Supplementary Material for: Analysis of Immune-Related Adverse Events of Atezolizumab and Bevacizumab in Patients with Hepatocellular Carcinoma: A Multicenter Cohort Study

Background: Despite the emergence of atezolizumab and bevacizumab (A+B) as standard first-line systemic therapy for unresectable hepatocellular carcinoma (HCC), a comprehensive understanding of the clinical significance of immune-related adverse events (irAEs) remains limited. We aimed to assess the impact of irAEs on patients with HCC undergoing A+B treatment.
Methods: This multicentre retrospective study included consecutive patients with HCC who were treated with the A+B regimen from September 2020 to December 2022. Patients were categorised into three groups based on the severity of irAEs, ranging from those without any experience of irAEs to those with severe irAEs, classified as grade 3 or higher.
Results: This study included 150 patients with HCC, with a mean age of 63.3 years. Among them, 93.3% of patients were classified as Barcelona Clinic Liver Cancer stage C, 52.0% had portal vein tumour thrombosis (PVTT), and 60.7% extrahepatic spread. Patients were classified as follows: Group 1 (n = 84) had no irAEs, Group 2 (n = 37) had mild irAEs (grade 1–2), and Group 3 (n = 29) had severe irAEs (grade ≥ 3). The median overall survival (OS), progression-free survival (PFS), and time-to-treatment discontinuation (TTD) were 13.6, 5.7, and 3.6 months, respectively. Group 2 demonstrated significantly superior OS compared to Group 1 (9.5 months) and Group 3 (5.6 months), with a median OS of 23.0 months (p < 0.001). Furthermore, Group 2 demonstrated significantly better outcomes in terms of PFS and TTD compared to both Group 1 and Group 3 (p < 0.001 for both). Multivariate analysis identified mild irAEs (hazard ratio [HR], 0.353; p = 0.010), ALBI grade 1 (HR, 0.389; p = 0.006), Child-Pugh class A (HR, 0.338; p = 0.002), and the absence of PVTT (HR, 0.556; p = 0.043) as independent predictors of better OS.
Conclusions: Our study highlights the significant impact of irAE severity on the outcomes of patients with HCC receiving A+B. Notably, the occurrence of mild irAEs was independently associated with favourable survival, suggesting their potential role as surrogate indicators of HCC prognosis.

背景：尽管阿替利珠单抗联合贝伐珠单抗（atezolizumab and bevacizumab, A+B）已成为不可切除肝细胞癌（hepatocellular carcinoma, HCC）的标准一线全身治疗方案，但目前对免疫相关不良事件（immune-related adverse events, irAEs）的临床意义仍缺乏全面认知。本研究旨在评估irAEs对接受A+B方案治疗的HCC患者的预后影响。
方法：本项多中心回顾性研究纳入了2020年9月至2022年12月期间连续接受A+B方案治疗的HCC患者。根据irAEs的严重程度将患者分为三组：无irAEs发生者、轻度irAEs（1~2级）患者以及分级为3级及以上的重度irAEs患者。
结果：本研究共纳入150例HCC患者，平均年龄为63.3岁。其中93.3%的患者为巴塞罗那临床肝癌分期（Barcelona Clinic Liver Cancer, BCLC）C期，52.0%合并门静脉癌栓（portal vein tumour thrombosis, PVTT），60.7%存在肝外扩散。患者分组情况如下：第1组（n=84）无irAEs发生，第2组（n=37）为轻度irAEs（1~2级），第3组（n=29）为重度irAEs（≥3级）。所有患者的中位总生存期（overall survival, OS）、无进展生存期（progression-free survival, PFS）与治疗终止时间（time-to-treatment discontinuation, TTD）分别为13.6个月、5.7个月和3.6个月。第2组的中位OS为23.0个月，显著优于第1组（9.5个月）与第3组（5.6个月）（p < 0.001）。此外，第2组在PFS与TTD方面的结局也显著优于第1组与第3组（二者p均<0.001）。多因素分析显示，轻度irAEs（风险比[HR]=0.353；p=0.010）、白蛋白-胆红素评分（Albumin-Bilirubin, ALBI）1级（HR=0.389；p=0.006）、Child-Pugh A级（HR=0.338；p=0.002）以及无PVTT（HR=0.556；p=0.043）是总生存期更佳的独立预测因素。
结论：本研究证实，irAEs的严重程度对接受A+B方案治疗的HCC患者的临床结局具有显著影响。值得注意的是，轻度irAEs的发生与更优的生存结局独立相关，提示其有望成为HCC预后的替代标志物。