Extract
Former or current smoking is common among adults with asthma [1], and past tobacco exposure has been associated with steroid insensitivity and greater disease severity [2–6]. However, the clinical impact of smoking history on response to biologic therapy remains uncertain, as most randomised trials exclude smokers. We evaluated the long-term effectiveness of benralizumab in former smokers with severe eosinophilic asthma (SEA) versus never-smokers in a post hoc analysis of the ANANKE real-world study.
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Benralizumab improves outcomes in severe eosinophilic asthma patients regardless of smoking history, with former smokers achieving similar benefits in exacerbation reduction, oral corticosteroid sparing, asthma control and lung function to never-smokers https://bit.ly/4grFy7e
To the Editor:
Former or current smoking is common among adults with asthma [1], and past tobacco exposure has been associated with steroid insensitivity and greater disease severity [2–6]. However, the clinical impact of smoking history on response to biologic therapy remains uncertain, as most randomised trials exclude smokers. We evaluated the long-term effectiveness of benralizumab in former smokers with severe eosinophilic asthma (SEA) versus never-smokers in a post hoc analysis of the ANANKE real-world study.
The ANANKE study (NCT04272463) was a retrospective multicentre cohort study conducted in Italy in patients with SEA treated with benralizumab in clinical practice [7]. Of 218 patients enrolled, 167 were evaluable at 96 weeks. Smoking status was known for 150 patients, of whom 44 were former smokers and 106 were never-smokers. Former smokers had a median 15-year smoking history and exhibited more severe disease at baseline, including higher blood eosinophil counts (625 versus 575 cells·mm−3), more frequent exacerbations (annualised exacerbation rate (AER) 5.33 versus 3.83), and lower asthma control test (ACT) scores (12.0 versus 15.0) than never-smokers. Baseline lung function (as measured by forced expiratory volume in 1 s (FEV1)) was slightly lower in former smokers (FEV1 1.7 versus 1.9 L).
Despite these differences, both groups showed robust and sustained responses to benralizumab. At 96 weeks, AERs were reduced to 0.35 in former smokers and 0.16 in never-smokers (figure 1a), while severe AERs dropped to 0.09 and 0.01, respectively (figure 1b). Oral corticosteroid (OCS) use declined significantly; 80% of former smokers and 76.9% of never-smokers achieved a reduction or complete discontinuation of OCS, and 70% versus 61.5% reduced their dose by at least 90%. ACT scores increased progressively, with 84.2% of former smokers and 75.4% of never-smokers achieving well-controlled asthma (ACT ≥20) by the end of follow-up. Lung function improved comparably in both groups, and blood eosinophils were almost completely depleted over the treatment period.
FIGURE 1.
Annualised exacerbation rate (AER) for a) any, and b) severe exacerbations during benralizumab treatment at index date and at 96 weeks, former smokers versus never-smokers.
Overall, these findings confirm that a history of smoking does not preclude clinical benefit from benralizumab in patients with SEA. Our findings align with previous studies investigating the impact of biologic therapies in severe asthma patients with different smoking histories. While some studies have suggested that former smoking may impair the response to biologics due to persistent airway remodelling and steroid insensitivity [8], others, including a recent Danish nationwide study, have reported similar efficacy of biologics in former and never-smokers [9].
Importantly, our data suggest that former smokers, despite a higher disease burden at baseline, can catch up with never-smokers in terms of asthma control and corticosteroid reduction. The magnitude of reduction in both any and severe exacerbations was notable, particularly given the initial differences in clinical parameters. This highlights the role of eosinophilic inflammation as a key therapeutic target in SEA, regardless of smoking history.
In terms of lung function, although former smokers started at a slightly lower level, both groups exhibited similar trajectories of improvement over the 96-week period. Likewise, the degree of eosinophil depletion and OCS sparing was almost identical. The treatment retention rate also reinforces the long-term tolerability and sustained efficacy of benralizumab across patient subgroups.
