Daily Respiratory Research Analysis
Three papers stood out today: an updated meta-analysis confirms that inhaled triple therapy (ICS/LABA/LAMA) meaningfully reduces severe exacerbations in moderate-to-severe asthma; a large genomic study identifies TP53 and BRCA2 germline pathogenic variants and a novel ALKBH2 variant associated with early-onset lung adenocarcinoma; and pooled clinical trial data show robust activity of datopotamab deruxtecan in heavily pretreated EGFR-mutated NSCLC.
Summary
Three papers stood out today: an updated meta-analysis confirms that inhaled triple therapy (ICS/LABA/LAMA) meaningfully reduces severe exacerbations in moderate-to-severe asthma; a large genomic study identifies TP53 and BRCA2 germline pathogenic variants and a novel ALKBH2 variant associated with early-onset lung adenocarcinoma; and pooled clinical trial data show robust activity of datopotamab deruxtecan in heavily pretreated EGFR-mutated NSCLC.
Research Themes
- Asthma step-up therapy and exacerbation prevention
- Germline genetics in early-onset lung adenocarcinoma
- Antibody–drug conjugates for EGFR-mutated NSCLC
Selected Articles
1. Triple therapy vs dual inhaler therapy for moderate-to-severe asthma: An updated systematic review and meta-analysis.
Across 26 RCTs (12,431 participants), triple therapy (ICS/LABA/LAMA) reduced severe exacerbations versus dual therapy in high-risk patients, with trivial changes in asthma control and quality of life and a small FEV1 gain, without increased serious adverse events. Effects were consistent across age, BMI, and exacerbation history, informing AAAAI/ACAAI guideline development.
Impact: This high-quality meta-analysis directly supports step-up therapy decisions in moderate-to-severe asthma and quantifies exacerbation reduction with high certainty. It is poised to influence guideline recommendations and clinical practice.
Clinical Implications: For patients at high risk of exacerbations who remain uncontrolled on ICS/LABA, stepping up to triple therapy should be considered, as it meaningfully reduces severe exacerbations without increasing serious adverse events. The small changes in ACQ/AQLQ and modest FEV1 gain suggest the primary benefit is exacerbation prevention.
Key Findings
- Triple therapy reduced severe exacerbations versus dual therapy in high-risk patients (RR 0.83, 95% CI 0.76–0.90; risk difference 5.3% fewer).
- Asthma control (ACQ-7) and quality of life (AQLQ) showed trivial improvements (MD -0.04 and 0.05, respectively).
- Pre-bronchodilator FEV1 improved modestly (MD 0.07 L) and serious adverse events did not increase.
- Effects were consistent across age, BMI, and exacerbation history; evidence certainty rated with GRADE.
Methodological Strengths
- Comprehensive search across multiple databases with paired independent screening and extraction.
- Random-effects meta-analyses with risk-of-bias assessment and GRADE certainty ratings; preregistered (OSF).
Limitations
- Heterogeneity across trials in drug formulations, devices, and dosing; varied trial durations.
- Patient-level modifiers (e.g., eosinophils, FeNO, smoking status) variably reported, limiting subgroup precision.
Future Directions: Head-to-head trials of specific triple combinations by biomarker strata (e.g., eosinophils/FeNO), longer-term safety, and implementation studies assessing exacerbation-driven step-up algorithms.
2. Genomic Profiles of Pathogenic and Moderate-Penetrance Germline Variants Associated With Risk of Early-Onset Lung Adenocarcinoma.
In Asians with early-onset LADC, germline TP53 (2.9%) and BRCA2 (1.7%) pathogenic variants were enriched versus later-onset cases, BRCA2 carriers showed homologous recombination deficiency, and a novel ALKBH2 frameshift variant (p.Glu35Alafs*54) was linked to risk with smoking-signature correlations. Findings support genetic predisposition and potential therapeutic vulnerabilities.
Impact: This large, integrated germline–somatic analysis identifies actionable hereditary risk in early-onset lung adenocarcinoma and a novel ALKBH2 variant, with implications for genetic testing, surveillance, and potential HRD-directed therapies.
Clinical Implications: Consider germline testing (TP53, BRCA2, and potentially ALKBH2) in early-onset LADC, particularly in never-smoking Asian women, to inform counseling and cascade testing. BRCA2-associated HRD suggests exploring platinum/PARP inhibitor sensitivity in trials.
Key Findings
- Germline TP53 and BRCA2 pathogenic variants were significantly more frequent in early-onset LADC (2.9% and 1.7%) than later-onset (0.14% and 0.21%).
- BRCA2 carriers exhibited homologous recombination deficiency via loss of the wild-type allele; BRCA1 GPV carriers had frequent concurrent TP53 somatic mutations.
- A novel germline ALKBH2 frameshift variant (p.Glu35Alafs*54) was associated with early-onset LADC risk and correlated with SBS4 smoking-related signatures and Brinkman index.
Methodological Strengths
- Large-scale multi-cohort design integrating WES/WGS with a case–control study (10,302 cases; 7,898 controls).
- Combined germline and somatic mutation analyses enabling mechanistic insights (e.g., HRD via LOH).
Limitations
- Predominantly Asian populations may limit generalizability beyond similar demographics.
- Observational design without interventional validation; ALKBH2 findings require external replication and functional studies.
Future Directions: External replication across ancestries, functional characterization of ALKBH2 variant, and trials testing HRD-directed therapies in BRCA2-mutated LADC.
3. A Pooled Analysis of Datopotamab Deruxtecan in Patients With EGFR-Mutated NSCLC.
Pooling EGFR-mutated NSCLC patients from TROPION-Lung05 and -Lung01, Dato-DXd achieved a 43% confirmed response rate (4% complete), median DOR 7.0 months, PFS 5.8 months, and OS 15.6 months, with grade ≥3 TRAEs in 23% and SAEs in 6%. Activity was observed in a heavily pretreated, predominantly Asian cohort.
Impact: These results suggest a meaningful post-TKI option for EGFR-mutated NSCLC with manageable toxicity, supporting further randomized evaluation and potential incorporation into treatment algorithms.
Clinical Implications: Dato-DXd may be considered in clinical trial or compassionate settings for patients with EGFR-mutated NSCLC after EGFR TKI and platinum chemotherapy failure; monitoring for ADC-class toxicities remains essential.
Key Findings
- Confirmed objective response rate was 43% including 4% complete responses in 117 heavily pretreated EGFR-mutated NSCLC patients.
- Median duration of response was 7.0 months; median PFS 5.8 months and OS 15.6 months.
- Safety was consistent with prior studies with grade ≥3 treatment-related AEs at 23% and serious AEs at 6%; no new safety signals.
Methodological Strengths
- Pooled patient-level data from phase II and III studies focusing on a clinically relevant EGFR-mutant subgroup.
- Uniform Dato-DXd dosing (6 mg/kg) and detailed reporting of response and survival endpoints.
Limitations
- Exploratory pooled analysis without a randomized comparator within the EGFR-mutant subgroup limits causal inference.
- Predominantly Asian cohort (69%) may affect generalizability; follow-up details not fully specified.
Future Directions: Prospective randomized trials comparing Dato-DXd to docetaxel or other ADCs in EGFR-mutant post-TKI settings, and biomarker studies to refine patient selection.