Clinical benefit without sweat chloride response after ETI therapy in an adult with cystic fibrosis bearing the L467F;F508del complex CFTR allele: a case report and the role of AI-assisted chest CT in longitudinal monitoring

Abstract

Background:

Elexacaftor/tezacaftor/ivacaftor (ETI) is the standard of care for most people with cystic fibrosis (CF) who carry at least one F508del allele. However, predicting responses to CFTR modulators in rare or complex CFTR genotypes is challenging. Sweat chloride concentration (SCC) and patient-derived functional assays assessing CFTR-mediated chloride transport are commonly used to classify modulator responsiveness. Carriers of the p.Leu467Phe;p.Phe508del (henceforward legacy nomenclature: L467F;F508del) complex CFTR allele have been considered unlikely to respond to ETI, based on short-term clinical, biomarker and ex vivo evidence. We report a discordant long-term response in an adult carrying this complex allele, with clinically meaningful benefit despite persistently negative CFTR chloride transport biomarkers.

Case presentation:

We describe an 8-year longitudinal pre- and post-treatment assessment of an adult woman with CF, adherent to therapy, with the L467F;F508del complex allele compounded with the non-responsive c.489 + 1G > T (621 + 1G > T) variant in trans. She has pancreatic insufficiency, progressive lung disease, and recurrent pulmonary exacerbations. After ETI commencement (at 40.5 years; July 2021) SCC remained unchanged at ∼100 mmol/L. Intestinal organoid and primary nasal epithelial cell assays showed no measurable ETI-related CFTR-mediated chloride transport rescue. Nevertheless, BMI increased from 22.0 to 26.8 kg/m², annual exacerbations decreased from 5 to 3, and ppFEV₁ improved from 51% to 55–59%. Serial chest CT showed a shift from pre-ETI progression to post-ETI stabilisation, with reductions in air trapping and the extent of bronchiectasis on manual Brody II scoring and LungQ/PRAGMA-AI quantification. Exploratory in vitro exposure of nasal epithelial cells to vanzacaftor/tezacaftor/ivacaftor yielded ∼5% CFTR-mediated rescue, contrasting with the negative ETI response.

Conclusion:

Persistent CFTR biomarker negativity may not fully exclude clinically meaningful ETI-associated benefit in rare or complex CFTR genotypes. The pulmonary and extrapulmonary improvements observed in this case support multidimensional response assessment beyond single-biomarker endpoints. These hypothesis-generating observations support individualised long-term monitoring and comprehensive interpretation of CFTR biomarkers in the clinical context. AI-assisted chest CT may provide complementary real-world evidence. An exploratory in vitro rescue study with vanzacaftor/tezacaftor supports the evaluation of emerging CFTR modulators. It suggests that similar studies should be conducted in other cases involving complex CFTR alleles.

1 Introduction

People with cystic fibrosis (pwCF) who carry at least one p.Phe508del (legacy nomenclature: F508del) variant in CF transmembrane conductance regulator (CFTR) benefit from elexacaftor/tezacaftor/ivacaftor (ETI) CFTR modulator therapy (CFTRm). In Czechia, more than 81% of ETI-eligible pwCF, mostly with at least one F508del, receive ETI, which rapidly lowers sweat chloride concentration (SCC) and improves lung function, nutritional status, and quality of life (QoL) (1, 2). However, several of our ETI-eligible pwCF show non-responsive post-treatment CFTR chloride transport rescue biomarker outcomes and atypical clinical trajectories, suggesting that clinically relevant effects are not fully captured by chloride transport-based in vitro analyses alone.

In the absence of CFTR sequencing, current diagnostic approaches that target a specific panel of “candidate variants” miss complex alleles (cCFTRa), defined by multiple variants in cis (i.e., within the same gene); cCFTRa may modify the ETI biomarker response (3) in seemingly eligible variants, such as F508del, when the corresponding CFTR allele in trans is non-responsive. CFTR sequencing and parental variant phasing address this limitation, but these approaches are not yet part of routine diagnostic practice (3).

