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.
BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is predominantly driven by type 2 inflammation. The biologics dupilumab and omalizumab, which target drivers and mediators of type 2 inflammation (interleukin [IL]-4/IL-13 signaling and immunoglobulin E [IgE], respectively), are efficacious in treating CRSwNP but direct comparisons are few. In EVEREST (EValuating trEatment RESponses of dupilumab versus omalizumab), the first head-to-head trial in respiratory biologics, we aimed to compare the efficacy and safety of dupilumab and omalizumab in patients with severe CRSwNP who had mild, moderate, or severe asthma. METHODS: EVEREST was an international, randomised, double-blind, phase 4 trial, conducted at 100 hospitals or clinical centres in 17 countries. Sites were selected with otolaryngology, pneumologist, allergist, and immunologist practices; needed to have previously conducted double-blind studies; and were required have nasal endoscopy and electrocardiogram machines. Eligible patients aged 18 years or older with severe uncontrolled CRSwNP (with a nasal polyp score of 5 or more [and ≥2 for each nostril]), symptoms of nasal congestion and loss of smell for at least 8 weeks before screening, and physician-diagnosed asthma. Patients were randomly assigned (1:1) to subcutaneous dupilumab 300 mg every 2 weeks or omalizumab weight-tiered and IgE-tiered dosing every 2 weeks or 4 weeks for 24 weeks, with background mometasone furoate nasal spray. Patients and investigators were masked to the study drugs. Primary endpoints were change from baseline in endoscopic nasal polyp score and University of Pennsylvania Smell Identification Test (UPSIT) at 24 weeks. Efficacy was assessed in the intention-to-treat population and safety was assessed in patients who received at least one dose of study medication. The trial was registered at ClinicalTrials.gov, NCT04998604. FINDINGS: Between Sept 27, 2021, and Dec 27, 2024, 819 individuals were screened for study inclusion, 459 were excluded (most common screen failures were: 167 did not meet nasal polyp score ≥5 or did not have ongoing symptoms of nasal congestion and loss of smell, 114 did not meet pre-bronchodilator FEV INTERPRETATION: Dupilumab was superior to omalizumab in patients with severe CRSwNP and coexisting asthma. These findings support the efficacy of dupilumab in patients with type 2 respiratory diseases versus an active biologic comparator, the known safety profiles of dupilumab and omalizumab, and could enable better treatment targeting for patients with CRSwNP and asthma in clinical practice. FUNDING: Sanofi and Regeneron Pharmaceuticals.
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.
BACKGROUND: The effectiveness of opioids for breathlessness seen in laboratory-based studies has not been replicated in clinical trials. We aimed to assess the effectiveness of oral morphine for breathlessness in long-term conditions. METHODS: This phase 3, parallel-group, double-blind, placebo-controlled trial across 11 centres randomly assigned consenting adults (1:1, stratified by site and causal disease) with a modified Medical Research Council breathlessness score of 3 or more due to cardiorespiratory conditions to receive 5-10 mg twice daily oral long-acting morphine or placebo (as well as a blinded laxative) for 56 days. The primary outcome was worst breathlessness score in the past 24 h at day 28, measured using a numerical rating scale (NRS; 0=not breathless at all; 10=worst imaginable breathlessness). Secondary outcomes included physical activity levels, worst cough NRS, quality of life, and morphine-related toxicities. Patients who received at least one dose of study drug were eligible for inclusion in efficacy and safety analyses. The trial was registered with ISRCTN (ISRCTN87329095) and the EU Clinical Trials Register (EudraCT 2019-002479-33). FINDINGS: Between March 18, 2021, and Oct 26, 2023, 143 participants were randomly assigned to receive either morphine (73 participants) or placebo (67 participants) and were included in the analyses; three participants did not receive the allocated treatment. Participants had a mean age of 70·5 (SD 9·4) years, were mostly male (93 [66%]), and were mostly White (132 [94%]). By day 28, 64 (88%) participants in the morphine group versus 66 (99%) in the placebo group had 90% adherence or greater. We found no evidence of difference in worst breathlessness at day 28 (morphine 6·19 [95% CI 5·57 to 6·81] vs placebo 6·10 [5·44 to 6·76]; adjusted mean difference 0·09 [95% CI -0·57 to 0·75], p=0·78) or any secondary measure, except for improved cough seen at day 56 (adjusted mean difference -1·41 [-2·18 to -0·64]). Increased moderate to vigorous physical activity was seen at day 28 (adjusted mean difference 9·51 min/day [0·54-18·48]) but this was not significant after multiple-measures correction. The morphine group had more adverse events (251 vs 162), serious adverse events (15 vs three, of which three in the morphine group and zero in the placebo group were deemed to be related to the study), and study drug withdrawals (13 vs two). There were no treatment-related deaths. INTERPRETATION: We found no evidence that morphine improves worst breathlessness intensity. Further research is needed to understand whether there is any role for morphine in chronic breathlessness, but our findings do not support its use in this setting. FUNDING: NIHR Health Technology Assessment programme (HTA Project 17/34/01).
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.
BACKGROUND: Treating patients with extensive-stage small-cell lung cancer (SCLC) with poor performance status poses considerable challenges. We aimed to evaluate the combination of an immune checkpoint inhibitor with platinum-based therapy in this population. METHODS: This open-label, single-arm phase 2 NEJ045A trial enrolled untreated patients with extensive-stage SCLC with performance status 2 or 3. Participants received four cycles of durvalumab, carboplatin, and etoposide, followed by durvalumab maintenance. A dose adjustment strategy was used, with initial reductions in carboplatin-etoposide dosages, subsequently adjusted based on adverse events, allowing for potential escalation. The primary endpoint was tolerability, assessed by the proportion of patients completing induction therapy. A key secondary endpoint was 1-year survival rate. This trial is registered at the Japan Registry of Clinical Trials (jRCTs031200319) and has been completed. FINDINGS: Between April 8, 2021, and Oct 3, 2023, 57 patients (performance status 2 n=43 and performance status 3 n=14) were enrolled with a median age of 73·5 years (IQR 69·0-77·5), 44 (79%) of 56 were male. 26 (67%; 80% CI 55·2-76·7; p<0·0001) of 39 patients with performance status 2 and five (50%; 26·7-73·3; p=0·0088) of ten with performance status 3 completed induction therapy, exceeding the pre-specified threshold. Grade 3 or higher adverse events occurred in 52 (93%) of 56 patients, and 12 (21%) of 56 discontinued due to adverse events. The 1-year survival rates were 43·4% (80% CI 34·1-53·1) overall (p<0·0001), 50·0% (39·1-60·9) in performance status 2 (p<0·0001), and 18·2% (5·0-41·5) in performance status 3. INTERPRETATION: Durvalumab, carboplatin, and etoposide showed tolerability and promising efficacy as a first-line treatment for patients with untreated extensive-stage SCLC with poor performance status, supporting the integration of immune checkpoint inhibitors in this therapeutically challenging population. FUNDING: AstraZeneca KK.