Daily Respiratory Research Analysis
A phase 3 randomized trial showed that add-on sotatercept markedly reduced death, transplant, or hospitalization in high-risk pulmonary arterial hypertension. In ALK-positive lung cancer, early resistance to first-line alectinib was frequently driven by off-target MET and NF2 alterations with EML4-ALK variant-specific patterns. An experimental ARDS study demonstrated that ventilator-induced lung injury depends on how mechanical power is distributed across tidal volume and respiratory rate, not m
Summary
A phase 3 randomized trial showed that add-on sotatercept markedly reduced death, transplant, or hospitalization in high-risk pulmonary arterial hypertension. In ALK-positive lung cancer, early resistance to first-line alectinib was frequently driven by off-target MET and NF2 alterations with EML4-ALK variant-specific patterns. An experimental ARDS study demonstrated that ventilator-induced lung injury depends on how mechanical power is distributed across tidal volume and respiratory rate, not mechanical power alone.
Research Themes
- Pulmonary hypertension therapeutics
- Targeted therapy resistance mechanisms in lung cancer
- Ventilator-induced lung injury and mechanical power components
Selected Articles
1. Sotatercept in Patients with Pulmonary Arterial Hypertension at High Risk for Death.
In a phase 3 trial of 172 high-risk PAH patients on maximal background therapy, add-on sotatercept reduced the composite of death, transplant, or PAH-related hospitalization by 76% versus placebo (HR 0.24). The trial stopped early for efficacy; epistaxis and telangiectasia were the most common adverse events.
Impact: This is a definitive, event-driven RCT showing substantial hard outcome benefits in a population with high unmet need, likely changing treatment algorithms for advanced PAH.
Clinical Implications: Consider sotatercept as add-on therapy for WHO FC III/IV PAH patients at high 1-year risk despite optimized background therapy, with monitoring for epistaxis and telangiectasia.
Key Findings
- Primary composite endpoint occurred in 17.4% with sotatercept vs 54.7% with placebo (HR 0.24, 95% CI 0.13–0.43).
- Reductions were seen across components: death (8.1% vs 15.1%), lung transplant (1.2% vs 7.0%), and hospitalization for PAH worsening (9.3% vs 50.0%).
- Trial stopped early at interim due to efficacy; epistaxis and telangiectasia were the most frequent adverse events.
Methodological Strengths
- Randomized, placebo-controlled, phase 3 design with hard, clinically meaningful endpoints.
- Event-driven analysis with prespecified interim stopping rules and multicenter enrollment.
Limitations
- Early stopping may overestimate effect size and limits long-term safety data.
- Modest sample size (n=172) and industry sponsorship may introduce biases.
Future Directions: Longer-term follow-up for survival and right heart remodeling, head-to-head or combination studies, and evaluation in broader PAH phenotypes.
2. MET and NF2 alterations confer primary and early resistance to first-line alectinib treatment in ALK-positive non-small-cell lung cancer.
Targeted sequencing of 108 relapsed ALK+ NSCLC cases showed that within 6 months of first-line alectinib, off-target MET and NF2 alterations predominate, driving primary/early resistance. Resistance mechanisms are EML4-ALK variant-specific (v1 skewed to off-target; v3 to on-target). Mutation spectra after second-line therapy also differed by variant.
Impact: Defines early resistance biology with actionable targets (e.g., MET) and variant-specific patterns, informing adaptive molecular monitoring and rational combinations upfront.
Clinical Implications: Baseline and early on-treatment profiling (including MET/NF2) and EML4-ALK variant determination may guide surveillance and early combination strategies (e.g., MET inhibitors) to preempt resistance.
Key Findings
- Within 6 months of first-line alectinib, off-target MET and NF2 alterations were more frequent than on-target ALK changes, indicating primary/early resistance drivers.
- Resistance patterns differed by EML4-ALK variant: variant 1 had 50% off-target-driven resistance (no on-target contribution), whereas variant 3 had 46% on-target resistance.
- After second-line therapy, common mutations were L1196M (42%) and G1269A (25%) in v1, and G1202R in 45% of v3 tumors.
Methodological Strengths
- Cohort of 108 relapsed patients with systematic targeted sequencing across first- and second-line settings.
- Granular analysis by EML4-ALK variants enabling biologically meaningful stratification.
Limitations
- Observational design with potential selection and treatment heterogeneity.
- Lack of functional validation and limited prospective correlation with combination treatment outcomes.
Future Directions: Prospective trials testing early MET-targeted combinations based on baseline/early alterations and variant-informed adaptive monitoring (including liquid biopsy).
3. Effects of Similar Mechanical Power Resulting From Different Combinations of Respiratory Variables on Lung Damage in Experimental Acute Respiratory Distress Syndrome.
In LPS-induced ARDS rats ventilated for 80 minutes at matched mechanical power, higher tidal volume/lower respiratory rate settings produced greater overdistension, edema, and biomarker evidence of epithelial, endothelial, and matrix injury than low Vt/high RR. Thus, VILI depends on how mechanical power is delivered, not its magnitude alone.
Impact: Challenges the prevailing use of mechanical power as a unitary target by demonstrating that its components (Vt vs RR) differentially drive injury, refining lung-protective ventilation concepts.
Clinical Implications: When titrating ventilator settings, prefer lower tidal volumes even if mechanical power is held constant; prioritize minimizing driving/plateau pressures to limit cyclical stress.
Key Findings
- At equal mechanical power, very-high Vt/very-low RR caused significantly greater overdistension, edema, and injury biomarkers than low Vt/high RR.
- Plateau and driving pressures rose progressively from low Vt/high RR to very-high Vt/very-low RR, paralleling injury severity.
- Markers of inflammation (IL-6), stretch (amphiregulin), epithelial damage (SP-B), endothelial injury (VCAM-1, ANGPT2), and ECM damage (versican, syndecan) were highest in the very-high Vt arm.
Methodological Strengths
- Controlled experimental ARDS model with predefined ventilation strategies achieving matched mechanical power.
- Comprehensive multiscale readouts: histopathology and molecular biomarkers for epithelial, endothelial, and ECM injury.
Limitations
- Animal model with short ventilation duration (80 minutes), limiting direct clinical generalizability.
- Single low PEEP and specific ARDS induction method may not reflect heterogeneous patient phenotypes.
Future Directions: Translational studies in large animals and clinical trials to test ventilation protocols that constrain driving/plateau pressures at a given mechanical power.