Theratyping and/or clinical observational studies (4) have broadened the range of rare CFTR variants predicted to respond to ETI (5), and the expected full clinical benefit is usually observed within weeks post administration (6). However, the magnitude of response may depend on age at treatment initiation, pre-existing structural lung damage, and the CFTR genotype, including the presence of cCFTRa. CFTRm-related clinical effects may also extend beyond measurable rescue of CFTR-mediated chloride transport, including reduced airway infections and inflammation (7). In addition, improvements in QoL and nutritional status may not be directly captured by biomarkers that assess rescue of CFTR-mediated chloride transport (8).

2 Case presentation

The adult woman with CF (awCF) was clinically diagnosed in 1982, at 2 years of age, and consistently demonstrated excellent adherence to CF care throughout follow-up. She had the classical CF phenotype, including pancreatic insufficiency from adolescence (faecal elastase I, 15 µg/g), progressive CF lung disease with bronchiectasis, mucus plugging, bronchial wall thickening and air trapping, frequent acute pulmonary exacerbations (aPEX), and early chronic Pseudomonas aeruginosa airway infection.

Microbiological surveillance was performed approximately six times per year using adequate-quality, spontaneously expectorated sputum samples. Chronic airway infection with Staphylococcus aureus had been documented since age 7 years, followed by chronic P. aeruginosa airway infection from age 9 years. Stenotrophomonas maltophilia and Haemophilus haemolyticus were also detected during follow-up. There was no evidence of allergic bronchopulmonary aspergillosis, nontuberculous mycobacterial pulmonary disease, or any clinically significant fungal pulmonary infection. Because adequate sputum samples were consistently available, bronchoscopy with bronchoalveolar lavage sampling was not performed. The patient received long-term inhaled antipseudomonal antibiotic therapy, predominantly colistin. Serial sputum cultures confirmed persistent chronic airway infection with S. aureus and P. aeruginosa, with no marked change in the overall microbiological pattern after ETI initiation.

Her concomitant chronic CF therapy also comprised once-daily inhaled dornase alfa, nebulised hypertonic saline once or twice daily, pancreatic enzyme replacement therapy, and regular respiratory physiotherapy incorporating airway clearance techniques. A Simeox device was incorporated into her airway clearance regimen in 2018.

She has a university education, is married, and remained in full-time employment as a physician. She was a lifelong non-smoker, reported no substance misuse, and had no relevant non-CF comorbidities. She had no history of CF-related diabetes, CF-associated liver disease, or nasal polyposis. There was no known family history of CF or any another relevant inherited disorder. Her reproductive history comprised one uncomplicated pregnancy, resulting in the caesarean delivery of a healthy daughter at the age 27. She had strong family support. An integrated timeline of the principal clinical, diagnostic, and therapeutic milestones is provided in Figure 1.

Figure 1

SCC was examined using the Macroduct Advanced Sweat Collection system (Elitech, USA). The CFTR gene was sequenced using an amplicon massively parallel sequencing assay (Devyser.com; Sweden) on the MiSeq platform (Illumina.com; USA), and the cCFTRa linkage phase was confirmed. ETI effects were assessed annually using aPEX frequency and duration, spirometry, body mass index (BMI), and chest computed tomography (CT). Structural lung disease was evaluated using manual Brody II scoring (9) and blinded automated AI-assisted LungQ analysis (Thirona; the Netherlands). Automated metrics included bronchus-artery ratios reflecting airway dilatation and wall thickening (10), a PRAGMA-AI percentage of structurally abnormal lung tissue, and LungQ mucus-plug quantification, including number and volume (11). Manual and automated CT assessments were compared descriptively across the pre- and post-ETI periods, using ETI initiation as baseline. Rescue of CFTR-mediated chloride transport was assessed in two independent in vitro patient-derived models: intestinal organoids (IOs) and nasal primary epithelial cultures (5, 12).

