Daily Respiratory Research Analysis
Three impactful respiratory studies stood out today: a large prospective study shows that elexacaftor-tezacaftor-ivacaftor can partially reverse bronchial dilatations in adolescents with cystic fibrosis; a double-blind RCT (COMPEL) demonstrates that continuing osimertinib with platinum chemotherapy improves PFS after first-line osimertinib progression in EGFR-mutated NSCLC; and near real-time surveillance in the Vaccine Safety Datalink supports the safety of RSV vaccines in older adults.
Summary
Three impactful respiratory studies stood out today: a large prospective study shows that elexacaftor-tezacaftor-ivacaftor can partially reverse bronchial dilatations in adolescents with cystic fibrosis; a double-blind RCT (COMPEL) demonstrates that continuing osimertinib with platinum chemotherapy improves PFS after first-line osimertinib progression in EGFR-mutated NSCLC; and near real-time surveillance in the Vaccine Safety Datalink supports the safety of RSV vaccines in older adults.
Research Themes
- Disease-modifying therapy and structural lung change in cystic fibrosis
- Post-progression treatment strategy in EGFR-mutated NSCLC
- Real-world vaccine safety surveillance for RSV vaccines in older adults
Selected Articles
1. Effect of elexacaftor-tezacaftor-ivacaftor on bronchial dilatations in adolescents with cystic fibrosis: a multicentre prospective observational study.
In a 12-month multicentre prospective cohort of 320 adolescents with cystic fibrosis, ETI therapy was associated with radiologic reversal of bronchial dilatations on chest CT, alongside improvements in lung function and biomarkers (e.g., sweat chloride) with correlations to reduced airway inflammation.
Impact: This study provides rare evidence that structural airway damage in cystic fibrosis can be partially reversible under CFTR modulator therapy, reframing disease-modifying expectations in adolescence.
Clinical Implications: ETI may not only stabilize but reverse airway structural damage in adolescents with cystic fibrosis, supporting early initiation and sustained therapy. Imaging and inflammation metrics could be integrated into longitudinal monitoring.
Key Findings
- Bronchial dilatations showed radiologic reversal over 12 months of ETI therapy in adolescents.
- Functional and biomarker improvements accompanied structural changes (e.g., improved lung function and reduced sweat chloride).
- Structural improvements correlated with reduced airway inflammation.
- Benefits were observed across both CFTR modulator–naïve patients and those switched from lumacaftor–ivacaftor.
Methodological Strengths
- Prospective, multicentre cohort across 33 pediatric CF centers with 12-month follow-up.
- Primary structural endpoint using standardized chest CT, complemented by functional and inflammatory measures.
Limitations
- Observational design without a randomized control group.
- Adolescent-only cohort with 12-month horizon may limit generalizability and long-term inference.
Future Directions: Randomized or controlled imaging substudies to confirm reversibility, mechanistic work linking CFTR restoration to airway remodeling, and evaluation of timing/age windows for maximal structural benefit.
BACKGROUND: Elexacaftor-tezacaftor-ivacaftor (ETI) is a cystic fibrosis transmembrane conductance regulator (CFTR) modulator that improves clinical outcomes in adolescents with cystic fibrosis. We aimed to investigate the effect of ETI on lung structural damage. METHODS: The Modul-CF prospective observational study is based at 33 paediatric cystic fibrosis reference centres in France. In the present analysis, we assessed the adolescent cohort of individuals with cystic fibrosis (aged 12-18 years) from the Modul-CF study who initiated treatment with ETI as part of routine care. These individuals were either homozygous for F508del and previously treated with lumacaftor-ivacaftor (LI), or F508del homozygous or compound heterozygous for F508del with a minimal function or residual function variant and naive to CFTR modulator treatment. The primary outcome measure was chest CT to investigate the effect of CFTR restoration on the natural history of cystic fibrosis lung disease. Secondary outcomes were sweat chloride, weight and height Z scores, quality of life, pulmonary function tests, lung clearance index at 2·5% of starting concentration (LCI FINDINGS: Between March 22, 2021, and May 25, 2022, a total of 330 adolescents with cystic fibrosis were enrolled in the study, of whom 320 were treated with ETI for 12 months and included in analyses (mean age at ETI initiation 14·1 years [SD 1·5]; 162 [51%] female and 158 [49%] male participants). Of the 320 participants, 112 (35%) were switched from LI to ETI, and 208 (65%) were CFTR modulator-naive. In the overall population, improvement in percent predicted FEV INTERPRETATION: Bronchial dilatations can reverse in adolescents with cystic fibrosis treated with ETI. The correlation with reduced airway inflammation provides insight into the effect of ETI on cystic fibrosis lung disease. FUNDING: Vaincre La Mucoviscidose, Mucoviscidose ABCF2, and the Cystic Fibrosis Foundation.
