Daily Respiratory Research Analysis
Three impactful respiratory studies stood out today: a multicentre phase 2 trial reported a 73% objective response rate with the HER2-directed antibody–drug conjugate trastuzumab rezetecan in previously treated HER2-mutant NSCLC; a large prospective IPF registry showed that even small absolute declines in FVC or DLCO signal higher subsequent risk of death or lung transplantation; and a meta-analysis confirmed BMPR2 mutation carriers with PAH have more severe hemodynamics, with ethnicity-specific
Summary
Three impactful respiratory studies stood out today: a multicentre phase 2 trial reported a 73% objective response rate with the HER2-directed antibody–drug conjugate trastuzumab rezetecan in previously treated HER2-mutant NSCLC; a large prospective IPF registry showed that even small absolute declines in FVC or DLCO signal higher subsequent risk of death or lung transplantation; and a meta-analysis confirmed BMPR2 mutation carriers with PAH have more severe hemodynamics, with ethnicity-specific differences in cardiac output indices.
Research Themes
- Targeted therapeutics in lung cancer (HER2-mutant NSCLC)
- Prognostic monitoring thresholds in idiopathic pulmonary fibrosis
- Genetic determinants of pulmonary arterial hypertension severity
Selected Articles
1. Trastuzumab rezetecan, a HER2-directed antibody-drug conjugate, in patients with advanced HER2-mutant non-small-cell lung cancer (HORIZON-Lung): phase 2 results from a multicentre, single-arm study.
In 94 treated patients with HER2-mutant NSCLC, trastuzumab rezetecan achieved a confirmed objective response in 69 patients (73%; 95% CI 63.3–82.0) after a median 8.7 months of follow-up. Grade 3–4 toxicities included neutropenia (40%), leukopenia (27%), anemia (23%), thrombocytopenia (11%), and lymphopenia (7%); treatment-related serious adverse events occurred in 23%, including interstitial lung disease in 5%, with no treatment-related deaths.
Impact: This study demonstrates clinically meaningful activity of a novel HER2-directed ADC in a genomically defined NSCLC population with limited options after chemo-immunotherapy.
Clinical Implications: Trastuzumab rezetecan may become a treatment option for previously treated HER2-mutant NSCLC, warranting ILD monitoring and hematologic surveillance. It supports routine HER2 mutation testing in NSCLC to guide targeted therapy.
Key Findings
- Confirmed objective response rate was 73% (69/94; 95% CI 63.3–82.0).
- Median follow-up was 8.7 months (IQR 7.0–10.4).
- Grade 3–4 treatment-related toxicities: decreased neutrophil count 40%, white blood cell count 27%, anemia 23%, platelets 11%, lymphocytes 7%.
- Treatment-related serious adverse events occurred in 23%; interstitial lung disease in 5%; no treatment-related deaths.
Methodological Strengths
- Multicentre design with independent review committee assessment of objective responses
- Clear inclusion criteria post platinum and anti–PD-1/PD-L1, standardized dosing
Limitations
- Single-arm design without a comparator limits causal inference
- Relatively short median follow-up; time-to-event outcomes not reported
Future Directions: Randomized comparative trials versus standard care (e.g., trastuzumab deruxtecan or chemotherapy) and biomarker studies to refine patient selection and ILD risk mitigation are warranted.
2. Changes in Lung Function and Mortality Risk in Patients With Idiopathic Pulmonary Fibrosis.
Among 1,001 IPF patients (median follow-up 38.4 months), absolute declines in FVC of ≥2%, ≥5%, and ≥10% were associated with 1.8-fold, 2.3-fold, and 2.7-fold higher risk of subsequent death or lung transplantation, respectively. Absolute declines in DLCO of ≥2%, ≥5%, ≥10%, and ≥15% were associated with 2.0-fold, 1.4-fold, 1.5-fold, and 1.9-fold higher risk, respectively; relative DLCO declines often conferred greater risk than absolute declines.
Impact: This large prospective registry quantifies prognostic thresholds showing that even small absolute declines in FVC or DLCO meaningfully predict adverse outcomes in IPF.
Clinical Implications: Clinicians should treat small absolute declines in FVC (≥2–5%) or DLCO as prognostically significant, prompting closer monitoring, therapy optimization, or trial consideration.
Key Findings
- Absolute FVC declines ≥2%, ≥5%, ≥10% associated with 1.8x, 2.3x, 2.7x higher risk of death or lung transplant (adjusted).
- Absolute DLCO declines ≥2%, ≥5%, ≥10%, ≥15% associated with 2.0x, 1.4x, 1.5x, 1.9x higher risk.
- Relative DLCO declines often conferred greater risk than absolute thresholds.
- Median follow-up was 38.4 months across 1,001 patients.
Methodological Strengths
- Prospective design with time-dependent Cox modeling and multivariable adjustment
- Large national registry with standardized lung function measures
Limitations
- Observational design precludes causal inference
- Decline thresholds evaluated without central spirometry adjudication
Future Directions: Incorporate small absolute decline thresholds into trial endpoints and care pathways; validate in antifibrotic-treated subgroups and with home spirometry.
3. Impact of BMPR2 mutation on the severity of pulmonary arterial hypertension: a systematic review and meta-analysis.
Across 17 studies (n=2,190), BMPR2 mutation carriers with PAH had higher mPAP and PVR and lower CI and CO at diagnosis than non-carriers. Ethnic subgroup analyses showed no mPAP/PVR differences between Asian and Caucasian carriers, but CI and CO reductions were greater in Caucasians, suggesting potential ethnic sensitivity to BMPR2-mediated hemodynamic impairment.
Impact: The study consolidates evidence that BMPR2 mutations confer a more severe hemodynamic phenotype in PAH and introduces ethnicity-stratified insights with implications for genetic testing and risk stratification.
Clinical Implications: Routine BMPR2 genetic testing in PAH can guide prognosis and follow-up intensity; carriers may warrant closer monitoring and early aggressive management regardless of ethnicity, with particular attention to cardiac output in Caucasian patients.
Key Findings
- BMPR2 mutation carriers had higher mPAP (WMD 6.41 mmHg) and PVR (WMD 3.66 Wood units) at diagnosis.
- Cardiac index and cardiac output were lower in carriers (CI WMD −0.38 L/min/m²; CO WMD −0.60 L/min).
- No ethnicity-related differences in mPAP/PVR, but CI/CO reductions were greater in Caucasians than Asians.
- Findings support genetic testing and closer follow-up in BMPR2 carriers.
Methodological Strengths
- Comprehensive search across multiple databases with quantitative synthesis
- Ethnicity-stratified subgroup analyses provide nuanced insights
Limitations
- Inclusion of nonrandomized studies introduces potential confounding and heterogeneity
- Outcome data largely cross-sectional at diagnosis; limited longitudinal outcomes
Future Directions: Prospective multicentre cohorts to validate ethnicity-specific effects and integrate BMPR2 status into risk models; mechanistic studies to explain differential CI/CO impacts.