ETI was initiated at the standard-recommended adult dose in July 2021 at age 40.5 years. The regimen comprised two fixed-dose combination tablets, each containing elexacaftor 100 mg, tezacaftor 50 mg, and ivacaftor 75 mg, taken in the morning, followed by one ivacaftor 150-mg tablet in the evening, approximately 12 h apart. Both doses were taken with fat-containing food and pancreatic enzyme replacement therapy. ETI was continued at the full dose without reduction or interruption throughout follow-up and was well tolerated, with no reported ETI-related adverse events, including sleep disturbances or psychological symptoms. The established chronic symptomatic CF treatment regimen was maintained after ETI initiation, with no new chronic therapy introduced and none discontinued or intensified.

Adherence to ETI and background therapy was assessed at each outpatient visit through targeted patient interviews, medication reconciliation including patient-reported quantities of medication remaining at home, and review of pharmacy dispensing records confirming regular ETI collection. All concomitant medications were reviewed, and no clinically relevant drug–drug interactions were identified; specifically, she was not taking any CYP3A-inducing agents expected to reduce ETI exposure.

However, her mean SCC remained close to baseline throughout follow-up (104 mmol/L at baseline vs. 101 mmol/L after 6 months and 94 mmol/L after 5 years of ETI; see Table 1). Subsequent CFTR gene sequencing detected the L467F;F508del cCFTRa in cis and an “ETI-nonresponsive” variant in trans (c.489 + 1G > T, legacy nomenclature: 621 + 1G > T). Repeated IOs and nasal epithelial cultures exposed to ETI demonstrated no restoration of CFTR-mediated chloride transport, with an absent forskolin response and a subsequent response to the CFTR-specific inhibitor Inh-172 (Figure 2). Nonetheless, recent in vitro vanzacaftor/tezacaftor/ivacaftor testing in her nasal epithelial cultures showed ∼5% CFTR-mediated rescue (Figure 3).

Figure 2

Figure 3

Despite the absence of measurable CFTR-dependent chloride transport after ETI administration, clinically apparent improvement was observed over a 4-year post-ETI period (Table 1). BMI increased from 22.0 to 26.8 kg/m², indicating improved nutritional status. The annual number of aPEX treated with oral antibiotics decreased from 5 to 3 with shorter treatment durations, while the need for intravenous antibiotics remained stable at no more than once yearly. Subjectively, nasal obstruction improved, while ppFEV₁ increased from 51% at baseline to 59% at 24 and 36 months, and remained above baseline at 48 months (55%). Absolute FEV₁ increased from 1.34 L (L) at baseline to 1.55 L at 24 months and was 1.40 L at 48 months. Although forced vital capacity (FVC) oscillated, particularly during the COVID-19 pandemic, functional decline did not progress, in contrast to the gradual progression observed on the pre-ETI CT. Her structural lung disease stabilised after commencing ETI (Table 1).

Both visual and AI-assisted CT analyses demonstrated a change in trajectory from pre-treatment progression to post-treatment stabilisation (Figure 4). Manual Brody II scoring confirmed pre-ETI progression followed by stabilisation after ETI initiation. Airway wall thickening decreased slightly from 35.2% to 33.3%, whereas air trapping decreased more markedly from 64.8% to 51.9%, suggesting reduced small-airway disease. Bronchiectasis and mucus plugging showed no visible progression. Serial visual review also indicated reduced expiratory tracheal flattening and greater parenchymal homogeneity, although these features were not quantified.

Figure 4

From 2022 onward, PRAGMA-AI showed a decrease in total CF lung disease from 11.4% to 7.19% during ETI therapy. LungQ-BA metrics indicated stabilisation of bronchial widening and wall thickening, with improvement in selected parameters, including a decrease in PRAGMA-AI bronchiectasis from 8.38% to 2.19% and in Bout/A from 1.54 to 1.10. Due to the single-case design, statistical analysis was not performed.