2. COMPEL: osimertinib plus platinum-based chemotherapy in patients with EGFR-mutated advanced NSCLC and progression on first-line osimertinib.
In the double-blind COMPEL RCT (n=98), continuing osimertinib with platinum-based chemotherapy after non-CNS progression on first-line osimertinib halved the risk of progression (median PFS 8.4 vs 4.4 months; HR 0.43), with a non-significant OS advantage and higher grade ≥3 toxicity.
Impact: Provides randomized evidence to support continuing EGFR-TKI with chemotherapy beyond progression, a common yet debated strategy in EGFR-mutated NSCLC.
Clinical Implications: For EGFR-mutated advanced NSCLC with non-CNS progression on first-line osimertinib, maintaining osimertinib with platinum doublet can be considered to extend PFS, with counseling on increased toxicity and uncertain OS benefit.
Key Findings
- Median PFS improved from 4.4 to 8.4 months (HR 0.43, 95% CI 0.27–0.70) with osimertinib plus chemotherapy.
- Median OS numerically longer (15.9 vs 9.8 months; HR 0.71, 95% CI 0.42–1.23) but not statistically significant.
- CNS PFS favored the combination in patients without baseline CNS metastases (HR 0.56, 95% CI 0.27–1.13).
- Grade ≥3 adverse events were more frequent with the combination (63% vs 46%).
Methodological Strengths
- Randomized, double-blind design with registered protocol (NCT04765059).
- Pre-specified CNS-related outcomes and robust PFS effect size.
Limitations
- Small sample size (n=98) limits power for OS and subgroup analyses.
- Increased grade ≥3 toxicity and absence of predictive biomarker stratification.
Future Directions: Larger phase III trials with biomarker-driven stratification and patient-reported outcomes to clarify OS, CNS control, and tolerability of TKI continuation beyond progression.
BACKGROUND: COMPEL (NCT04765059) was a global, randomized, double-blind study that evaluated osimertinib plus chemotherapy versus placebo plus chemotherapy in patients with epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) following non-central nervous system (CNS) progression on first-line osimertinib. PATIENTS AND METHODS: Patients were randomly assigned to receive osimertinib 80 mg, or placebo, once daily (o.d.) in combination with chemotherapy [cisplatin 75 mg/m RESULTS: Ninety-eight patients were randomly assigned (49 per arm). Median PFS in all patients was 8.4 months [95% confidence interval (CI) 5.7-11.8 months] with osimertinib plus chemotherapy versus 4.4 months (95% CI 3.5-5.6 months) with placebo plus chemotherapy [hazard ratio (HR) 0.43, 95% CI 0.27-0.70]. CNS PFS was longer with osimertinib plus chemotherapy versus placebo plus chemotherapy (HR 0.56, 95% CI 0.27-1.13) in patients without baseline CNS metastases (n = 75). Median OS in all patients was 15.9 months (95% CI 12.4-20.8 months) with osimertinib plus chemotherapy versus 9.8 months (95% CI 8.4-17.2 months) with placebo plus chemotherapy (HR 0.71, 95% CI 0.42-1.23). Grade ≥3 adverse events occurred more frequently with osimertinib plus chemotherapy (63%) than placebo plus chemotherapy (46%). CONCLUSIONS: In patients with non-CNS progression on first-line osimertinib, osimertinib plus chemotherapy was associated with improved PFS and longer OS compared with placebo plus chemotherapy. These findings support osimertinib as a backbone treatment for EGFR-mutated advanced NSCLC through lines of therapy.
