Daily Respiratory Research Analysis

BACKGROUND: Squamous non-small-cell lung cancer (NSCLC) is associated with worse clinical outcomes than non-squamous NSCLC, but treatment options are scarce. We aimed to evaluate the efficacy and safety of ivonescimab plus chemotherapy versus tislelizumab plus chemotherapy as a first-line therapy for patients with advanced squamous NSCLC. METHODS: We conducted a randomised, double-blind, phase 3 trial at 50 sites across China (HARMONi-6). Patients aged 18-75 years with previously untreated, pathologically confirmed, unresectable stage IIIB, IIIC, or stage IV squamous NSCLC and an Eastern Cooperative Oncology Group performance status score of 0 or 1 were eligible for inclusion. Patients were randomly assigned (1:1) to receive intravenous ivonescimab (20 mg/kg) or tislelizumab (200 mg), plus intravenous paclitaxel (175 mg/m FINDINGS: From Aug 17, 2023, to Jan 21, 2025, 761 patients were screened for eligibility, among whom 532 (70%) patients were enrolled and randomly assigned to receive ivonescimab plus chemotherapy (266 [50%] patients) or tislelizumab plus chemotherapy (266 [50%] patients). As of Feb 28, 2025, median follow-up time was 10·3 months (95% CI 9·5-11·0). Median progression-free survival was 11·1 months (95% CI 9·9-not evaluable) in the ivonescimab group and 6·9 months (5·8-8·6) in the tislelizumab group (hazard ratio 0·60 [95% CI 0·46-0·78]; one-sided p<0·0001). The progression-free survival benefit with ivonescimab plus chemotherapy was consistent regardless of PD-L1 status. 170 (64%) patients in the ivonescimab group and 144 (54%) patients in the tislelizumab group had grade 3 or higher treatment-related adverse events, with grade 3 or higher immune-related adverse events occurring in 24 (9%) patients in the ivonescimab group and in 27 (10%) patients in the tislelizumab group. Grade 3 or higher treatment-related haemorrhage occurred in five (2%) patients in the ivonescimab group and in two (1%) patients in the tislelizumab group. INTERPRETATION: In patients with untreated advanced squamous NSCLC, ivonescimab plus chemotherapy showed significantly improved progression-free survival compared with tislelizumab plus chemotherapy, regardless of PD-L1 status, as well as a manageable safety profile. This regimen could be used as a novel first-line treatment in this patient group. FUNDING: Akeso Biopharma.

BACKGROUND: Leptomeningeal metastatic disease (LMD) represents a devastating complication of non-small-cell lung cancer (NSCLC) with a poor prognosis. Our understanding of LMD is limited in the era of molecular testing and emerging therapeutic options for lung cancer. PATIENTS AND METHODS: We conducted an international, multicenter, retrospective study involving eight institutions across Asia, United States, and Europe. Patients diagnosed with LMD from advanced NSCLC were identified (2007-2024). Clinicopathological characteristics, treatment patterns, and outcomes were analyzed. The primary endpoint was overall survival from the LMD diagnosis (LMOS). RESULTS: A total of 2052 patients with NSCLC and LMD were included and analyzed by molecular subtypes: epidermal growth factor receptor (EGFR) (n = 1610), ALK (n = 141), other actionable genomic alterations (other AGA; n = 137), and non-AGA (n = 164). The cumulative prevalence of LMD by molecular subgroups was EGFR, 11.1%; ALK, 11.2%; ROS1, 16%; ERBB2, 12.3%, non-AGA, 3.6%. A higher proportion of LMD was diagnosed >3 years after initial metastatic diagnosis. By the European Association of Neuro-Oncology (EANO)-European Society for Medical Oncology (ESMO) diagnostic criteria, type I (cerebrospinal fluid cytology positive) had significantly shorter LMOS than type II (magnetic resonance imaging and/or symptom positive). Median LMOS was 10.9 months [95% confidence interval (CI) 10.0-11.8 months] in all patients. Compared with historical cohorts, patients demonstrated improved LMOS in contemporary cohorts (7.3 versus 11.5 months, P < 0.0001), across all molecular subtypes. In AGA NSCLC, tyrosine kinase inhibitors (TKIs) were associated with improved LMOS [hazard ratio (HR) 0.39, 95% CI 0.31-0.48, P < 0.0001]. Immune checkpoint inhibitors (ICIs) conferred survival benefit in non-AGA patients (HR 0.45, 95% CI 0.25-0.84, P = 0.012). For the EGFR-mutated cohort, central nervous system (CNS)-penetrant TKI usage delayed LMD onset (P < 0.0001). Continued CNS-penetrant TKIs after LMD diagnosis were associated with longer LMOS (12.4 versus 6.0 months, P < 0.0001). CONCLUSIONS: The prevalence of LMD is rising, largely due to prolonged survival in advanced NSCLC. Contemporary systemic treatments, including TKIs and ICIs, were the main contributors to delayed LMD onset and improved LMD survival.