3 Discussion

We report discordance between current biomarker readouts assessing rescue of CFTR-mediated chloride transport and the objectively stabilised CF lung disease and overall improved clinical trajectory in a longitudinally monitored adult woman with CF receiving ETI and carrying the “revertant” complex CFTR allele (3) and an “ETI-non-responsive” CFTR variant in trans.

Thus, in patients in whom SCC remain at baseline after ETI administration and who were not sequenced, the presence of cCFTRa should be examined. The L467F;F508del cCFTRa attenuates response to ETI and has previously been associated with the classification of carriers as “non-responders” based on short-term biomarker and clinical grounds (3). Our case does not contradict the exclude previously documented impairment of CFTR-mediated chloride transport but suggests that persistent biomarker negativity does not preclude delayed, potentially tissue-dependent clinical benefit from ETI; responsiveness to CFTRm should therefore be interpreted multimodally over the long term (13). Recent real-world data from adults with CF, including pwCF ineligible for pivotal clinical trials, have also highlighted the broader intra- and extrapulmonary impact of ETI, supporting the need for multidimensional response assessment beyond single-biomarker endpoints (14, 15).

Our findings do not challenge the overall predictive value of SCC or theratyping but suggest that exceptions may occur. Although theratyping and SCC most often align with clinical outcomes, these analyses may not capture all clinically relevant effects in the airways (5) or reliably predict individual clinical outcomes (12). Indeed, CFTR is much more than a "simple" chloride channel (16). In this regard, Pranke et al. underscore knowledge gaps when ex vivo biomarkers and clinical outcomes diverge (16). N1303K-related data show respiratory improvement despite minimal SCC reduction, supporting tissue-dependent rescue following ETI therapy, although caution is warranted in drawing analogies with L467F;F508del.

The patient started ETI therapy in adulthood, after years of progressive CF lung disease, when irreversible airway remodelling likely occurred. In adults with advanced CF, established structural lung disease is unlikely to reverse substantially; therefore, lung disease stabilisation and a decrease in aPEX represent clinically relevant outcome measures (11, 17).

In this awCF, CT improvement was modest, but the pre-treatment progression trajectory markedly improved after ETI initiation. Automated CT analysis added sensitivity beyond Brody scoring, with PRAGMA-AI and LungQ-BA indicating a more favourable trajectory, supporting AI-assisted imaging as a complementary tool when CFTR transport-based biomarker readouts are inconclusive or discordant.

An alternative interpretation is that stabilisation occurred for reasons unrelated to ETI. However, her full adherence, the absence of changes in long-term multidisciplinary care, including nutritional management and chronic symptomatic CF therapy, and the lack of any marked shift in sputum microbiology during follow-up, together with the combined BMI gain, reduced aPEX burden, sustained ppFEV₁ above baseline, and stabilised structural lung disease, argue against this notion.

3.1 Strengths and limitations

The principal strength of this report is the depth of longitudinal clinical, imaging and laboratory phenotyping in a rare and clinically challenging CFTR genotype. The case integrates pre- and post-ETI clinical follow-up, repeated SCC measurements, two independent patient-derived functional models, manual Brody II CT scoring, and blinded automated LungQ/PRAGMA-AI quantification. This multidimensional design is particularly informative for complex CFTR alleles, where a single readout may underrepresent the clinical phenotype. In our patient, a change from pre-ETI structural progression to post-ETI stabilisation was documented, despite persistently unchanged SCC and the absence of ETI-related CFTR-mediated chloride transport rescue ex vivo.

