Biologics for chronic rhinosinusitis with nasal polyposis: What should we do now without direct comparison trials?

Abstract

In this issue of the Annals of Allergy, Asthma & Immunology, Borish et al1Bolish L Cohen NA Chupp G Hopkins C Wagenmann M Sousa AR. et al.Evaluating severity of chronic rhino sinusitis with nasal polyps: implications for biologic trials.Ann Allergy Asthma Immunol. 2022; 129: 160-168Google Scholar describe differences in clinical trials of biologics for chronic rhinosinusitis with nasal polyposis (CRSwNP). The authors present a detailed analysis of populations from 6 pivotal phase III biological trials (SINUS-24, SINUS-52, POLYP 1, POLYP 2, SYNAPSE, OSTRO) and explore whether variations in supplemental entry criteria could explain efficacy differences between biologics for CRSwNP. Although all trials were placebo controlled and required an endoscopic polyp score of at least 5 (scale 0 to 8) with a minimum score of 2 in each nostril, study populations were not identical. Severity of CRSwNP can be judged using several metrics, including patient-reported symptoms and quality of life questionnaires (eg, Sinonasal Outcome Test-22 [SNOT-22]), objective smell testing (University of Pennsylvania Smell Identification Test), nasal polyp scores, and comorbid conditions. In the review by Borish et al,1Bolish L Cohen NA Chupp G Hopkins C Wagenmann M Sousa AR. et al.Evaluating severity of chronic rhino sinusitis with nasal polyps: implications for biologic trials.Ann Allergy Asthma Immunol. 2022; 129: 160-168Google Scholar the mean SNOT-22 scores per trial ranged from 48.0 to 69.3 suggesting a minor amount of variation from study-to-study (scale 0 to 110). The mean University of Pennsylvania Smell Identification Test scores per trial ranged from 12.8 to 14.7 also suggesting only a small level of variation from study-to-study (scale 0-40). Having comorbid aspirin-exacerbated respiratory disease and asthma varied slightly between trials (range 17%-39% for aspirin-exacerbated respiratory disease and 49%-74% for asthma). How do these outcomes for people with CRSwNP treated with biologics compare? Oykhman et al2Oykhman P Paramo FA Bousquet J Kennedy DW Brignardello-Petersen R Chu DK. Comparative efficacy and safety of monoclonal antibodies and aspirin desensitization for chronic rhinosinusitis with nasal polyposis: a systematic review and network meta-analysis.J Allergy Clin Immunol. 2022; 149: 1286-1295Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar recently performed a network meta-analysis and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) of biologics for CRSwNP. In that analysis of 29 randomized controlled trials evaluating 8 treatments (n = 3461), dupilumab ranked among the most beneficial agents in 7 of 7 outcomes, omalizumab in 2 of 7 outcomes, and mepolizumab and aspirin therapy after desensitization in 1 of 7 outcomes for CRSwNP, with moderate to high certainty evidence. Oykhman et al2Oykhman P Paramo FA Bousquet J Kennedy DW Brignardello-Petersen R Chu DK. Comparative efficacy and safety of monoclonal antibodies and aspirin desensitization for chronic rhinosinusitis with nasal polyposis: a systematic review and network meta-analysis.J Allergy Clin Immunol. 2022; 149: 1286-1295Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar assessed the evidence using a transparent process to account for several important aspects of study design and performance, including risk of bias, inconsistency, indirectness, imprecision, intransitivity, and incoherence, evaluating each trial on a per-outcome basis to provide a final assessment of the evidence certainty. In GRADE, when high certainty of evidence is determined, it is likely that the estimate is very near to the true effect and less likely that additional future studies will change the estimate of effect. With moderate certainty, it is likely that the estimated effect is close to the true effect but more studies could come along and potentially change this judgment. For example, when comparing dupilumab and omalizumab to placebo, Oykhman et al2Oykhman P Paramo FA Bousquet J Kennedy DW Brignardello-Petersen R Chu DK. Comparative efficacy and safety of monoclonal antibodies and aspirin desensitization for chronic rhinosinusitis with nasal polyposis: a systematic review and network meta-analysis.J Allergy Clin Immunol. 