IMPORTANCE: Emerging biomarkers, such as hypoxic burden (HB), have demonstrated utility in estimation of cardiovascular (CV) risk in adults with obstructive sleep apnea (OSA). Its applicability in pediatric OSA remains unexplored. OBJECTIVE: To explore whether HB is associated with disturbances in blood pressure (BP) patterns in pediatric OSA. DESIGN, SETTING, AND PARTICIPANTS: Children with suspected OSA were included in this secondary analysis performed within the framework of the Kids Trial, a prospective, multicenter nonrandomized clinical trial, with data accrued between January 30, 2018, and August 28, 2023, at 2 university hospitals in Spain. A total of 286 children with suspected OSA were assessed for eligibility. Ninety-six children for whom HB was unavailable or with BP data that did not fulfill quality criteria were excluded. MAIN OUTCOMES AND MEASURES: Children underwent polysomnography and 24-hour ambulatory BP monitoring (ABPM). HB was quantified as the area under the desaturation curve of each respiratory event, relative to the pre-event baseline oxygen saturation. BP variables were obtained from ABPM. RESULTS: A total of 190 children were included in the analysis. Median age was 6 (IQR, 5-8) years, and 108 participants (56.8%) were male. Median apnea hypopnea index was 6.0 (IQR, 3.1-10.3) events per hour with a median HB of 9.6 (IQR, 3.8-22.5) %min/h. A comparison of the HB quartiles revealed that higher HB levels were associated with greater nocturnal diastolic BP (quartile 1: 56.0 [IQR, 52.0-60.0] mm Hg; quartile 2: 57.0 [IQR, 54.0-61.0] mm Hg; quartile 3: 59.0 [IQR, 53.0-61.0] mm Hg; and quartile 4: 58.0 [IQR, 55.0-61.0] mm Hg; P = .03), a reduced nocturnal decrease in mean BP (quartile 1: 13.5 [IQR, 8.0-18.2] mm Hg; quartile 2: 10.8 [IQR, 8.3-15.1] mm Hg; quartile 3: 11.4 [IQR, 8.7-15.2] mm Hg; and quartile 4: 8.9 [IQR, 6.6-13.5] mm Hg; P = .01), and an increased prevalence of a nondipping pattern (NDP) (quartile 1: 15 of 47 [31.9%]; quartile 2: 21 of 47 [44.7%]; quartile 3: 19 of 46 [41.3%]; and quartile 4: 26 of 47 [55.3%]; P = .04). Multivariable analysis showed an increased risk of NDP in the higher quartile of HB (odds ratio, 2.41; 95% CI, 1.00-5.79; P = .05). CONCLUSIONS AND RELEVANCE: In this secondary analysis of a nonrandomized clinical trial, elevated HB values were associated with an NDP and reduced nocturnal decrease in BP in children with OSA, both of which are established markers of CV risk. These results suggest the potential utility of HB as a biomarker for CV risk stratification and clinical management in the pediatric population with OSA.