Daily Respiratory Research Analysis
A phase 3 RCT showed that the DLL3-directed T-cell engager tarlatamab significantly prolongs overall survival versus chemotherapy in previously treated small-cell lung cancer, with fewer severe adverse events. A network meta-analysis clarified optimal pulmonary rehabilitation content and timing in COPD, highlighting benefits of multi-component training in stable disease and early, pre-discharge endurance training after exacerbations. A prospective study (PET-FIRST) demonstrated that obtaining PE
Summary
A phase 3 RCT showed that the DLL3-directed T-cell engager tarlatamab significantly prolongs overall survival versus chemotherapy in previously treated small-cell lung cancer, with fewer severe adverse events. A network meta-analysis clarified optimal pulmonary rehabilitation content and timing in COPD, highlighting benefits of multi-component training in stable disease and early, pre-discharge endurance training after exacerbations. A prospective study (PET-FIRST) demonstrated that obtaining PET/CT before biopsy of intermediate–high-risk lung nodules alters biopsy decisions and reduces procedural costs.
Research Themes
- Practice-changing immunotherapy in thoracic oncology
- Optimization of pulmonary rehabilitation content and timing in COPD
- Imaging-led decision-making for lung nodule biopsy
Selected Articles
1. Tarlatamab in Small-Cell Lung Cancer after Platinum-Based Chemotherapy.
In a multinational phase 3, open-label trial (n=509), tarlatamab significantly improved overall survival versus physician’s-choice chemotherapy in relapsed SCLC after platinum (median 13.6 vs 8.3 months; HR 0.60), with lower rates of grade ≥3 adverse events and fewer discontinuations. Progression-free survival and patient-reported respiratory symptoms (dyspnea, cough) also favored tarlatamab.
Impact: This is the first phase 3 RCT to demonstrate a survival advantage of a DLL3-directed T-cell engager over chemotherapy in previously treated SCLC, a setting with limited effective options. The magnitude and consistency of benefit with a favorable safety profile suggest near-term practice impact.
Clinical Implications: Tarlatamab should be considered a preferred second-line option after platinum-based chemotherapy for SCLC, with improved OS and tolerability over current chemotherapy standards. Clinicians should monitor for immune-related and neurologic toxicities consistent with T-cell engagers.
Key Findings
- Median overall survival improved to 13.6 months with tarlatamab vs 8.3 months with chemotherapy (HR 0.60, P<0.001).
- Lower incidence of grade ≥3 adverse events (54% vs 80%) and fewer treatment discontinuations (5% vs 12%) with tarlatamab.
- Progression-free survival and patient-reported dyspnea and cough also favored tarlatamab.
Methodological Strengths
- Multinational phase 3 randomized design with overall survival as the primary endpoint
- Clinically relevant comparator arm with physician’s-choice chemotherapy and comprehensive safety reporting
Limitations
- Open-label design may introduce assessment bias despite hard endpoints
- Interim analysis; longer follow-up needed for durability and late toxicity
- Generalizability across global practice settings and prior lines may vary
Future Directions: Define biomarker subsets (e.g., DLL3 expression, TME features) predicting response, optimize sequencing with lurbinectedin/IO, and assess real-world effectiveness and quality-of-life outcomes.
