Is Switching Biologics in CRSwNP Promising? Real-World Evidence for Clinical Outcome Measures in Comparison

Abstract

Objective:

Biologics are well established in treating severe chronic rhinosinusitis with nasal polyps (CRSwNP). Most patients benefit from the first chosen biologic agent, in a few cases switching biologics can be a further therapeutic strategy.

Methods:

In this monocentric retrospective study, patients with CRSwNP and biologic therapy were compared with respect to Sino-Nasal Outcome Test-22 (SNOT-22) score, bilateral nasal polyp score (NPS), and change in biologic agent as primary variables. Statistical analysis was performed using independent sample t-tests or Welch’s t-tests for continuous variables and Pearson’s chi-squared test for categorical data.

Results:

A total of 48 patients with CRSwNP who received biologic therapy between 2020 and 2024 were included in this study. During the course of treatment, 10 patients (20.4%) required a switch to a different biologic agent. A significant reduction in both the SNOT-22 score and NPS was observed in patients regardless of whether a biologic switch occurred, following a minimum post-treatment observation period of 6 months. No significant differences in clinical outcomes were found between patients who switched biologics and those who continued with their initial agent.

Conclusions:

Most patients switched from anti-immunoglobulin E or anti-IL-5 treatment to anti-IL-4/-IL-13, with good improvement in therapy control. Notably, symptom control after switching biologics does not differ significantly from that achieved in patients who remained on their initial biologic therapy.

Introduction

Chronic rhinosinusitis with nasal polyps (CRSwNP) affects ~1% to 4% of the general population and is associated with a significant reduction in quality of life and the presence of relevant comorbidities.^1,2 Despite multimodal treatment approaches—including endoscopic sinus surgery, topical corticosteroids, and intermittent systemic steroids—symptom relapse, such as nasal obstruction and hyposmia, occurs in up to 40% of patients within 3 years. ³ CRSwNP is primarily driven by type 2 inflammation in over 80% of patient population. ⁴ This pathophysiological pathway has led to new therapeutic strategies: Since 2019, 3 monoclonal antibodies (biologics) have been approved by FDA and EMA as add-on therapy to topical steroids in cases of severe CRSwNP. ⁵ Some of these agents were already approved for other indications such as asthma, chronic spontaneous urticaria, and hypereosinophilic syndrome. Dupilumab, omalizumab, and mepolizumab target different pathways within the type 2 inflammatory process. Dupilumab targets the cytokines interleukin IL-4 and IL-13, whereas mepolizumab targets IL-5. Omalizumab binds immunoglobulin E (IgE).^{6 -8} All 3 approved biologics are considered to have similar safety profiles and comparable response according to their approval studies. However, in some cases patients do not benefit from the initially-chosen biologic, due to inadequate therapy control or adverse events.^9,10 To date, there is a lack of evidence regarding treatment recommendations for nonresponders to biologic therapies. Nonresponders are patients who do not respond to the first chosen biologic or require further treatment strategies, for example, change in biologic, addition of another biologic, addition of cortisol therapy to the biologic, sinus surgery under biologic therapy or discontinuation of biologic treatment, and “rescue” sinus surgery.

Although switching biologics is mentioned in the current German guidelines, specific recommendations regarding timing, sequence, or selection criteria for alternative agents are lacking. In order to be able to make more precise therapy recommendations regarding the switch of biologic therapy in the future, investigations of potential causes and therapy success in patients undergoing a biologic switch appears to be essential. The aim of this study was to investigate the reasons for switching biologic therapy in patients with CRSwNP and to compare clinical outcomes between patients who switched biologics and those who remained on their initial agent, using a real-world evidence approach.

Materials and Methods

This retrospective monocentric study included adult patients (≥18 years) diagnosed with CRSwNP who regularly presented to the university outpatient allergy clinic in the ENT department at our tertiary referral center between 2020 and 2024. Eligible patients received biologic therapy as an add-on to topical corticosteroids, in accordance with EUFOREA and German guideline criteria for the treatment of severe CRSwNP.^10,11 Patients with other indications for biologic therapy, for example, asthma with secondary nasal polyps, were excluded. Ethics approval was obtained. A total of 67 patients received biologic treatment for CRSwNP during the study period, of whom 48 met the inclusion criteria and were included in the analysis. Patients and disease-specific clinical information was obtained from the medical records of the included patients. Collected variables included age, gender, number and date of previous functional endoscopic sinus surgeries, bilateral nasal polyp score (NPS) through endoscopic examination (ranging from 0 to 8 points), Sino-Nasal Outcome Test (SNOT-22) questionnaire (ranging from 0 to 110 points), duration of treatment with biologics, biologic agent, and reason for and time of biologic switching. A biologic switch was defined as a change in biologic agent followed by at least 6 months of continued treatment with the new agent. Patients who switched biologics did not have a planned washout period between the treatments. Patients were stratified into 2 groups: patients with ongoing biologic treatment with the initially-chosen agent (Group 1) and patients who underwent a switch to a different biologic (Group 2). Comparative analyses between and within groups were performed.