2022; 149: 1286-1295Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar concluded that the differences in treatment effects for SNOT-22 had high certainty of evidence, but evidence certainty was moderate when describing incremental improvements of dupilumab over mepolizumab. Borish et al1Bolish L Cohen NA Chupp G Hopkins C Wagenmann M Sousa AR. et al.Evaluating severity of chronic rhino sinusitis with nasal polyps: implications for biologic trials.Ann Allergy Asthma Immunol. 2022; 129: 160-168Google Scholar highlight that the proportion of patients with prior surgery varied among trials, with all patients entering SYNAPSE having been required to have had at least 1 surgery. In SYNAPSE, 30% of the patients had at least 3 surgeries at baseline, compared with 15% in the SINUS trials, although patients in the SINUS and OSTRO trials had greater rates of systemic corticosteroid use (64%-81% and 72%-78%) at baseline compared with those in SYNAPSE (45%-51%). Is this level of variation in surgical history enough to hamstring trial comparisons? Oykhman et al2Oykhman P Paramo FA Bousquet J Kennedy DW Brignardello-Petersen R Chu DK. Comparative efficacy and safety of monoclonal antibodies and aspirin desensitization for chronic rhinosinusitis with nasal polyposis: a systematic review and network meta-analysis.J Allergy Clin Immunol. 2022; 149: 1286-1295Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar considered differences in baseline characteristics between trials within the GRADE framework, with judgments of intransitivity, the use of both random and fixed effect models, and subgroup analyses; however, surgery history was not a prespecified subgroup analysis. It is important to take a closer look at the results from Oykhman et al2Oykhman P Paramo FA Bousquet J Kennedy DW Brignardello-Petersen R Chu DK. Comparative efficacy and safety of monoclonal antibodies and aspirin desensitization for chronic rhinosinusitis with nasal polyposis: a systematic review and network meta-analysis.J Allergy Clin Immunol. 2022; 149: 1286-1295Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar to evaluate whether surgical history is likely to be a credible reason to doubt the results of the analysis. First, consider the transitivity analysis. Overall, each of the medication groups is similar to each other. A range of 50% to 92% of the trials, grouped by biologic, had prior surgery. More specifically, surgery rates for mepolizumab (92%), aspirin desensitization (85%) and benralizumab (77%) were very similar. Rates for omalizumab (69%) and dupilumab (63%) were also very similar. Next, consider the differences in outcomes for studies that used the same intervention. Take, for example, dupilumab, where 72% and 58% had prior surgery in SINUS 24 and 52, respectively. A post hoc subgroup analysis recently suggested that outcome measures improved similarly regardless of number of prior surgeries.3Hopkins C Wagenmann M Bachert C Desrosiers M Han JK Hellings PW et al.Efficacy of dupilumab in patients with a history of prior sinus surgery for chronic rhinosinusitis with nasal polyps.Int Forum Allergy Rhinol. 2021; 11: 1087-1101Crossref PubMed Scopus (19) Google Scholar In this analysis of 724 patients, dupilumab improved outcomes regardless of the number of prior surgeries, although it was more effective in patients with less than 3 years since the previous surgery when compared with those who had a previous surgery more than 5 years ago. This information argues against baseline number of surgeries as being a credible subgroup modifier of outcomes in biologic studies for CRSwNP and increases the confidence in a likely advantage of dupilumab over mepolizumab, as there was a mean of 3.8 to 4.2 years between previous surgeries and study start in SYNAPSE vs a mean of 7.2 years in SINUS, and still dupilumab outperformed mepolizumab.1Bolish L Cohen NA Chupp G Hopkins C Wagenmann M Sousa AR. et al.Evaluating severity of chronic rhino sinusitis with nasal polyps: implications for biologic trials.Ann Allergy Asthma Immunol. 2022; 129: 160-168Google Scholar,2Oykhman P Paramo FA Bousquet J Kennedy DW Brignardello-Petersen R Chu DK. Comparative efficacy and safety of monoclonal antibodies and aspirin desensitization for chronic rhinosinusitis with nasal polyposis: a systematic review and network meta-analysis.J Allergy Clin Immunol. 