BACKGROUND: Tarlatamab, a bispecific delta-like ligand 3-directed T-cell engager immunotherapy, received accelerated approval for the treatment of patients with previously treated small-cell lung cancer. Whether tarlatamab is more effective than chemotherapy in the treatment of patients whose small-cell lung cancer has progressed during or after initial platinum-based chemotherapy is not known. METHODS: We conducted a multinational, phase 3, open-label trial to compare tarlatamab with chemotherapy as second-line treatment in patients with small-cell lung cancer whose disease had progressed during or after platinum-based chemotherapy. Patients were randomly assigned to receive tarlatamab or chemotherapy (topotecan, lurbinectedin, or amrubicin). The primary end point was overall survival. Key secondary end points were investigator-assessed progression-free survival and patient-reported outcomes. Results of the prespecified interim analysis (data-cutoff date, January 29, 2025) are reported. RESULTS: A total of 509 patients were randomly assigned to receive tarlatamab (254 patients) or chemotherapy (255 patients). Treatment with tarlatamab resulted in significantly longer overall survival than chemotherapy (median, 13.6 months [95% confidence interval {CI}, 11.1 to not reached] vs. 8.3 months [95% CI, 7.0 to 10.2]; stratified hazard ratio for death, 0.60; 95% CI, 0.47 to 0.77; P<0.001). Tarlatamab treatment also had a significant benefit with respect to progression-free survival and cancer-related dyspnea and cough as compared with chemotherapy. The incidence of adverse events of grade 3 or higher was lower with tarlatamab than with chemotherapy (54% vs. 80%), as was the incidence of adverse events resulting in treatment discontinuation (5% vs. 12%). CONCLUSIONS: Treatment with tarlatamab led to longer overall survival than chemotherapy among patients with small-cell lung cancer whose disease had progressed during or after platinum-based chemotherapy. (Funded by Amgen; DeLLphi-304 ClinicalTrials.gov number, NCT05740566.).
2. Optimal Pulmonary Rehabilitation Program and Timing of Program Initiation for Patients With Chronic Obstructive Pulmonary Disease: A Systematic Review and Network Meta-Analysis.
Across 52 trials (n=2,828), multi-component pulmonary rehabilitation (endurance+resistance+respiratory muscle training) significantly improved 6MWD in stable COPD by ~72 m. After AECOPD, starting endurance training before discharge yielded the largest gains in both readmissions (OR 0.09) and 6MWD (~168 m), while post-discharge endurance+resistance also reduced readmissions (OR 0.44).
Impact: This synthesis provides actionable, comparative evidence on both the content and timing of pulmonary rehabilitation, addressing a frequent source of clinical uncertainty and informing program design to reduce readmissions and improve capacity.
Clinical Implications: For stable COPD, implement multi-component PR (endurance, resistance, respiratory muscle training) to maximize functional gains. After AECOPD, prioritize initiating endurance training before discharge to substantially reduce readmissions and improve 6MWD; post-discharge endurance+resistance also reduces readmissions.
Key Findings
- In stable COPD, multi-component PR (endurance+resistance+respiratory muscle training) improved 6MWD by 72.09 m (95% CI 48.16–96.02) vs usual care.
- In AECOPD, pre-discharge initiation of endurance training alone yielded the largest reductions in readmissions (OR 0.09, 95% CI 0.01–0.56) and increased 6MWD by 167.69 m.
- Post-discharge endurance+resistance training reduced readmission risk (OR 0.44, 95% CI 0.21–0.91).
Methodological Strengths
- Comprehensive network meta-analysis of 52 RCTs with 2,828 participants, separating stable vs AECOPD contexts
- Risk-of-bias assessed with RoB 2.0 and random-effects models for comparative effectiveness
Limitations
- Heterogeneity in intervention components, intensity, and settings; indirect comparisons inherent to NMA
- Search through August 2022; potential publication bias and need for updated trials
- Outcomes focused on 6MWD and readmissions; limited patient-reported outcomes
Future Directions: Head-to-head trials comparing prioritized pre-discharge vs early post-discharge PR starts; standardized multi-component protocols; integration of PROs and cost-effectiveness across health systems.
PURPOSE: Evidence for optimal timing of pulmonary rehabilitation initiation, especially during stable chronic obstructive pulmonary disease (COPD) or following its acute exacerbation (AE), is conflicting. REVIEW METHODS: PubMed, EMBASE, and Cochrane CENTRAL were systematically searched before August 2022. The identified interventions were classified as single-component programs (endurance, resistance, and respiratory muscle training) and multi-component programs (combinations of these interventions). The revised risk-of-bias tool 2.0 was used to assess the risk of bias of the included studies. Network meta-analyses were performed separately for stable COPD and AECOPD using a random-effects model to calculate mean differences (MD). A total of 52 trials with 2,828 patients were included. For patients with stable COPD, multi-component programs combining endurance, resistance, and respiratory muscle training significantly improved the six-minute walk test (6MWT) distance (MD = 72.09: 95% CI, 48.16-96.02 meters) compared to usual care. In AECOPD, post-discharge initiation of rehabilitation with a combination of endurance and resistant training significantly reduced the readmission rate (OR = 0.44: 95% CI, 0.21-0.91); conversely, pre-discharge initiation with endurance training alone achieved the most significant improvements in both the readmission rate (OR = 0.09: 95% CI, 0.01-0.56) and 6MWT distance (MD = 167.69: 95% CI, 81.23-254.15 meters). SUMMARY: The integration of endurance, resistance, and respiratory muscle training improved exercise capacity in patients with stable COPD. Prioritizing endurance training prior to discharge demonstrated the most favorable outcomes in both readmission rates and exercise capacity for patients with AECOPD, although further validation is needed.