A major strength of this analysis is its real-world setting, which contributes to the generalisability of our findings. The extended 96-week follow-up period also provides valuable insights into the long-term effectiveness of benralizumab. However, this analysis has limitations, including its retrospective design, the absence of detailed pack-year data, and the lack of a comparator group of current smokers. Nevertheless, the long-term follow-up and real-life setting enhance its external validity, despite the retrospective design, the absence of detailed pack-year and smoking cessation timing data, and the lack of a comparator group of current smokers. Furthermore, smoking history was only available for 150 out of 218 enrolled patients, limiting the statistical power of the subgroup comparison. Although many former smokers had a smoking history exceeding 10 pack-years, we could not assess the presence of fixed airway obstruction due to insufficient spirometric data. It should be noted that fixed airway obstruction is not an exclusive feature of COPD but may also be observed in severe eosinophilic asthma. Since COPD was not reported as a comorbidity in this cohort, it seems reasonable to consider the fixed airway obstruction as a functional expression of remodelling characterising SEA evolution trajectory. The absence of confidence intervals or standard deviations for key outcomes further limits the interpretability of the findings.
While smoking remains a modifiable risk factor and smoking cessation should always be a therapeutic goal [10], our data reinforce that former smokers with SEA can achieve substantial clinical benefit from benralizumab comparable to never-smokers. These results extend the applicability of benralizumab to a population often underrepresented in clinical trials and support its real-world use based on phenotype rather than smoking history alone.
Acknowledgements
Medical writing support by Lisa Mathiasen, PhD, and statistical analysis by Fabio Gallo, both of EDRA S.p.A.
Footnotes
Provenance: Submitted article, peer reviewed.
Ethics statement: This study followed the ethical principles outlined in the Declaration of Helsinki and the regulations and guidelines governing medical practice and ethics in Italy. All patients provided informed consent before enrolling in the study and signed additional and amended study informed consent and privacy forms for the extended observation period. Ethical approval was provided by the ethics committees/institutional review boards at each participating site.
Author contributions: All authors contributed equally to the study's conception and design, data collection, manuscript drafting, critical revision, and final approval of the version to be submitted. All authors agree to be accountable for all aspects of the work.
Conflict of interest: P. Cameli has received grants and fees as a speaker from AstraZeneca-MedImmune, Sanofi, and GlaxoSmithKline (GSK) in the last three years. G.W. Canonica reports research or clinical trials grants paid to his institution from Menarini, AstraZeneca, GSK, Sanofi Genzyme and fees for lectures or advisory board participation from Menarini, AstraZeneca, CellTrion, Chiesi, Faes Farma, Firma, Genentech, GuidottiMalesci, GSK, HAL Allergy, Innovacaremd, Novartis, OM-Pharma, Red Maple, Sanofi-Aventis, SanofiGenzyme, Stallergenes-Greer, and Uriach Pharma. S. Del Giacco declares fees from AstraZeneca, Chiesi, GSK, Novartis, Sanofi, Menarini; unrestricted grants from AstraZeneca, GSK, Novartis, and Sanofi. F. Di Marco declares personal fees and support for research from AstraZeneca, Boehringer Ingelheim, Chiesi, Eurodrugs Laboratories, Laboratori Guidotti, GlaxoSmithKline, Levante Pharma, Menarini, Sanofi, Zambon. P. Rogliani reports grants/research support to her institution from Arcede Pharma, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, Sanofi, Verona Pharma and Zambon and honoraria or consultation fees from AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline, Menarini Group, Novartis, Pfizer, Recipharm, Regeneron, Roche and Sanofi. J.W. Schroeder declares personal fees and support for research from AstraZeneca, GSK, Sanofi and Stallergenes. The authors M. Aliani, E. Altieri, P. Bracciale, L. Brussino, M.F. Caiaffa, M. Caminati, C. Caruso, S. Centanni, M. D'Amato, F. De Michele, L. Malerba, F. Menzella, G. Pelaia, M. Romagnoli, P. Schino, G. Senna, and A. Vultaggio declare no competing interests.
Support statement: AstraZeneca SpA Italy provided financial support for the article's preparation. The company participated in the study design and data collection and analysis. Funding information for this article has been deposited with the Open Funder Registry.
Data availability
The datasets used in the current study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets used in the current study are available from the corresponding author upon reasonable request.