Is Elexacaftor/Tezacaftor/Ivacaftor Effective in Treating Sinonasal Disease in Patients with Cystic Fibrosis?
This work was unfunded and there are no relevant conflicts of interest from any authors.
BACKGROUND
Cystic Fibrosis (CF) results from a deficiency or a defect in the CF transmembrane conductance regulator protein (CFTR). Loss of function of the CFTR anion channel causes increased viscosity of secreted mucus and results in significant impairment of the sinonasal mucosa natural mucociliary clearance mechanism. It follows that a high proportion of people with CF (PwCF) are diagnosed with chronic rhinosinusitis (CF-CRS) based on radiographic imaging and/or symptomatology.
Management of CF has changed significantly with the development of CFTR modulator therapy. Ivacaftor was the first commercially available CFTR modulator. Since then, multiple combination medications have been released including Lumacaftor/Ivacaftor and Tezacaftor/Ivacaftor. Most recently, in 2019 Elexacaftor/Tezacaftor/Ivacaftor (ETI) was released as a triple therapy. ETI has been shown to have positive effects on multiple organ systems. Though ETI has continued to show promise in studies pertaining to CF-CRS, guidelines have not strongly endorsed administration of CFTR modulator therapy for the primary indication of CF-CRS. Instead, the most recent Cystic Fibrosis Foundation guidelines only suggest considering CFTR modulator therapy for the isolated indication of CF-CRS.1 This review outlines recent prospective data on the effect of ETI on CF-CRS and necessitates reconsideration of Cystic Fibrosis Foundation guidelines about this treatment to one that recommends it.
LITERATURE REVIEW
Studies relevant to ETI use in PwCF were identified by utilizing the PubMed MEDLINE database. Only studies assessing sinonasal disease were included in this analysis. Studies excluding adults were not included. This search yielded four prospective cohort studies as the highest level of evidence assessing sinonasal outcomes in PwCF treated with ETI (Table I).
| Authors | Design | Inclusion Criteria | Number of patients | Exposure and follow up | Outcomes |
|---|---|---|---|---|---|
| DiMango et al.2 | Single arm, single center, prospective cohort study |
|
43 patients |
|
|
| Beswick et al.3 | Single arm, single center, prospective cohort study |
|
25 patients |
|
|
| Beswick et al.4 | Single arm, single center, prospective cohort study |
|
25 patients |
|
|
| Stapleton et al.5 | Single arm, multicenter, prospective cohort study |
|
28 patients |
|
|
DiMango et al. published a prospective cohort study of 43 PwCF starting ETI.2 Patients completed the 22-item sinonasal outcome test (SNOT-22) and the respiratory domain of the Cystic Fibrosis Questionnaire—Revised (CFQ-R) prior to initiation of ETI and 3 months after treatment. Mean SNOT-22 scores decreased from 34.8 to 24.4. This was found to be significant and surpassed the minimal clinically important difference (MCID) for SNOT-22. In addition, all domains saw significant improvement, however only the extranasal rhinologic domain surpassed MCID. Mean CFQ-R respiratory domain scores improved from 60.6 to 83.3. An interesting component of this study looked at patients who previously were on CFTR modulator therapy and transitioned to ETI. This subset analysis showed a greater improvement in SNOT-22 and CFQ-R respiratory domain scores in patients who previously received CFTR modulator therapy compared to those who were naïve to CFTR modulators.
Following this, Beswick et al. performed a prospective cohort analysis that evaluated 25 adults with CF who also were diagnosed with CF-CRS.3 All patients were started on ETI and assessed with computed tomography (CT), spirometry, and patient reported outcome measures (PROMs) including SNOT-22. Pre-treatment and post-treatment CT scans were evaluated with both Lund-Mackay (LM) scoring and a deep learning algorithm that calculated the percent of sinus opacification seen. Both sinus opacification and LM scores were significantly improved. The subgroup of patients who were CFTR modulator naive trended toward more significant improvement compared to patients who had been on CFTR modulators in the past, though this did not reach significance. This relatively lesser improvement in patients who were previously on CFTR modulator therapy deviates from what DiMango et al. found.2 Beswick et al. also assessed SNOT-22 scores and found significant improvement. This improvement was consistent between CFTR modulator naive patients and patients with a history of other CFTR modulator therapy. Health utility scores and productivity scores improved with ETI as well. Overall, significant benefit was found in patients with CF-CRS treated with ETI.
An additional analysis of olfaction within this cohort was published later in 2021.4 This study assessed Questionnaire of Olfactory Disorders-Negative Statements (QOD) surveys, Smell Identification Test (SIT) scores, and percent opacification of the olfactory cleft on CT before and after ETI treatment. Patients showed a mean improvement in QOD by 2.5 points. This was unaffected by prior modulator use. In contrast, patients demonstrated worsening SIT scores with a mean worsening by 2.1 points. This did not meet the pre-defined clinically significant change of 4 points. Mean percent opacification of the olfactory cleft did not show any significant change. Overall, the authors concluded that ETI does not appear to improve olfaction.
Stapleton et al. published a two-site prospective cohort study assessing the impact of ETI in 34 PwCF.5 CT, nasal endoscopy, and SNOT-22 scores were obtained prior to initiation of ETI and at set points after initiation of therapy. Deviating from the prior 3 studies, this study included patients 12 and older. SNOT-22 scores improved within 7 days of initiation of treatment and results were durable out to 180 days. Lund-Kennedy and LM scores improved significantly as well. The authors state that in PwCF and CF-CRS, ETI is likely to improve sinonasal function regardless of baseline lung function. The impact of ETI on CF-CRS was significant and durable.
These 4 prospective single-arm cohort studies comprise the highest quality evidence currently available on the effect of ETI on sinonasal disease in PwCF. While one of the studies used a cohort that had previously been assessed, the study expanded on the original study in a useful way. Overall, ETI offers significant sinonasal benefits to patients naive to CFTR modulator therapy with CF-CRS and/or PwCF. However, the data in patients with a history of prior CFTR modulator use is more heterogeneous. The significance of this is unclear at this time and further study is needed to analyze this cohort.
BEST PRACTICE SUMMARY
Best current evidence regarding ETI in patients with PwCF and CF-CRS consists of prospective single-arm cohort studies. ETI is highly effective in improving CT findings, nasal endoscopy findings, and quality of life as measured by various PROMs in both patient groups. However, ETI does not appear to improve olfaction in CF-CRS. Future larger multicenter prospective trials confirming these conclusions are warranted. Given the recent studies outlined above, it is recommended that CFTR modulator therapy not only be considered but used in CF-CRS and Pw-CF who qualify based on age and genotype.
LEVEL OF EVIDENCE
The highest quality studies on ETI are prospective cohort studies. Recommendations are therefore based on level 2 evidence.
