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Target trial emulation to evaluate the effect of immune-related adverse events on outcomes in metastatic urothelial cancer

R. Pichler, J. Fritz, S. Maier, MR. Hassler, J. Krauter, D. D Andrea, E. Laukhtina, K. Gust, K. Mori, KH. Tully, D. Niedersuess-Beke, L. Korber, JA. Spiegelberg, T. Bauernhofer, JD. Subiela, R. Mayr, A. Kronbichler, M. Moschini, J. Teoh, B....

. 2024 ; 74 (1) : 30. [pub] 20241221

Jazyk angličtina Země Německo

Typ dokumentu časopisecké články, multicentrická studie

Perzistentní odkaz   https://www.medvik.cz/link/bmc25002984

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.

Department of Internal Medicine 4 Nephrology and Hypertension Medical University of Innsbruck Innsbruck Austria

Department of Medical Statistics Informatics and Health Economics Medical University of Innsbruck Innsbruck Austria

Department of Surgery S H Ho Urology Centre The Chinese University of Hong Kong Hong Kong China

Department of Surgical Oncology Netherlands Cancer Institute Amsterdam The Netherlands

Department of Urology 2nd Faculty of Medicine Charles University Prague Czechia

Department of Urology and Neurourology Marien Hospital Herne Ruhr University Bochum Herne Germany

Department of Urology Comprehensive Cancer Center Medical University of Innsbruck Anichstraße 35 6020 Innsbruck Austria

Department of Urology Comprehensive Cancer Center Medical University of Vienna Vienna Austria

Department of Urology Hospital Universitario Ramón y Cajal IRYCIS Universidad de Alcala Madrid Spain

Department of Urology IRCCS Ospedale San Raffaele and Vita Salute San Raffaele University Milan Italy

Department of Urology La Croix du Sud Hospital Quint Fonsegrives France

Department of Urology Medical University of Vienna Vienna Austria

Department of Urology St Josef Medical Center University of Regensburg Regensburg Germany

Department of Urology The Jikei University School of Medicine Tokyo Japan

Department of Urology University of Texas Southwestern Medical Center Dallas TX USA

Department of Urology Weill Cornell Medical College New York NY USA

Division of Oncology Department of Internal Medicine Medical University of Graz Graz Austria

Klinik Ottakring 1 Medizinische Abteilung Zentrum Für Onkologie Hämatologie Und Palliativmedizin Vienna Austria

Citace poskytuje Crossref.org

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$a 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.
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