Pichler, Renate and Fritz, Josef and Maier, Sarah and Hassler, Melanie R. and Krauter, Johanna and D'Andrea, David and Laukhtina, Ekaterina and Gust, Kilian and Mori, Keiichiro and Tully, Karl H. and Niedersuess-Beke, Dora and Korber, Lea and Spiegelberg, Jasmin Alija and Bauernhofer, Thomas and Subiela, Jose D. and Mayr, Roman and Kronbichler, Andreas and Moschini, Marco and Teoh, Jeremy and Pradere, Benjamin and Shariat, Shahrokh F. and Ulmer, Hanno and Mertens, Laura S. (2024) Target trial emulation to evaluate the effect of immune-related adverse events on outcomes in metastatic urothelial cancer. CANCER IMMUNOLOGY IMMUNOTHERAPY, 74 (1): 30. ISSN 0340-7004, 1432-0851
Full text not available from this repository. (Request a copy)Abstract
BackgroundImmune 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).MethodsTTE was contrasted to adjusted na & iuml;ve 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.ResultsAmong 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 na & iuml;ve 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 na & iuml;ve 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.ConclusionUsing 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 na & iuml;ve analysis. These findings demonstrate that TTE is a suitable formal framework to avoid immortal time bias in studies with time-dependent non-interventional exposures.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | BIAS; Urothelial cancer; Metastatic; Immunotherapy; Immune checkpoint inhibitors; Adverse events; Target trial emulation; Immortal time bias |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Urologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 20 Aug 2025 08:25 |
| Last Modified: | 20 Aug 2025 08:25 |
| URI: | https://pred.uni-regensburg.de/id/eprint/65557 |
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