Daily Respiratory Research Analysis
Two rigorously designed, practice-informing trials from The Lancet Respiratory Medicine stand out: a head-to-head phase 4 RCT shows dupilumab outperforms omalizumab for severe CRSwNP with asthma, while the MABEL phase 3 RCT finds no clinically meaningful benefit of oral morphine for chronic breathlessness. A single-arm phase 2 study supports the feasibility of durvalumab plus carboplatin–etoposide in extensive-stage SCLC with poor performance status, with careful attention to toxicity.
Summary
Two rigorously designed, practice-informing trials from The Lancet Respiratory Medicine stand out: a head-to-head phase 4 RCT shows dupilumab outperforms omalizumab for severe CRSwNP with asthma, while the MABEL phase 3 RCT finds no clinically meaningful benefit of oral morphine for chronic breathlessness. A single-arm phase 2 study supports the feasibility of durvalumab plus carboplatin–etoposide in extensive-stage SCLC with poor performance status, with careful attention to toxicity.
Research Themes
- Biologic therapy selection in airway inflammatory disease
- Evidence reassessment of opioids for chronic breathlessness
- Chemoimmunotherapy feasibility in frail SCLC populations
Selected Articles
1. Dupilumab versus omalizumab in patients with chronic rhinosinusitis with nasal polyps and coexisting asthma (EVEREST): a multicentre, randomised, double-blind, head-to-head phase 4 trial.
In the first head-to-head biologic trial for respiratory disease, dupilumab outperformed omalizumab over 24 weeks in severe CRSwNP with coexisting asthma, improving endoscopic polyp scores and olfaction. Safety was consistent with known profiles.
Impact: This direct comparative RCT provides decisive evidence to guide biologic selection in severe CRSwNP with asthma, an area with multiple approved options but limited head-to-head data.
Clinical Implications: For severe CRSwNP with asthma, dupilumab should be prioritized when choosing between biologics given superior reductions in polyp burden and improved olfaction over 24 weeks, alongside guideline-directed intranasal corticosteroids.
Key Findings
- Dupilumab was superior to omalizumab in reducing endoscopic nasal polyp score at 24 weeks.
- Dupilumab led to greater improvement in olfaction measured by UPSIT at 24 weeks.
- Safety findings were consistent with established profiles for both biologics.
Methodological Strengths
- Multicentre, randomised, double-blind, head-to-head phase 4 design
- Prespecified dual primary endpoints (polyp score and smell) with ITT analysis
Limitations
- 24-week duration limits assessment of long-term durability and safety
- Details of sample size analyzed and some baseline characteristics are not fully reported in the abstract
Future Directions: Longer-term comparative effectiveness, cost-effectiveness, and biomarker-driven personalization studies are warranted to refine biologic selection and sequencing in CRSwNP with asthma.
2. Morphine for chronic breathlessness (MABEL) in the UK: a multi-site, parallel-group, dose titration, double-blind, randomised, placebo-controlled trial.
In adults with chronic breathlessness due to cardiorespiratory disease, long-acting oral morphine (5–10 mg BID) did not reduce worst breathlessness at 28 days versus placebo, and increased adverse events and withdrawals; a cough benefit at 56 days was observed.
Impact: High-quality negative evidence challenges routine opioid use for chronic breathlessness and supports guideline restraint due to lack of efficacy and safety concerns.
Clinical Implications: Avoid routine prescription of long-acting oral morphine for chronic breathlessness; prioritize non-opioid strategies (pulmonary rehabilitation, optimised disease therapy, psychological support) and reserve opioids, if at all, for carefully selected, closely monitored cases.
Key Findings
- No significant difference in worst breathlessness NRS at day 28 (adjusted mean difference 0.09; p=0.78).
- Cough improved at day 56 (adjusted mean difference −1.41), but physical activity gains did not survive multiple testing correction.
- More adverse events, serious adverse events, and study drug withdrawals occurred with morphine versus placebo.
Methodological Strengths
- Phase 3 multicentre double-blind randomized, placebo-controlled design
- Patient-centred outcomes with activity monitoring and predefined endpoints
Limitations
- Modest sample size and heterogeneous cardiorespiratory etiologies may dilute subgroup effects
- Adherence imbalance and multiple comparisons complicate interpretation of secondary outcomes
Future Directions: Define phenotypes most likely to benefit or be harmed by opioids, test non-opioid pharmacologic options, and integrate digital activity endpoints in larger pragmatic trials.
3. Durvalumab, carboplatin, and etoposide in patients who are treatment-naive with extensive-stage small-cell lung cancer and poor performance status (NEJ045A): a single-arm phase 2 trial.
In untreated ES-SCLC with PS 2–3, durvalumab plus carboplatin–etoposide achieved induction completion exceeding thresholds (PS2 67%, PS3 50%) and a 1-year survival of 43.4% overall, with high grade ≥3 toxicity (93%). Dose-adjusted chemoimmunotherapy is feasible but requires vigilant toxicity management.
Impact: This study provides needed prospective data on chemoimmunotherapy feasibility in frail ES-SCLC patients who are often excluded from RCTs, informing real-world treatment decisions.
Clinical Implications: Chemoimmunotherapy with initial dose reduction and careful escalation can be considered in ES-SCLC with PS 2–3, with clear counseling on high toxicity risk, close monitoring, and individualized goals of care.
Key Findings
- Induction completion exceeded prespecified thresholds: PS2 67% and PS3 50%.
- One-year survival was 43.4% overall, 50.0% in PS2, and 18.2% in PS3 patients.
- Grade ≥3 adverse events occurred in 93% and treatment discontinuation in 21%.
Methodological Strengths
- Prospective phase 2 design targeting an understudied frail population (PS 2–3)
- Predefined feasibility thresholds and pragmatic dose-adjustment strategy
Limitations
- Single-arm open-label design without a comparator limits causal inference
- Small sample size, especially in PS3 subgroup, and high toxicity rates
Future Directions: Randomized comparative studies and real-world registries are needed to benchmark outcomes versus attenuated chemotherapy or best supportive care and to refine dose algorithms.