Pichler Renate, Fritz Josef, Maier Sarah, Hassler Melanie R, Krauter Johanna, D Andrea David, Laukhtina Ekaterina, Gust Kilian, Mori Keiichiro, Tully Karl H, Niedersuess-Beke Dora, Korber Lea, Spiegelberg Jasmin Alija, Bauernhofer Thomas, Subiela José D, Mayr Roman, Kronbichler Andreas, Moschini Marco, Teoh Jeremy, Pradere Benjamin, Shariat Shahrokh F, Ulmer Hanno, Mertens Laura S
Department of Urology, Comprehensive Cancer Center, Medical University of Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria.
Department of Medical Statistics, Informatics and Health Economics, Medical University of Innsbruck, Innsbruck, Austria.
Cancer Immunol Immunother. 2024 Dec 21;74(1):30. doi: 10.1007/s00262-024-03871-7.
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).
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.
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.
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.
免疫检查点抑制剂（ICIs）是转移性尿路上皮癌（mUC）的重要治疗支柱。在观察性研究中，免疫相关不良事件（irAEs）的发生似乎与预后改善有关。然而，这些关联可能受到生存时间偏倚的影响，并不代表因果效应。本研究的目的是通过目标试验模拟（TTE），在纠正生存时间偏倚的同时评估irAEs对预后的影响。
将TTE与调整后的朴素Cox模型和时间更新Cox模型进行对比。我们进行了一项多机构回顾性研究，纳入接受ICI治疗的mUC患者。主要目的是评估irAEs对无进展生存期（PFS）和总生存期（OS）的影响。次要终点包括irAEs对ICI客观缓解率（ORRs）的影响以及全身糖皮质激素对预后的影响。
在335例患者（中位年龄：69岁）中，69.6%在二线或更后线接受ICI治疗。在中位随访21.1个月期间，122例（36.4%）患者发生了任何级别的irAEs（≥3级：14.9%）。PFS的风险比（HRs）范围从朴素调整Cox模型的0.37到时间更新协变量时的0.88（95%置信区间（CI），0.59 - 1.30），OS的HRs范围从0.41到1.10（95%CI，0.69 - 1.75）。考虑生存时间偏倚的TTE得出PFS的HR为1.02（95%CI，0.72 - 1.44），OS的HR为0.90（95%CI，0.62 - 1.30）。与朴素Cox模型（HR = 2.26，95%CI 1.26 - 4.05）相比，在时间更新Cox模型（HR = 1.27，95%CI 0.68 - 2.36）和TTE（HR = 1.43，95%CI 0.89 - 2.29）中，irAEs的存在不再是ORR改善的预测因素。在发生irAEs的患者中，全身糖皮质激素对生存没有负面影响。
与朴素分析相比，使用TTE我们能够表明，在mUC患者中，irAEs的发生不再与更好的生存或对ICI的缓解率改善相关。这些发现表明，TTE是一个合适的正式框架，可避免在具有时间依赖性非干预性暴露的研究中出现生存时间偏倚。