Qualitative variables were described as frequencies and percentages, and categorical differences among groups were tested using Pearson’s chi-squared test. Continuous variables were analyzed using independent samples t-tests or Welch’s t-tests where appropriate. Statistical tests were 2-tailed, and significance was set at P ≤ .05. SPSS (IBM SPSS Statistics) for Windows (version 28, 2022) was used for statistical analyses.

The primary clinical outcome measures were changes in SNOT-22 scores and bilateral NPS, which were compared between the 2 groups to assess treatment effectiveness in a real-world setting.

Results

Thirty-one patients were treated with dupilumab (65.5%), followed by 11 patients with omalizumab (22%) and 6 patients with mepolizumab (12.5%). The mean age of patients at the initiation of the first biologic therapy was 53.6 years in Group 1 and 53.7 years in Group 2. Among the 48 patients included in the study, 52% were female and 48% male. The gender distribution within the groups was balanced in Group 1 (50% female, 50% male), while Group 2 consisted of 60% female and 40% male patients. Ten patients switched biological treatment (20.8%). Switching patterns are illustrated in Figure 1, with the majority switching from mepolizumab and omalizumab to dupilumab. The reasons for switching included lack of symptom improvement in 7 patients (70%), a suspected allergic reaction in 1 patient, suspected biologic-associated polyneuropathy in 1 patient, and pregnancy in 1 case. Of the patients who switched their initial biologic therapy, 8 out of 10 (80%) had comorbid asthma. In comparison, 29 out of 38 patients (76.3%) in Group 1 (no switch) also had comorbid asthma, which did not represent a statistically-significant difference between the groups. The mean therapy time to switch was 12 ± 8.4 months. The average number of sinus surgeries prior to the initiation of biologic therapy was 2.9 ± 0.83 in Group 1 (no switch) and 2.7 ± 1.68 in Group 2 (switch), with no statistically-significant difference between the groups (P = .3375). Similarly, the mean interval between the last sinus surgery and the initiation of biologic therapy did not differ significantly between Group 1 (67.9 ± 42.67 months) and Group 2 (66.71 ± 53.21 months; P = .4746). The evaluation of the SNOT-22 score in Group 1 (53.82 ± 23.27 points and 26.79 ± 23.00 points; P < .001) and Group 2 (49.70 ± 22.50 points and 33.20 ± 12.46 points; P = .035) showed a significant reduction after 6 months of biologic therapy, as shown in Figure 2. Bilateral NPS also showed a significant reduction after 6 months of biologic therapy both in Group 1 (4.63 ± 2.22 points and 1.87 ± 2.09 points; P < .001) and Group 2 (4.60 ± 2.06 points and 2.50 ± 1.12 points; P = .035), as shown in Figure 3. There were no significant differences between the groups in baseline SNOT-22 scores (P = .6326) or baseline bilateral NPSs (P = .9682) prior to therapy initiation or biologic switching.

Figure 1.

Switching patterns of biologic treatment in Group 2.

Figure 2.

SNOT-22 questionnaire (0-110) before the start of biologic therapy and after 6 months of ongoing biologic therapy, respectively, before switch and after 6 months of ongoing switched biology therapy in Groups 1 and 2. SNOT-22, Sino-Nasal Outcome Test-22.

Figure 3.

Bilateral nasal polyp score (0-8) before the start of biologic therapy and after 6 months of ongoing biologic therapy, respectively, before switch and after 6 months of ongoing switched biology therapy in Groups 1 and 2.

Discussion

In recent years, clinicians have gained experience with biologics and therapy monitoring in CRSwNP. Accordingly, indication criteria and guidelines have been developed and numerous real-world evidence studies have been published in addition to the pivotal studies showing safety and efficacy profile of biologic therapy in patients with CRSwNP.^{10,12 -14} However, real-world data on switching from one biologic agent to another in CRSwNP remain limited. To date, only 5 publications have addressed this topic.^{14 -18}