3. Biopsy decision for intermediate-high-risk lung nodules is significantly changed when guided by prior positron emission tomography/CT (PET/CT) results: results of the prospective PET-FIRST study.
In this two-center prospective study (n=168) using a blinded-then-unblinded MDT process, pre-biopsy PET/CT altered biopsy recommendations in 35% of intermediate–high-risk lung nodules and changed the decision to biopsy or not in 25% (p<0.01). Benefits spanned Brock risk strata, and estimated procedural cost savings were $AA60,796 in total ($AA362 per patient).
Impact: Demonstrates that PET/CT meaningfully reshapes biopsy decision-making for lung nodules across risk strata and can reduce unnecessary procedures and costs, informing diagnostic pathways and MDT workflows.
Clinical Implications: For intermediate–high-risk nodules, incorporating PET/CT prior to biopsy can refine patient selection for invasive procedures, potentially lowering unnecessary biopsies and associated costs while maintaining diagnostic yield.
Key Findings
- Biopsy recommendations changed in 35% (59/168) after PET/CT; decision to biopsy or not changed in 25% (p<0.01).
- Effect observed across Brock score strata, supporting broad applicability.
- Estimated cost reduction from avoided procedures totaled $AA60,796 ($AA362 per patient).
Methodological Strengths
- Prospective design with a pre-specified two-stage MDT consensus (CT-only vs PET/CT-informed)
- Sensitivity analyses across risk strata and pragmatic cost assessment
Limitations
- Open-label diagnostic pathway in two centers; no randomization to PET/CT vs standard care
- Primary endpoint was decision change rather than patient outcomes; external cost generalizability may vary
Future Directions: Randomized trials of PET/CT-first vs standard pathways with patient-centered outcomes and cost-effectiveness; integration with risk calculators and AI to further optimize biopsy selection.
INTRODUCTION: Positron emission tomography/CT (PET/CT) may have an important role in guiding decisions regarding biopsy of high-risk lung nodules suspicious for lung cancer. The PET-FIRST study aimed to assess the role of PET/CT prior to any biopsy of a high-risk lung nodule. METHODS: A prospective study was performed in two tertiary hospitals. A study multidisciplinary team (MDT) was established (independent of the hospital Tumour Board) to review referrals of lung nodules with an intermediate-high (≥10%) risk of malignancy by Brock score. A two-stage consensus assessment was undertaken by the MDT regarding choice of biopsy: (1) based on the referral CT alone and then (2) after unblinding the results of PET/CT. The primary study outcome was change in biopsy decision. RESULTS: 168 patients were included in the study; of these, 53% of nodules were malignant, 44% were benign and 3% cases refused follow-up. In 59 of the 168 patients (35%), the initial recommended biopsy decision was changed based on PET/CT findings. Regarding whether to biopsy the nodule or not, in 42 cases (25%), the initial management decision was changed after PET/CT (p<0.01). Sensitivity analysis showed that the benefit of having PET/CT before nodule biopsy was observed across all ranges of Brock scores. There was an estimated total cost reduction by procedure avoidance of $AA60 796 ($AA362 per patient). CONCLUSIONS: In patients with lung nodules of intermediate-high risk for lung cancer, fluorodeoxyglucose PET/CT performed prior to any biopsy of the nodule has a significant effect in determining biopsy choice.