN (34.5%). CONCLUSIONS: In this retrospective analysis, CSTE-HTN was associated with improved OS but not PFS. CSTE-HTN did not impair the outcomes of patients with HCC treated with lenvatinib when detected early and managed appropriately.

Validation of the Survey of Sleep Quality in the Pediatric Intensive Care Unit (SSqPICU).

STUDY OBJECTIVES: Observational data suggest pediatric intensive care unit-related sleep and circadian disruption (PICU-SCD) affects many critically ill children. Multicenter trials exploring PICU-SCD have been impractical because measuring sleep in this setting is challenging. This study validates a questionnaire for caregivers to describe children's sleep in the PICU. METHODS: This prospective, multicenter, case-control study enrolled caregivers of children in 4 PICUs or in a hospital-based sleep laboratory (controls). Survey items were compiled from validated adult ICU and pediatric in- and outpatient sleep questionnaires. Control responses were compared to polysomnography to determine accuracy. A score was calculated by summing the level of disruption of sleep timing, duration, efficiency, quality, and daytime sleepiness and irritability. RESULTS: In responses from 152 PICU and 61 sleep laboratory caregivers, sleep survey items had acceptable internal reliability (α = 0.75) and reproducibility on retest surveys (interclass correlation coefficient > 0.600). Caregivers could not assess sleep of sedated children. Factor analysis identified 3 subscales of PICU-SCD. Control parents had good agreement with polysomnography sleep onset time (κ = 0.823) and sleep onset latency (κ = 0.707). There was a strong correlation between sleep scores derived by parental reporting to those by polysomnography (r = .844, P < .001). Scores had a linear association with caregiver-reported child sleep quality. There were no site-specific differences in sleep quality. Nearly all respondents found the survey easy to understand and of appropriate length. CONCLUSIONS: The Survey of Sleep Quality in the Pediatric Intensive Care Unit provides a reliable, accurate description of inpatient sleep disruption in nonsedated children, generalizable across PICUs. It offers practical means to quantify PICU-SCD daily in future investigations. CITATION: Hassinger AB, Mody K, Gomez R, et al. Validation of the Survey of Sleep Quality in the Pediatric Intensive Care Unit (SSqPICU). J Clin Sleep Med. 2024;20(8):1251-1258.

A Phase 1b Study of Lenvatinib plus Pembrolizumab in Patients with Unresectable Hepatocellular Carcinoma: Extended Analysis of Study 116.

Introduction: Lenvatinib (dosing for patients who weigh ≥60 kg was 12 mg/day; for patients who weigh <60 kg, the dose was 8 mg/day) plus pembrolizumab 200 mg once every 3 weeks demonstrated antitumor activity and a manageable safety profile in patients with first-line unresectable hepatocellular carcinoma (uHCC) in the open-label phase 1b Study 116/KEYNOTE-524 (primary analysis data cutoff date: October 31, 2019; median follow-up: 10.6 months). This analysis (updated data cutoff date: March 31, 2021) reports efficacy results from 17 months of additional follow-up time. Methods: 100 patients with uHCC were included in the primary analysis (median follow-up: 27.6 months). Endpoints included overall survival (OS), investigator-assessed progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR) per modified RECIST. Landmark analyses of OS by the best response at 3 and 9 months were performed. Pembrolizumab antidrug antibodies (ADAs) and concentrations were also measured (cutoff date: August 7, 2020). Results: ORR was 43.0% (95% CI 33.1-53.3%) and median DOR was 17.1 months (95% CI 6.9-19.3 months). Median PFS and OS were 9.3 months (95% CI 7.4-9.8 months) and 20.4 months (95% CI 14.4-25.9 months), respectively. No treatment-emergent ADAs were detected. Conclusion: Results show a sustained treatment effect with lenvatinib plus pembrolizumab in patients with uHCC in the first-line setting.