Daily Respiratory Research Analysis
A double-blind phase 3 trial (HARMONi-6) showed that ivonescimab plus chemotherapy significantly prolonged progression-free survival versus tislelizumab plus chemotherapy in first-line advanced squamous NSCLC. A large international cohort of NSCLC with leptomeningeal disease demonstrated improved survival in the modern era, with CNS-penetrant TKIs delaying onset and extending survival, and ICIs benefiting non-actionable genotypes. In pediatric OSA, higher hypoxic burden correlated with nondippin
Summary
A double-blind phase 3 trial (HARMONi-6) showed that ivonescimab plus chemotherapy significantly prolonged progression-free survival versus tislelizumab plus chemotherapy in first-line advanced squamous NSCLC. A large international cohort of NSCLC with leptomeningeal disease demonstrated improved survival in the modern era, with CNS-penetrant TKIs delaying onset and extending survival, and ICIs benefiting non-actionable genotypes. In pediatric OSA, higher hypoxic burden correlated with nondipping nocturnal blood pressure patterns, supporting its use as a cardiovascular risk biomarker.
Research Themes
- First-line immuno-oncology advancements in squamous NSCLC
- Evolving outcomes and management of leptomeningeal metastases in lung cancer
- Biomarker-based cardiovascular risk stratification in pediatric obstructive sleep apnea
Selected Articles
1. Ivonescimab plus chemotherapy versus tislelizumab plus chemotherapy as first-line treatment for advanced squamous non-small-cell lung cancer (HARMONi-6): a randomised, double-blind, phase 3 trial.
This double-blind phase 3 RCT showed that ivonescimab plus chemotherapy significantly improved median progression-free survival (11.1 vs 6.9 months; HR 0.60) compared with tislelizumab plus chemotherapy in first-line advanced squamous NSCLC, independent of PD-L1 status. Grade ≥3 treatment-related AEs occurred in 64% vs 54% and immune-related AEs in 9% vs 10%, with grade ≥3 hemorrhage in 2% vs 1%, indicating a manageable safety profile.
Impact: Head-to-head evidence supports a novel bispecific PD-1/VEGF-A–targeting strategy combined with chemotherapy as a potential new first-line standard in squamous NSCLC, a population with limited options.
Clinical Implications: Ivonescimab plus chemotherapy may be adopted as a first-line option regardless of PD-L1 status; clinicians should monitor for hemorrhagic events and immune-related AEs and consider comparative positioning versus established PD-1 plus chemotherapy regimens.
Key Findings
- Median PFS: 11.1 months with ivonescimab+chemo vs 6.9 months with tislelizumab+chemo (HR 0.60; one-sided p<0.0001).
- Benefit was consistent regardless of PD-L1 status.
- Grade ≥3 treatment-related AEs: 64% vs 54%; grade ≥3 immune-related AEs: 9% vs 10%.
- Grade ≥3 treatment-related hemorrhage occurred in 2% vs 1% of patients.
- Randomized, double-blind, multicenter design with 532 participants and median follow-up of 10.3 months.
Methodological Strengths
- Randomized, double-blind, phase 3 design with robust comparator and stratification.
- Consistent efficacy across PD-L1 subgroups, enhancing generalizability.
Limitations
- Overall survival and quality-of-life outcomes not yet mature at median follow-up of 10.3 months.
- Study conducted in China; external generalizability and comparisons with other global standards (e.g., pembrolizumab-based regimens) require consideration.
Future Directions: Assess overall survival, patient-reported outcomes, biomarker correlatives (e.g., angiogenesis signatures), and global confirmatory trials; clarify optimal management of hemorrhagic and immune-related AEs.
2. The evolving landscape of leptomeningeal metastases from NSCLC: an international, contemporary, multicenter cohort study.