The relevant literature provides both contrasting and supportive contexts. Previous studies of L467F;F508del showed that this complex allele hampers ETI-mediated pharmacological rescue and supported classifying affected carriers as “non-responders” on short-term biomarker and clinical grounds (3, 13). Our SCC, intestinal organoid and nasal epithelial data are fully consistent with impaired chloride-transport rescue. However, recent reports indicate that CFTR variant responsiveness may differ across CFTR modulator combinations, including differential responses to vanzacaftor- versus elexacaftor-based treatment (18). Most directly, Capurro et al. described ex vivo prediction and exploratory clinical assessment of vanzacaftor-tezacaftor as an alternative therapeutic option for the ETI-resistant L467F;F508del allele (19). Therefore, lack of response to one modulator combination should not necessarily be extrapolated to all current or emerging CFTRm regimens. Our case contrasts with these reports by focusing on long-term, real-world ETI exposure with persistently negative chloride-transport biomarkers, and by adding serial AI-assisted chest CT as an objective structural outcome of disease stabilisation.

The limitations are inherent to an observational single-case report. Causality cannot be proven, and residual confounding by infection dynamics, microbiology, antibiotic exposure, physiotherapy, nutrition, adherence, regression to the mean, COVID-19-related perturbations, or other aspects of multidisciplinary care cannot be completely excluded. However, the awCF is fully adherent to therapy, and the impact of ETI is demonstrated beyond age 40, despite sparse clinical studies. Although patient-reported symptom changes were documented narratively during routine follow-up, no standardised longitudinal QoL instrument or other patient-reported outcome measure, such as the Cystic Fibrosis Questionnaire–Revised, was administered, precluding formal assessment of patient-perceived treatment benefit. The CT findings were interpreted descriptively, and no statistical inference was possible. Quantitative AI-assisted imaging may also be affected by acquisition parameters, differences in inspiratory and expiratory volumes, segmentation performance, and the still-evolving validation of automated CF CT metrics. Similarly, intestinal organoids and nasal epithelial cultures may not fully capture all airway compartments, inflammation, mucus properties, host modifiers, or extrapulmonary effects of CFTRm therapy. Finally, the adult age at treatment initiation and the presence of established bronchiectasis limit generalisability to children, to less advanced CF lung disease, or to other complex CFTR alleles.

The main takeaway is that persistent SCC negativity and the absence of short-term ex vivo chloride-transport rescue should prompt careful reassessment of the CFTR genotype by sequencing the entire gene, including phasing for complex alleles. Still, it should not automatically preclude continued ETI therapy when the broader longitudinal phenotype suggests a clear benefit. In rare or complex CFTR genotypes, response should be assessed as a patient-specific trajectory across symptoms, aPEX frequency, nutrition, spirometry, microbiology, CT morphology, and patient-derived functional data. AI-assisted CT cannot replace established biomarkers or clinical judgment. Still, in biomarker-discordant cases, it may strengthen real-world evidence by providing reproducible, regionally resolved quantification of structural lung disease over time. We consider this case unique because it combines an ETI-biomarker-negative L467F;F508del complex allele with objective long-term clinical stabilisation documented by AI-assisted serial chest CT, thereby supporting a time-extended, multimodal framework for assessing modulator benefit and prioritising emerging alternatives such as the vanzacaftor/tezacaftor/deutivacaftor combination.

4 Patient perspective

After starting ETI, I noticed my breathing felt freer and clearer and my nasal obstruction improved. My respiratory condition became more stable in daily life, and I needed antibiotics less often when my cough worsened. However, contracting COVID-19 took quite a toll on me. Initially, I did not understand why my sweat chloride levels had not decreased, especially since I felt a bit better. Detailed genetic testing finally provided an explanation, which made me joke, “ I suppose I always have to be exceptional in some way”. I am grateful that I remain active and can continue working full-time. I have not experienced any noticeable treatment-related adverse effects. I sleep well, my appetite has greatly improved (sometimes almost too much), and I have no mood swings, unless I count those associated with raising a teenage daughter. Although my sweat chloride concentrations remain high, I consider the overall stabilisation of my condition a real benefit. I am very happy that ETI is reimbursed in our country, and I remain hopeful that in the future, even more effective drugs will become available even for me, given my specific genotype. Above all, I am deeply grateful to my CF team and my family for their long-term support, and I am absolutely overjoyed to have a beautiful, healthy daughter!