In the present study, 10 out of 48 patients switched from one biologic to another (20.8%), which is a relatively-high rate compared with those in previously-published studies investigating the switching of biologics. Switching rates ranging from 4.4% to 16% have been reported.^15,16 The mean time between the last sinus surgery before the start of biologic therapy (67.9 ± 42.67 months, Group 1 and 66.71 ± 53.21 months, Group 2; P = .4746) also did not differ significantly between the 2 groups and was comparable to time periods published in other studies. ¹⁶ The number of previous sinus surgeries also did not differ significantly between both groups, suggesting that the number of previous sinus surgeries has no influence on the efficacy of biologic therapy. Alicandri-Ciufelli et al evaluated the completeness of sinus surgery using the Amsterdam Classification of Completeness of Endoscopic Sinus Surgery (ACESS) score prior to initiating dupilumab. Their findings demonstrated a significant positive correlation between higher ACESS scores and improved therapeutic response to dupilumab, indicating that more complete sinus surgery may enhance the effectiveness of subsequent biologic therapy.^19,20 Age and gender distribution were almost equal between Group 1 (continuous biologic therapy) and Group 2 (switched biologic therapy), suggesting that these factors had no influence on the initial selection of biologic agents. This observation aligns with findings from the large European real world evidence study CHRINOSOR, which demonstrated that the effectiveness of dupilumab was independent of patient age or gender. ²¹ A gender-specific factor was observed only in Patient 2, where pregnancy—rather than initial biologic selection—served as the determining reason for switching therapy.

In our study, two-thirds of patients who did not switch biologic therapy received treatment with dupilumab (65.5%), followed by omalizumab (22%) and mepolizumab (12.5%). In contrast, among patients who required a switch in biologic therapy, dupilumab was notably underrepresented. Consequently, the most frequent switch observed was from mepolizumab or omalizumab to dupilumab. This is in line with recently-published studies looking at switching biologics in patients with CRSwNP.^{14 -18} For example, Otten et al concluded that most patients who had inadequate disease control with anti-IgE and/or anti-IL-5 biologics are adequately controlled with dupilumab and recommended dupilumab as the first choice when switching to another biologic. ¹⁹ In contrast to the present study, Otten et al also included biologic agents primarily approved for severe asthma, such as rezlizumab and benralizumab. Nevertheless, the conclusion of this study may refer to our study showing good treatment control after switching to dupilumab. The average interval between the initiation of the first biologic and the switch to a different agent in our cohort was 12 ± 8.4 months, which is comparable to the durations reported by Rosso et al and Dorling et al.^14,16

Regarding the reasons for switching biologic therapy, most patients treated with CRSwNP and anti-IL-5-, or anti-IgE-agents usually switch biologics due to insufficient efficacy of the therapy and most patients with CRSwNP and anti-IL-4/-IL-13 (dupilumab) usually switch due to adverse events.^14,18 In the current study, only 3 patients were switched from dupilumab to another agent.

Patient 1 (Table 1) had inadequate treatment control after 9 months of dupilumab treatment and was switched to mepolizumab without a washout period, resulting in an overall improvement in SNOT-22 and NPS status. Patients 2 and 3 (Table 1) switched from dupilumab to anti-IgE omalizumab because disease control was inadequate and additionally in 1 patient due to pregnancy. Interestingly, Patient 2 (Table 1) also showed symptom improvement after switching from dupilumab to omalizumab; however, the SNOT-22 score may be influenced by the 14 week break from biologic therapy prior to the switch. Patient 3 (Table 1) was unable to achieve adequate treatment control even after switching from dupilumab to omalizumab, and discontinuation of biologic therapy and rescue surgery was subsequently considered. Patients 4 to 10 (Table 1) all switched to dupilumab, either from omalizumab (Patients 4-7) or from mepolizumab (Patients 8-10). This is in line with Otten et al who suggest dupilumab as the first choice when switching to other biologics and show that most patients who have failed omalizumab and/or mepolizumab seem to be well controlled on dupilumab. ¹⁹ Rosso et al also concluded that dupilumab improves outcomes in patients with CRSwNP, even if omalizumab or mepolizumab/benralizumab did not achieve sufficient treatment control. ¹⁷ Meta-analyses comparing biologic therapies as initial treatment in CRSwNP have shown that dupilumab seems to be the most beneficial therapy.^22,23 In our study, all patients who transitioned from omalizumab to dupilumab initially presented with insufficient symptom control. Three quarters of these patients were able to achieve adequate treatment control after switching to dupilumab and improved in both SNOT-22 and NPS. Patient 5 (Table 1), however, showed no improvement in NPS and a worsening in SNOT-22 after switching to dupilumab. Despite this, the patient reported subjective improvements in rhinorrhea and general quality of life during clinical consultation. This discrepancy highlights the challenges in evaluating treatment success when patient-reported outcomes during consultations do not align with standardized questionnaire data. Three patients switched from mepolizumab to dupilumab, all for different reasons. Patient 8 (Table 1) reported chest tightness and dyspnea after the second dose of mepolizumab, without accompanying allergic symptoms such as rash. Therefore, a treatment switch to dupilumab was suggested, which led to an improvement in SNOT-22 and NPS, but a true comparison between the 2 biologic agents cannot be made due to the short treatment interval with mepolizumab. Patient 9 achieved substantial symptom control after switching to dupilumab, further supporting recommendations favoring dupilumab as the preferred alternative following inadequate response to anti-IL-5 therapy. ¹⁸ Patient 10 (Table 1) developed tingling paresthesia and lower limb weakness ~4 hours after her mepolizumab injection, after 18 months of treatment. Despite discontinuing mepolizumab in consultation with her general practitioner, symptoms persisted. A neurologic assessment was recommended, and therapy was switched to dupilumab due to suspected biologic-associated polyneuropathy. Following the switch, NPS improved, although no change was observed in the SNOT-22 score. Dorling et al investigated adverse events using real-world data following the use of type 2 biologics in patients with CRSwNP. In comparative analysis with mepolizumab, IL-4/IL-13 pathway inhibition via dupilumab was associated with a higher frequency of adverse events, predominantly arthralgia, dermatologic manifestations, ophthalmic complications, and injection-site reactions. Polyneuropathy-related adverse events, however, were not reported. ¹² Otten et al recommend initiating the new biologic therapy immediately, without a washout period, when switching from anti-IL-5 agents to dupilumab. This strategy is intended to take advantage of the transient period of reduced eosinophil levels and minimize the risk of post-treatment eosinophilic rebound. ¹⁸ Elevated eosinophil counts are one of the main reasons why CRSwNP patients with comorbid asthma are often treated with mepolizumab. Pavord et al further recommends that patients with blood eosinophil levels between 150 and 1500 cells/µL may benefit from dupilumab therapy, while those with levels above 1500 cells/µL should be evaluated for possible eosinophilic granulomatosis with polyangiitis. ²³ No significant difference in comorbid asthma status was observed between the 2 groups, suggesting that the decision to switch biologic therapy was not directly associated with the presence of comorbid asthma. Overall, 8 out of 10 patients who switched biologics in the current study showed adequate treatment control. The distribution of different biologics after switching therapy was similar to the continuous therapy group where no switching was necessary. Dupilumab increased from 30% to 70% (Figure 1). This suggests that dupilumab may be the biologic of first choice when switching therapy is considered.