In 2052 NSCLC patients with leptomeningeal disease, median survival after LMD diagnosis was 10.9 months, significantly improved versus historical cohorts. CNS-penetrant TKIs delayed LMD onset and extended survival; continuing them after LMD was associated with LMOS 12.4 vs 6.0 months. ICIs improved survival in non-actionable genotypes, underscoring modern systemic therapies’ impact on CNS disease.
Impact: This contemporary, large, international cohort provides actionable insights on timing, prognosis, and therapy for NSCLC LMD, including benefits of CNS-penetrant TKIs and ICIs by genotype.
Clinical Implications: Prefer CNS-penetrant TKIs in EGFR/ALK/other AGA NSCLC and consider continuing them after LMD diagnosis; integrate ICIs in non-AGA LMD when appropriate; apply standardized EANO–ESMO diagnostic criteria to guide management and trial eligibility.
Key Findings
- Median LMOS was 10.9 months with significant improvement versus historical cohorts (7.3 vs 11.5 months; P<0.0001).
- CNS-penetrant TKIs delayed LMD onset (P<0.0001) and continuing them post-LMD improved LMOS (12.4 vs 6.0 months; P<0.0001).
- In actionable genotypes (AGA), TKIs were associated with improved survival (HR 0.39; 95% CI 0.31–0.48).
- In non-AGA patients, ICIs conferred survival benefit (HR 0.45; 95% CI 0.25–0.84).
- Type I LMD by EANO–ESMO criteria (CSF cytology-positive) had shorter survival than type II (MRI/symptom-positive).
Methodological Strengths
- Very large, international, multicenter cohort with molecular stratification and standardized diagnostic framework.
- Robust survival analyses including historical comparisons and genotype-specific treatment associations.
Limitations
- Retrospective design with potential selection bias and confounding; therapy heterogeneity across centers and time.
- Non-randomized treatment exposure limits causal inference regarding TKIs/ICIs.
Future Directions: Prospective studies to optimize sequencing and continuation strategies of CNS-penetrant TKIs/ICIs, integration with radiotherapy/IT therapies, and harmonized diagnostics to enable trial enrollment and comparative effectiveness.
3. Cardiovascular Risk Through Hypoxic Burden in Children With Sleep Apnea: A Secondary Analysis of a Nonrandomized Clinical Trial.
Among 190 children with suspected OSA, higher hypoxic burden was associated with higher nocturnal diastolic BP, reduced nocturnal BP dipping, and a higher prevalence of nondipping. Adjusted analyses indicated a two-fold increased odds of nondipping for the highest HB quartile, supporting HB as a candidate biomarker for pediatric cardiovascular risk stratification.
Impact: This study translates an adult-established respiratory biomarker (hypoxic burden) into pediatrics, linking it with clinically meaningful blood pressure phenotypes.
Clinical Implications: Incorporate hypoxic burden into PSG-based assessment to identify children with OSA at higher cardiovascular risk; consider ABPM in high-HB cases and tailor interventions beyond AHI-centric decision-making.
Key Findings
- Higher HB quartiles were associated with greater nocturnal diastolic BP (P=0.03).
- Higher HB was linked to reduced nocturnal BP dipping (P=0.01) and increased nondipping prevalence (P=0.04).
- Multivariable models showed increased odds of nondipping in the highest HB quartile (OR 2.41; 95% CI 1.00–5.79; P=0.05).
- Median AHI was 6.0 events/h and median HB was 9.6 %min/h in this cohort.
Methodological Strengths
- Prospective, multicenter framework with objective PSG and 24-hour ABPM measures.
- Use of hypoxic burden as a quantitative desaturation metric beyond AHI.
Limitations
- Secondary analysis with exclusions for missing or low-quality data; observational associations limit causal inference.
- Conducted at two centers in Spain; external generalizability and outcome linkages (events) require longitudinal validation.
Future Directions: Define pediatric HB cutoffs linked to long-term CV outcomes; test whether OSA therapies reduce HB and improve ABPM phenotypes; evaluate implementation in community and diverse populations.