Ng Kennedy Yao Yi, Tan Sze Huey, Tan Jack Jie En, Tay Desiree Shu Hui, Lee Ailica Wan Xin, Ang Andrea Jing Shi, Wong Lawrence Wen Jun, Choo Su Pin, Tai David Wai-Meng, Lee Joycelyn Jie Xin
Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
Division of Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore, Singapore, Singapore.
Liver Cancer. 2021 Oct 26;11(1):9-21. doi: 10.1159/000518619. eCollection 2022 Jan.
Development of immune-related adverse events (irAEs) has been associated with enhanced efficacy with the use of immune checkpoint inhibitors (ICIs). It remains unknown whether such an association exists in advanced hepatocellular carcinoma (aHCC). This study aims to evaluate the association between irAEs and ICI efficacy in patients with aHCC.
We performed a retrospective cohort study on patients with aHCC who received at least one dose of an ICI between May 2015 and November 2019 at the National Cancer Centre Singapore. The primary study objectives were to compare the overall survival (OS) and progression-free survival (PFS) between patients with and without irAEs. Complementary multivariable landmark analyses were performed at the 6-week and 12-week landmarks. Data cutoff was December 31, 2020.
One hundred and sixty-eight patients were included. Median age was 69 years, 85.7% were male, 57.7% had hepatitis B infection, 60.7% had ECOG 0, and 78.0% had Child-Pugh A liver cirrhosis. 82.7% received ICI monotherapy, while 17.3% received ICI in combination. Development and severity of irAE were correlated with survival. The median PFS for grade ≥3 irAE versus grades 1-2 irAE versus no irAE was 8.5 versus 3.6 versus 1.3 mths ( < 0.001). The median OS for grade ≥3 irAE versus grades 1-2 irAE versus no irAE was 26.9 versus 14.0 versus 4.6 mths ( < 0.001). Patients with ≥2 irAEs had a significantly longer OS on multivariable analysis (adjusted hazard ratio [aHR]0.35, < 0.001). The presence of grade ≥3 irAEs was associated with a significantly longer OS on the multivariable analysis at the 6-week landmark (aHR0.34, = 0.030) and 12-week landmark (aHR0.28, = 0.011). The use of systemic corticosteroids in patients with irAE was associated with a trend toward a longer OS (20.7 vs. 14.3 mths, = 0.064).
Our study suggests that the presence of all-grade irAEs may be a potential prognostic biomarker in patients with aHCC treated with ICI. Patients with more severe irAEs and multisystem involvement have better prognosis. The prompt use of systemic corticosteroids to treat patients with irAEs is key to ensure the best long-term outcomes for these patients.
免疫相关不良事件（irAEs）的发生与使用免疫检查点抑制剂（ICIs）疗效增强有关。在晚期肝细胞癌（aHCC）中是否存在这种关联尚不清楚。本研究旨在评估aHCC患者中irAEs与ICI疗效之间的关联。
我们对2015年5月至2019年11月在新加坡国立癌症中心接受至少一剂ICI的aHCC患者进行了一项回顾性队列研究。主要研究目标是比较有和没有irAEs患者的总生存期（OS）和无进展生存期（PFS）。在6周和12周时间点进行了补充性多变量标志性分析。数据截止日期为2020年12月31日。
纳入168例患者。中位年龄为69岁，85.7%为男性，57.7%有乙型肝炎感染，60.7%的东部肿瘤协作组（ECOG）体能状态评分为0，78.0%有Child-Pugh A级肝硬化。82.7%接受ICI单药治疗，17.3%接受ICI联合治疗。irAE的发生和严重程度与生存相关。≥3级irAE患者、1-2级irAE患者和无irAE患者的中位PFS分别为8.5个月、3.6个月和1.3个月（P<0.001）。≥3级irAE患者、1-2级irAE患者和无irAE患者的中位OS分别为26.9个月、14.0个月和4.6个月（P<0.001）。多变量分析显示，发生≥2次irAEs的患者OS显著更长（调整后风险比[aHR]0.35，P<0.001）。在6周时间点（aHR0.34，P=0.030）和12周时间点（aHR0.28，P=0.011）的多变量分析中，≥3级irAEs的存在与显著更长的OS相关。对有irAE的患者使用全身性皮质类固醇与OS延长的趋势相关（20.7个月对14.3个月，P=0.064）。
我们的研究表明，所有级别的irAEs的存在可能是接受ICI治疗的aHCC患者的一种潜在预后生物标志物。irAEs更严重且有多系统受累的患者预后更好。及时使用全身性皮质类固醇治疗有irAE的患者是确保这些患者获得最佳长期结局的关键。
