Target trial emulation to evaluate the effect of immune-related adverse events on outcomes in metastatic urothelial cancer
Abstract Background Immune checkpoint inhibitors (ICIs) are an important therapeutic pillar in metastatic urothelial carcinoma (mUC). The occurrence of immune-related adverse events (irAEs) appears to be associated with improved outcomes in observational studies. However, these associations are like...
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2024-12-01
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| Online Access: | https://doi.org/10.1007/s00262-024-03871-7 |
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| author | Renate Pichler Josef Fritz Sarah Maier Melanie R. Hassler Johanna Krauter David D`Andrea Ekaterina Laukhtina Kilian Gust Keiichiro Mori Karl H. Tully Dora Niedersuess-Beke Lea Korber Jasmin Alija Spiegelberg Thomas Bauernhofer José D. Subiela Roman Mayr Andreas Kronbichler Marco Moschini Jeremy Teoh Benjamin Pradere Shahrokh F. Shariat Hanno Ulmer Laura S. Mertens European Association of Urology–Young Academic Urologists (EAU-YAU): Urothelial Carcinoma Working Group |
| author_facet | Renate Pichler Josef Fritz Sarah Maier Melanie R. Hassler Johanna Krauter David D`Andrea Ekaterina Laukhtina Kilian Gust Keiichiro Mori Karl H. Tully Dora Niedersuess-Beke Lea Korber Jasmin Alija Spiegelberg Thomas Bauernhofer José D. Subiela Roman Mayr Andreas Kronbichler Marco Moschini Jeremy Teoh Benjamin Pradere Shahrokh F. Shariat Hanno Ulmer Laura S. Mertens European Association of Urology–Young Academic Urologists (EAU-YAU): Urothelial Carcinoma Working Group |
| author_sort | Renate Pichler |
| collection | DOAJ |
| description | Abstract Background Immune checkpoint inhibitors (ICIs) are an important therapeutic pillar in metastatic urothelial carcinoma (mUC). The occurrence of immune-related adverse events (irAEs) appears to be associated with improved outcomes in observational studies. However, these associations are likely affected by immortal time bias and do not represent causal effects. The aim of this study was to assess the effect of irAEs on outcomes while correcting for immortal time bias, using target trial emulation (TTE). Methods TTE was contrasted to adjusted naïve and time-updated Cox models. We performed a multi-institutional retrospective study involving mUC patients under ICI. The primary objective was to assess the impact of irAEs on progression-free survival (PFS) and overall survival (OS). Secondary endpoints included the influence of irAEs on objective response rates (ORRs) to ICI and the influence of systemic corticosteroids on outcomes. Results Among 335 patients (median age: 69 yrs), 69.6% received ICI in the second line or further lines. During a median follow-up of 21.1 months, 122 (36.4%) patients developed irAEs of any grade (grade ≥ 3: 14.9%). Hazard ratios (HRs) for PFS ranged from 0.37 for naïve adjusted Cox model to 0.88 (95% confidence interval (CI), 0.59–1.30) with time-updated covariates, and from 0.41 to 1.10 (95% CI, 0.69–1.75) for OS. TTE accounting for immortal time bias yielded a HR of 1.02 (95% CI, 0.72–1.44) for PFS, and 0.90 (95% CI, 0.62–1.30) for OS. In contrast to the naïve Cox model (HR = 2.26, 95% CI 1.26–4.05), the presence of irAEs was no longer a predictive factor for improved ORR in time-updated Cox models (HR = 1.27, 95% CI 0.68–2.36) and TTE (HR = 1.43, 95% CI 0.89–2.29). In patients with irAEs, systemic corticosteroids did not negatively impact survival. Conclusion Using TTE, we were able to show that the occurrence of irAEs is no longer associated with better survival or improved response rates to ICI in mUC patients, in contrast to the naïve analysis. These findings demonstrate that TTE is a suitable formal framework to avoid immortal time bias in studies with time-dependent non-interventional exposures. Graphical abstract |
| format | Article |
| id | doaj-art-dabe3b175be24efc9e75632af91127fd |
| institution | Kabale University |
| issn | 1432-0851 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Springer |
| record_format | Article |
| series | Cancer Immunology, Immunotherapy |
| spelling | doaj-art-dabe3b175be24efc9e75632af91127fd2025-02-02T12:26:45ZengSpringerCancer Immunology, Immunotherapy1432-08512024-12-0174111010.1007/s00262-024-03871-7Target trial emulation to evaluate the effect of immune-related adverse events on outcomes in metastatic urothelial cancerRenate Pichler0Josef Fritz1Sarah Maier2Melanie R. Hassler3Johanna Krauter4David D`Andrea5Ekaterina Laukhtina6Kilian Gust7Keiichiro Mori8Karl H. Tully9Dora Niedersuess-Beke10Lea Korber11Jasmin Alija Spiegelberg12Thomas Bauernhofer13José D. Subiela14Roman Mayr15Andreas Kronbichler16Marco Moschini17Jeremy Teoh18Benjamin Pradere19Shahrokh F. Shariat20Hanno Ulmer21Laura S. Mertens22European Association of Urology–Young Academic Urologists (EAU-YAU): Urothelial Carcinoma Working GroupDepartment of Urology, Comprehensive Cancer Center, Medical University of InnsbruckDepartment of Medical Statistics, Informatics and Health Economics, Medical University of InnsbruckDepartment of Medical Statistics, Informatics and Health Economics, Medical University of InnsbruckDepartment of Urology, Comprehensive Cancer Center, Medical University of ViennaDepartment of Urology, Comprehensive Cancer Center, Medical University of ViennaDepartment of Urology, Comprehensive Cancer Center, Medical University of ViennaDepartment of Urology, Comprehensive Cancer