Reply to “The confounding effect of baselined characteristics in the assessment of efficacy of biologics”

We read with great interest the network analysis by Cai et al,1Cai S. Xu S. Lou H. Zhang L. Comparison of different biologics for treating chronic rhinosinusitis with nasal polyps: a network analysis.J Allergy Clin Immunol Pract. 2022; 19: 1876-1886.e7Abstract Full Text Full Text PDF Scopus (18) Google Scholar which compared the different biologics for treating patients with chronic rhinosinusitis with nasal polyps (CRSwNP). Based on the analysis of 7 randomized controlled trials (RCTs), they suggested that dupilumab exhibits the best efficacy and safety for this clinical entity. However, we have serious concerns about the different baseline characteristics, such as treatment history, comorbidities, and disease severity, in each included RCT that might influence the analysis of clinical efficacy. First, the different baseline clinical characteristics in the included RCTs could affect the comparison of clinical efficacy. The baseline nasal polyp score, which was correlated with polyp size, could range from 5.4 in SYNAPSE2Han J.K. Bachert C. Fokkens W. Desrosiers M. Wagenmann M. Lee S.E. et al.Mepolizumab for chronic rhinosinusitis with nasal polyps (SYNAPSE): a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet Respir Med. 2021; 9: 1141-1153Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar to 6.3 in Bachert et al’s study.3Bachert C. Sousa A.R. Lund V.J. Scadding G.K. Gevaert P. Nasser S. et al.Reduced need for surgery in severe nasal polyposis with mepolizumab: randomized trial.J Allergy Clin Immunol. 2017; 140: 1024-1031.e1014Abstract Full Text Full Text PDF PubMed Scopus (350) Google Scholar Furthermore, the prevalence of asthma was different in each included study, which ranged from 53.6% (in POLYP 14Gevaert P. Omachi T.A. Corren J. Mullol J. Han J. Lee S.E. et al.Efficacy and safety of omalizumab in nasal polyposis: 2 randomized phase 3 trials.J Allergy Clin Immunol. 2020; 146: 595-605Abstract Full Text Full Text PDF PubMed Scopus (300) Google Scholar) to 78.1% (in Bachert et al, 20173Bachert C. Sousa A.R. Lund V.J. Scadding G.K. Gevaert P. Nasser S. et al.Reduced need for surgery in severe nasal polyposis with mepolizumab: randomized trial.J Allergy Clin Immunol. 2017; 140: 1024-1031.e1014Abstract Full Text Full Text PDF PubMed Scopus (350) Google Scholar); and the baselined eosinophil count and the prevalence of eosinophilia varied as well. Both asthma and eosinophilia could be associated with more severe type 2 (T2) inflammation and further affect the response to T2-targeting biologic therapies. Second, the prior use of systemic corticosteroid within 1 year, which indicates poorly controlled disease, varied. The proportion ranged from 18.8% in POLYP 14Gevaert P. Omachi T.A. Corren J. Mullol J. Han J. Lee S.E. et al.Efficacy and safety of omalizumab in nasal polyposis: 2 randomized phase 3 trials.J Allergy Clin Immunol. 2020; 146: 595-605Abstract Full Text Full Text PDF PubMed Scopus (300) Google Scholar to 72% to 78% in OSTRO.5Bachert C. Han J.K. Desrosiers M.Y. Gevaert P. Heffler E. Hopkins C. et al.Efficacy and safety of benralizumab in chronic rhinosinusitis with nasal polyps: A randomized, placebo-controlled trial.J Allergy Clin Immunol. 2022; 149: 1309-1317.e2Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar In addition, the proportion of patients with prior surgery differed. All patients had prior surgery in 2 mepolizumab studies (SYNAPSE2Han J.K. Bachert C. Fokkens W. Desrosiers M. Wagenmann M. Lee S.E. et al.Mepolizumab for chronic rhinosinusitis with nasal polyps (SYNAPSE): a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet Respir Med. 2021; 9: 1141-1153Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar and Bachert et al’s RCTs3Bachert C. Sousa A.R. Lund V.J. Scadding G.K. Gevaert P. Nasser S. et al.Reduced need for surgery in severe nasal polyposis with mepolizumab: randomized trial.J Allergy Clin Immunol. 2017; 140: 1024-1031.e1014Abstract Full Text Full Text PDF PubMed Scopus (350) Google Scholar), but the other RCTs had 57.2% to 73.2% patients with prior surgery. Moreover, SYNAPSE2Han J.K. Bachert C. Fokkens W. Desrosiers M. Wagenmann M. Lee S.E. et al.Mepolizumab for chronic rhinosinusitis with nasal polyps (SYNAPSE): a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet Respir Med. 2021; 9: 1141-1153Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar had the shortest time between previous nasal surgery and enrollment. Thus, it is possible that the patients in SYNAPSE2Han J.K. Bachert C. Fokkens W. Desrosiers M. Wagenmann M. Lee S.E. et al.Mepolizumab for chronic rhinosinusitis with nasal polyps (SYNAPSE): a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet Respir Med. 2021; 9: 1141-1153Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar had more severe and treatment-refractory disease than the other trials. In conclusion, many confounding factors can affect the clinical efficacy of biologics in the treatment of patients with CRSwNP. Without adjusting for these confounding effects, the findings of the present study by Cao et al1Cai S. Xu S. Lou H. Zhang L. Comparison of different biologics for treating chronic rhinosinusitis with nasal polyps: a network analysis.J Allergy Clin Immunol Pract. 2022; 19: 1876-1886.e7Abstract Full Text Full Text PDF Scopus (18) Google Scholar should be interpreted with caution. Comparison of Different Biologics for Treating Chronic Rhinosinusitis With Nasal Polyps: A Network AnalysisThe Journal of Allergy and Clinical Immunology: In PracticeVol. 10Issue 7PreviewSeveral promising clinical trials have demonstrated the effects of type 2 biologics compared with placebos in chronic rhinosinusitis with nasal polyps (CRSwNP). However, there are no head-to-head randomized controlled trials (RCTs) between the biologics. Full-Text PDF Reply to “The confounding effect of baselined characteristics in the assessment of efficacy of biologics”The Journal of Allergy and Clinical Immunology: In PracticeVol. 10Issue 9PreviewWe appreciate the correspondence by Hsu and Lai1 concerning our recent publication.2 It is of great importance to understand how the baseline characteristics of patients with different disease severity of chronic rhinosinusitis with nasal polyps (CRSwNP) would affect the efficacy of biologics. We acknowledge that the patients from SYNAPSE and OSTRO might exhibit more severe illness than those from other included studies.3 In addition, we have previously reported that dupilumab efficacy may be exaggerated owing to heterogeneity of the trials. Full-Text PDF