5 Conclusions

Although limited by its single-case design, our report provides comprehensive long-term clinical, functional, AI-assisted lung imaging, and in vitro biomarker data for an adult with CF carrying the L467F;F508del complex CFTR allele. The case suggests that persistently elevated baseline SCC values should not automatically preclude continued ETI when other clinical indicators indicate benefit. Therapeutic decisions should therefore integrate the broader clinical context with individualised long-term monitoring of nutritional status and CF lung disease trajectory, while also considering emerging CFTRm options (18, 20). Guided by the theratyping concepts (5), exploratory in vitro testing of vanzacaftor/tezacaftor combinations in our case demonstrated a potentially clinically relevant 5% rescue of CFTR-mediated chloride transport. The observed in vitro response supports further evaluation of vanzacaftor/tezacaftor/deutivacaftor therapy in additional individuals carrying the L467F;F508del cCFTRa, as recently reported (19). Longitudinal AI-assisted lung imaging may provide complementary real-world evidence for assessing treatment response in such rare or complex CFTR genotypes, particularly when conventional CFTR biomarker readouts are inconclusive or discordant.

References

• 1.

  HisertKBBirketSEClancyJPDowneyDGEngelhardtJFFajacIet al. Understanding and addressing the needs of people with cystic fibrosis in the era of CFTR modulator therapy. Lancet Respir Med. (2023) 11:916–931. 10.1016/S2213-2600(23)00324-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 2.

  Czechia register of cystic fibrosis, (accessed 23 May, 2026) (2026). Available online at:https://cfregistr.cz/

  • Google Scholar
  • View reference in article

• 3.

  SondoECrestaFPastorinoCTomatiVCapurroVPesceEet al. The L467F-F508del complex allele hampers pharmacological rescue of mutant CFTR by elexacaftor/tezacaftor/ivacaftor in cystic fibrosis patients: the value of the ex vivo nasal epithelial model to address non-responders to CFTR-modulating drugs. Int J Mol Sci. (2022) 23:3175. 10.3390/ijms23063175

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 4.

  BurgelP-RSermet-GaudelusIDurieuIKanaanRMaceyJGrenetDet al. The French compassionate programme of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis with advanced lung disease and no F508del CFTR variant. Eur Respir J. (2023) 61(5):2202437. 10.1183/13993003.02437-2022

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 5.

  DreanoEBurgelPRHattonABouazzaNChevalierBMaceyJet al. Theratyping cystic fibrosis patients to guide elexacaftor/tezacaftor/ivacaftor out-of-label prescription. Eur Respir J. (2023) 62:2300110. 10.1183/13993003.00110-2023

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 6.

  BurgelP-RDurieuIChironRRamelSDanner-BoucherIPrevotatAet al. Rapid improvement after starting elexacaftor-tezacaftor-ivacaftor in patients with cystic fibrosis and advanced pulmonary disease. Am J Respir Crit Care Med. (2021) 204:64–73. 10.1164/rccm.202011-4153OC

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 7.

  ÅrmanFDiemerSHapponenLJPåhlmanLI. Cftr modulator therapy reshapes airway inflammation in cystic fibrosis: insights from proteomics and machine learning. J Cyst Fibros. (2026) S1569-1993(26):00108-6. 10.1016/j.jcf.2026.05.002

  • CrossRef
  • Google Scholar
  • View reference in article

• 8.

  De BoeckKBurgelP-RBierlaaghMHillKAmaralMBirimberg-SchwartzLet al. Ecfs statement on theratyping and theranostics in the context of rare and ultrarare CFTR variants in people with CF. J Cyst Fibros. (2026) 25(26):584–593. 10.1016/j.jcf.2026.04.013

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 9.