3. Near real-time surveillance and tree-based data mining to assess the safety of respiratory syncytial virus vaccines in older adults in the vaccine safety datalink.
Using rapid cycle analysis (n=436,823) and self-controlled tree-based data mining (n=248,056), post-licensure surveillance found no confirmed safety signals for RSV vaccines in adults ≥60 years; an initial ITP signal for Arexvy was not supported after medical record confirmation.
Impact: Delivers high-quality, near real-time population safety data supporting RSV vaccine deployment in older adults, addressing a key evidence gap shortly after licensure.
Clinical Implications: Clinicians can counsel older adults that current surveillance shows no confirmed increased risk for evaluated AESIs after RSV vaccination, supporting uptake while continuing vigilance for rare events.
Key Findings
- Rapid cycle analysis of 436,823 vaccinees showed no statistical signal for 11 of 12 prespecified adverse events.
- An initial signal for immune thrombocytopenic purpura following Arexvy was not confirmed after medical record review and re-analysis.
- Self-controlled tree-based data mining (248,056 vaccinees) identified no significant clusters of ICD-10 diagnoses 1–56 days post-vaccination.
Methodological Strengths
- Near real-time rapid cycle analysis with sequential monitoring across multiple sites.
- Complementary, hypothesis-free self-controlled tree-based data mining and outcome confirmation via medical record review.
Limitations
- Limited power to detect very rare adverse events and short risk windows post-vaccination.
- Observational design susceptible to misclassification and residual confounding despite robust methods.
Future Directions: Extended surveillance across subsequent seasons, linkage with additional data sources, and targeted studies for rare outcomes (e.g., Guillain–Barré syndrome) to refine risk estimates.
BACKGROUND: Two respiratory syncytial virus (RSV) vaccines, Pfizer's Abrysvo and GSK's Arexvy, were licensed in 2023 in the U.S. However, population-based assessments of their safety in adults ≥60 years have not been widely published. We provide results from two complementary investigations of vaccinated adults in the Vaccine Safety Datalink (VSD). METHODS: The rapid cycle analysis (RCA) used a sequential cohort design and biweekly analyses of near real-time data to compare the incidence of 12 pre-specified outcomes in two post-vaccination risk intervals (1-21, 1-42 days) with the incidence in comparison intervals. The surveillance period was August 1, 2023, through September 28, 2024; nine of 13 VSD sites participated. Statistically significant signals were investigated by medical record review with re-analysis of confirmed outcomes. The self-controlled tree-based data mining analysis was designed to identify temporal clustering of ICD-10 diagnosis codes in the inpatient or emergency department settings 1-56 days post-vaccination, without pre-specifying outcomes or risk intervals. The study period was July 1, 2023, through December 31, 2023; 10 sites participated. RESULTS: The RCA analysis included 436,823 persons who received an RSV vaccine. No statistical signal was identified for 11 of 12 adverse events. A signal was detected for immune thrombocytopenic purpura following Arexvy, but re-analysis following medical record review did not confirm an association. The tree-based data mining analysis included 248,056 vaccinees, identified 53,734 counts of 3429 diagnosis codes, and identified no statistically significant clusters for either vaccine. CONCLUSIONS: These post-licensure safety assessments provide evidence supporting the safety of RSV vaccines in older adults. As more data accrue, additional monitoring is warranted for rare adverse events.