Center, Medical University of ViennaDepartment of Urology, Comprehensive Cancer Center, Medical University of ViennaDepartment of Urology, The Jikei University School of MedicineDepartment of Urology and Neurourology, Marien Hospital Herne, Ruhr-University BochumKlinik Ottakring, I. Medizinische Abteilung, Zentrum Für Onkologie, Hämatologie Und PalliativmedizinKlinik Ottakring, I. Medizinische Abteilung, Zentrum Für Onkologie, Hämatologie Und PalliativmedizinDivision of Oncology, Department of Internal Medicine, Medical University of GrazDivision of Oncology, Department of Internal Medicine, Medical University of GrazDepartment of Urology, Hospital Universitario Ramón y Cajal, IRYCIS, Universidad de AlcalaDepartment of Urology, St. Josef Medical Center, University of RegensburgDepartment of Internal Medicine IV, Nephrology and Hypertension, Medical University of InnsbruckDepartment of Urology, IRCCS Ospedale San Raffaele and Vita-Salute San Raffaele UniversityDepartment of Surgery, S.H. Ho Urology Centre, The Chinese University of Hong KongDepartment of Urology, La Croix du Sud HospitalDepartment of Urology, Medical University of ViennaDepartment of Medical Statistics, Informatics and Health Economics, Medical University of InnsbruckDepartment of Surgical Oncology (Urology), Netherlands Cancer InstituteAbstract Background Immune checkpoint inhibitors (ICIs) are an important therapeutic pillar in metastatic urothelial carcinoma (mUC). The occurrence of immune-related adverse events (irAEs) appears to be associated with improved outcomes in observational studies. However, these associations are likely affected by immortal time bias and do not represent causal effects. The aim of this study was to assess the effect of irAEs on outcomes while correcting for immortal time bias, using target trial emulation (TTE). Methods TTE was contrasted to adjusted naïve and time-updated Cox models. We performed a multi-institutional retrospective study involving mUC patients under ICI. The primary objective was to assess the impact of irAEs on progression-free survival (PFS) and overall survival (OS). Secondary endpoints included the influence of irAEs on objective response rates (ORRs) to ICI and the influence of systemic corticosteroids on outcomes. Results Among 335 patients (median age: 69 yrs), 69.6% received ICI in the second line or further lines. During a median follow-up of 21.1 months, 122 (36.4%) patients developed irAEs of any grade (grade ≥ 3: 14.9%). Hazard ratios (HRs) for PFS ranged from 0.37 for naïve adjusted Cox model to 0.88 (95% confidence interval (CI), 0.59–1.30) with time-updated covariates, and from 0.41 to 1.10 (95% CI, 0.69–1.75) for OS. TTE accounting for immortal time bias yielded a HR of 1.02 (95% CI, 0.72–1.44) for PFS, and 0.90 (95% CI, 0.62–1.30) for OS. In contrast to the naïve Cox model (HR = 2.26, 95% CI 1.26–4.05), the presence of irAEs was no longer a predictive factor for improved ORR in time-updated Cox models (HR = 1.27, 95% CI 0.68–2.36) and TTE (HR = 1.43, 95% CI 0.89–2.29). In patients with irAEs, systemic corticosteroids did not negatively impact survival. Conclusion Using TTE, we were able to show that the occurrence of irAEs is no longer associated with better survival or improved response rates to ICI in mUC patients, in contrast to the naïve analysis. These findings demonstrate that TTE is a suitable formal framework to avoid immortal time bias in studies with time-dependent non-interventional exposures. Graphical abstracthttps://doi.org/10.1007/s00262-024-03871-7Urothelial cancerMetastaticImmunotherapyImmune checkpoint inhibitorsAdverse eventsTarget trial emulation |
| spellingShingle | Renate Pichler Josef Fritz Sarah Maier Melanie R. Hassler Johanna Krauter David D`Andrea Ekaterina Laukhtina Kilian Gust Keiichiro Mori Karl H. Tully Dora Niedersuess-Beke Lea Korber Jasmin Alija Spiegelberg Thomas Bauernhofer José D. Subiela Roman Mayr Andreas Kronbichler Marco Moschini Jeremy Teoh Benjamin Pradere Shahrokh F. Shariat Hanno Ulmer Laura S. Mertens European Association of Urology–Young Academic Urologists (EAU-YAU): Urothelial Carcinoma Working Group Target trial emulation to evaluate the effect of immune-related adverse events on outcomes in metastatic urothelial cancer Cancer Immunology, Immunotherapy Urothelial cancer Metastatic Immunotherapy Immune checkpoint inhibitors Adverse events Target trial emulation |
| title | Target trial emulation to evaluate the effect of immune-related adverse events on outcomes in metastatic urothelial cancer |
| title_full | Target trial emulation to evaluate the effect of immune-related adverse events on outcomes in metastatic urothelial cancer |
| title_fullStr | Target trial emulation to evaluate the effect of immune-related adverse events on outcomes in metastatic urothelial cancer |
| title_full_unstemmed | Target trial emulation to evaluate the effect of immune-related adverse events on outcomes in metastatic urothelial cancer |
| title_short | Target trial emulation to evaluate the effect of immune-related adverse events on outcomes in metastatic urothelial cancer |
| title_sort | target trial emulation to evaluate the effect of immune related adverse events on outcomes in metastatic urothelial cancer |
| topic | Urothelial cancer Metastatic Immunotherapy Immune checkpoint inhibitors Adverse events Target trial emulation |
| url | https://doi.org/10.1007/s00262-024-03871-7 |
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