  BrodyASKleinJSMolinaPLQuanJBeanJAWilmottRW.High–resolution computed tomography in young patients with cystic fibrosis: distribution of abnormalities and correlation with pulmonary function tests. J Pediatr. (2004) 145(1):32–8. 10.1016/j.jpeds.2004.02.038

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 10.

  LvQGallardo-EstrellaLAndrinopoulouE-RChenYCharbonnierJ-PSandvikRMet al. Automatic analysis of bronchus-artery dimensions to diagnose and monitor airways disease in cystic fibrosis. Thorax. (2024) 79:13–22. 10.1136/thorax-2023-220021

  • CrossRef
  • Google Scholar
  • View reference in article

• 11.

  RautPChenYTalebABonteMAndrinopoulouERCietPet al. Validation of an artificial intelligence-based automated PRAGMA and mucus plugging algorithm in pediatric cystic fibrosis. J Cyst Fibros. (2025) 24:970–978. 10.1016/j.jcf.2025.08.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 12.

  FurstovaEDrevinekPNovotnaSLibikMBenesovaKBorek-DohalskaLet al. Precision medicine in cystic fibrosis: predictive role of forskolin-induced swelling assay. Eur Respir J. (2024) 63:2400156. 10.1183/13993003.00156-2024

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 13.

  KondratyevaEEfremovaAMelyanovskayaYVoronkovaAPolyakovABulatenkoNet al. Evaluation of the complex p.[Leu467Phe;Phe508del] CFTR allele in the intestinal organoids model: implications for therapy. Int J Mol Sci. (2022) 23:10377. 10.3390/ijms231810377

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 14.

  VinckenSVerbanckSBraunSBuyckNZieneberghCKnoopCet al. The proof of the pudding is in the eating: real-life intra- and extrapulmonary impact of elexacaftor/tezacaftor/ivacaftor. Respiration. (2025) 104(6):388–396. 10.1159/000543009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 15.

  FilaLGrandcourtovaABilkovaADrevinekP. Elexacaftor-tezacaftor-ivacaftor in patients with cystic fibrosis ineligible for clinical trials: a 24-week observational study. Front Pharmacol. (2023) 14:1178009. 10.3389/fphar.2023.1178009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 16.

  PrankeISermet-GaudelusI. Theratyping in cystic fibrosis: filling the knowledge gaps. Eur Respir J. (2025) 65:2500778. 10.1183/13993003.00778-2025

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 17.

  DettmerSWeinheimerOSauer-HeilbornALammersOWielpützMOFugeJet al. Qualitative and quantitative evaluation of computed tomography changes in adults with cystic fibrosis treated with elexacaftor-tezacaftor-ivacaftor: a retrospective observational study. Front Pharmacol. (2023) 14:1245885. 10.3389/fphar.2023.1245885

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 18.

  Rodriguez MierNCallebautIProesmansMVan BraeckelEVan BiervlietSBoonMet al. Rethinking CFTR variant responsiveness: differential responses to vanzacaftor and elexacaftor. J Cyst Fibros. (2026) 25(2):314–318. 10.1016/j.jcf.2025.12.018

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 19.

  CapurroVPesceECrestaFPastorinoCManteroATomatiVet al. Vanzacaftor-Tezacaftor as an alternative therapeutic resource for the ETI-resistant L467F-F508del Allele: ex vivo prediction and exploratory clinical assessment. J Cyst Fibros. (2026) S1569-1993(26)01638-3. 10.1016/j.jcf.2026.05.015

  • CrossRef
  • Google Scholar
  • View reference in article

• 20.

  CastellaniC. When triple therapy is not working: a reverse iceberg perspective. J Cyst Fibros. (2023) 22:367–369. 10.1016/j.jcf.2023.02.012

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article