2022; 149: 1286-1295Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar What is a practicing Allergist-Immunologist to do with the currently available information? One option is to wait for direct comparison studies before deciding on how to use biologics in current treatment paradigms. This should be considered in the broader context of additional CRSwNP management options.4Borish L Baroody FM Kim MS Lieberman JA Peters A Stevens WW et al.Yardstick for the medical management of chronic rhinosinusitis.Ann Allergy Asthma Immunol. 2022; 128: 118-128Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar A trial comparing omalizumab and dupilumab using inclusion criteria similar to previous biologic studies for CRSwNP is underway with an estimated completion date of October 17, 2023 (NCT#04998604). Perhaps additional trials comparing biologics for CRSwNP will begin. The other option is the use the best available information we have currently, which includes high and moderate certainty of important treatment effects for multiple biologics. We suggest using the most comprehensive and current evaluation comparing biologics for CRSwNP to inform these discussions rather than waiting for additional studies. We applaud Borish et al1Bolish L Cohen NA Chupp G Hopkins C Wagenmann M Sousa AR. et al.Evaluating severity of chronic rhino sinusitis with nasal polyps: implications for biologic trials.Ann Allergy Asthma Immunol. 2022; 129: 160-168Google Scholar for providing a glimpse into what could be next for understanding on how to use biologics in people with CRSwNP. They review the comprehensive 2019 National Institutes of Health workshop findings where adaptive study designs comparing multiple biologics were discussed, among many important topics and future recommendations for research related to CRS.5Naclerio R, Baroody F, Bachert C, Bleier B, Borish L, Brittain E, et al. Clinical research needs for the management of chronic rhinosinusitis with nasal polyps in the new era of biologics: a National Institute of Allergy and Infectious Diseases workshop. J Allergy Clin Immunol Pract. 2020;8(5):1532-1549.e1.Google Scholar In addition to comparison of biologics with each other, it will be important to directly compare biologics with other existing management options, such as surgery, corticosteroids, and aspirin therapy after desensitization. Borish et al1Bolish L Cohen NA Chupp G Hopkins C Wagenmann M Sousa AR. et al.Evaluating severity of chronic rhino sinusitis with nasal polyps: implications for biologic trials.Ann Allergy Asthma Immunol. 2022; 129: 160-168Google Scholar also note the importance of using clinical characteristics and biomarkers to predict which people will respond better to which biologic. This personalized, precision-medicine based approach is likely to be the next frontier of therapy for CRSwNP. In conclusion, the body of evidence for the use of biologics for CRSwNP has been assessed using a transparent framework and certainty of evidence is moderate to high for several interventions and outcomes.2Oykhman P Paramo FA Bousquet J Kennedy DW Brignardello-Petersen R Chu DK. Comparative efficacy and safety of monoclonal antibodies and aspirin desensitization for chronic rhinosinusitis with nasal polyposis: a systematic review and network meta-analysis.J Allergy Clin Immunol. 2022; 149: 1286-1295Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar The evidence, as with all such bodies of evidence, falls far short of perfect. However, we suggest that the important concerns raised by Borish et al1Bolish L Cohen NA Chupp G Hopkins C Wagenmann M Sousa AR. et al.Evaluating severity of chronic rhino sinusitis with nasal polyps: implications for biologic trials.Ann Allergy Asthma Immunol. 2022; 129: 160-168Google Scholar about differences in baseline characteristics between studies be considered along with the counterbalancing strengths in the overall body of evidence. Evaluating enrollment and outcome criteria in trials of biologics for chronic rhinosinusitis with nasal polypsAnnals of Allergy, Asthma & ImmunologyVol. 129Issue 2PreviewTreatment for chronic rhinosinusitis with nasal polyps (CRSwNP) generally involves intranasal corticosteroids (INCS) and saline irrigation, followed by short courses of systemic corticosteroids (SCS) or surgery with postoperative medical therapy for patients who do not respond to INCS. However, both SCS use and surgery are associated with a range of adverse effects or complications, have a high recurrence rate, and are unsuitable for some patients. Biologics targeting the underlying pathophysiology are promising treatment alternatives for these patients. Full-Text PDF Open Access