Daily Respiratory Research Analysis
A phase 3 trial showed that adding platinum–pemetrexed chemotherapy to first-line osimertinib improved overall survival in EGFR-mutated lung cancer, albeit with more grade ≥3 adverse events. Real-world data confirmed high effectiveness of nirsevimab against RSV infection and severe outcomes in infants. Mechanistic work identified SLC26A9 as essential for neonatal airway chloride secretion and mucociliary clearance, linking ion transport to early-life respiratory failure.
Summary
A phase 3 trial showed that adding platinum–pemetrexed chemotherapy to first-line osimertinib improved overall survival in EGFR-mutated lung cancer, albeit with more grade ≥3 adverse events. Real-world data confirmed high effectiveness of nirsevimab against RSV infection and severe outcomes in infants. Mechanistic work identified SLC26A9 as essential for neonatal airway chloride secretion and mucociliary clearance, linking ion transport to early-life respiratory failure.
Research Themes
- Optimization of targeted therapy in EGFR-mutated NSCLC
- Real-world effectiveness of RSV immunoprophylaxis in infants
- Ion transport mechanisms driving neonatal respiratory disease
Selected Articles
1. Survival with Osimertinib plus Chemotherapy in
In a phase 3, international, open-label trial (n=557), adding platinum–pemetrexed chemotherapy to first-line osimertinib improved median overall survival from 37.6 to 47.5 months (HR 0.77; P=0.02) in EGFR-mutated NSCLC. Toxicity increased, with grade ≥3 adverse events in 70% vs 34%.
Impact: This is definitive phase 3 evidence of an overall survival benefit with a new first-line strategy for EGFR-mutated NSCLC, likely to influence treatment guidelines.
Clinical Implications: For appropriate patients, consider osimertinib plus platinum–pemetrexed as a first-line option, balancing a meaningful OS gain against higher toxicity and the need for supportive care.
Key Findings
- Median overall survival improved to 47.5 months with osimertinib plus platinum–pemetrexed versus 37.6 months with osimertinib alone.
- Hazard ratio for death was 0.77 (95% CI 0.61–0.96; P=0.02).
- Grade ≥3 adverse events occurred in 70% with combination versus 34% with monotherapy; discontinuation of osimertinib in 12% vs 7%.
Methodological Strengths
- Randomized, international, phase 3 design with overall survival endpoint
- Adequate sample size (n=557) and clear reporting of safety outcomes
Limitations
- Open-label design could introduce bias in some secondary endpoints
- Higher toxicity burden may limit applicability in frail patients
Future Directions: Assess optimal sequencing and duration, biomarker-driven selection for combination therapy, and comparative effectiveness versus modern chemoimmunotherapy backbones.
2. Lack of SLC26A9-mediated chloride secretion causes mucus plugging and severe respiratory distress in neonatal mice.
Genetic deletion of Slc26a9 in neonatal mice led to lethal respiratory distress due to MUC5B-positive mucus plugging, reduced transepithelial potential difference indicating impaired chloride secretion, and sterile neutrophilic inflammation. SLC26A9-mediated chloride transport is essential for mucociliary clearance and survival after birth.
Impact: This study provides in vivo mechanistic proof that SLC26A9 drives airway chloride secretion and mucociliary clearance at birth, highlighting a potential therapeutic modifier/target in cystic fibrosis and muco-obstructive lung diseases.
Clinical Implications: Therapeutic strategies that augment SLC26A9 function or chloride secretion could improve mucociliary clearance in CF and neonatal muco-obstructive conditions; SLC26A9 status may inform precision therapy alongside CFTR modulators.
Key Findings
- Slc26a9-/- neonatal mice exhibited severe respiratory distress with high mortality and MUC5B-positive mucus plugs causing airway obstruction.
- Tracheal explants showed reduced transepithelial potential difference, consistent with decreased chloride secretion.
- Neonatal Slc26a9-/- mice developed hypoxic epithelial degeneration with sterile neutrophilic airway inflammation.
Methodological Strengths
- Multimodal phenotyping (histology, immunohistochemistry, μCT, bioelectric measurements)
- Clear causality via genetic deletion in vivo
Limitations
- Mouse neonatal model—translation to human neonates requires validation
- Mechanisms of SLC26A9 interaction with other ion channels (e.g., CFTR) not directly dissected
Future Directions: Evaluate pharmacologic activation or gene therapy approaches targeting SLC26A9; interrogate interactions with CFTR modulators and assess human neonatal/infant tissues or organoids.
3. Effectiveness of Nirsevimab in Preventing Respiratory Syncytial Virus-related Burden: A Test-negative Case-control Study in Infants With Bronchiolitis in Lombardy Region, Italy.
In a test-negative case-control analysis of 208 infants with bronchiolitis presenting to an ED in Lombardy, nirsevimab effectiveness was 82% against RSV infection, 78% against RSV-related hospitalization, and 84% against ICU admission. Findings support programmatic use during RSV season.
Impact: Provides real-world effectiveness across clinically meaningful outcomes, reinforcing policy decisions to deploy nirsevimab broadly in infant populations.
Clinical Implications: Prioritize timely administration of nirsevimab to eligible infants before RSV season to reduce ED burden, hospitalizations, and ICU admissions.
Key Findings
- Effectiveness against laboratory-confirmed RSV infection: 82%.
- Effectiveness against RSV-related hospitalization: 78%.
- Effectiveness against ICU admission: 84%.
Methodological Strengths
- Test-negative case-control design reduces healthcare-seeking and testing bias
- Evaluation of multiple clinically relevant endpoints (infection, hospitalization, ICU)
Limitations
- Single-region study with modest sample size (n=208) may limit generalizability
- Potential residual confounding inherent to observational designs
Future Directions: Expand multicenter evaluations, assess duration of protection across seasons, and evaluate impact in subgroups (e.g., preterm, comorbidities) and program logistics.