Table 1.

Switching Patients SNOT-22 (0-110), bilateral NPS (0-8).

Switching patient no.	First biologic	Biologic switch	Age	Gender	SNOT-22 before/after switch	NPS before/after switch	Reason to switch
1	Dupilumab	Mepolizumab	51	Female	46/28	5/2	Insufficient therapy control
2	Dupilumab	Omalizumab	29	Female	79/54	2/2	Pregnancy
3	Dupilumab	Omalizumab	41	Male	5/9	2/3	Insufficient therapy control
4	Omalizumab	Dupilumab	57	Male	70/34	5/2	Insufficient therapy control
5	Omalizumab	Dupilumab	66	Male	28/47	5/5	Insufficient therapy control
6	Omalizumab	Dupilumab	64	Female	50/28	8/2	Insufficient therapy control
7	Omalizumab	Dupilumab	52	Female	57/29	3/2	Insufficient therapy control
8	Mepolizumab	Dupilumab	73	Female	79/22	5/1	Questionable allergic reaction
9	Mepolizumab	Dupilumab	33	Male	53/36	8/4	Insufficient therapy control
10	Mepolizumab	Dupilumab	69	Female	30/45	3/2	Suspected biologic associated polyneuropathy

Abbreviations: NPS, nasal polyp score; SNOT-22, Sino-Nasal Outcome Test-22.

Colors were used to align the color-design of Table 1 regarding different biologic therapies.

One limitation of the current study is certainly the low number of patients included. Although only 10 patients could be analyzed, the results are relevant for clinical decision-making on a daily basis. Overall, the number of cases is relatively small. In the future, these findings should be validated in larger cohorts as well as possible in multicenter studies. In addition, a possible bias in these study results because the group sizes varied with regard to the different biologics and that most patients received dupilumab from the start. The present study contributes to the systematic documentation of clinical observations, thereby enhancing the current understanding of the clinical application of biologic therapies, which remain relatively novel. Such observational data are essential for the scientific community to develop evidence-based recommendations for future therapeutic decision-making.

It should also be noted that the reasons for switching treatment were highly individualized and must be evaluated on a case-by-case basis. In certain instances—such as pregnancy or the suspected case of polyneuropathy, which has not previously been documented as a typical adverse effect of the respective biologic—decisions to change therapy were based on unique patient-specific considerations. However, these very individual reasons for a change in therapy are exactly what occurs in everyday clinical practice and deserve more attention.

The present study highlights patterns of biologic switching in a limited cohort of patients in whom continuation of the initial biologic therapy was not feasible. The majority of observed outcomes following a switch to an alternative biologic are consistent with existing literature and suggest a favorable potential for improved disease control. However, further real-world studies are warranted to systematically compare treatment pathways in patients who are unable to maintain the initially-selected biologic. Such investigations are essential to inform evidence-based switching guidelines and optimize therapeutic strategies for the management of uncontrolled CRSwNP under biologic treatment.