Background: Immune checkpoint inhibition (ICI) is the standard treatment for advanced melanoma patients. Despite its high efficacy compared to previous treatment options, immune-related adverse events (irAEs) occur frequently. While most of the patients experience mild to moderate irAEs, some patients develop severe to lethal irAEs under ICI treatment; hence, biomarkers are urgently required.Methods: In this retrospective single-center study, 157 advanced melanoma patients treated with ICI at the University Medical Center Hamburg–Eppendorf were included. IrAEs were correlated with clinico-pathological parameters, disease-related outcomes, and irAE-free survival.Results: In our cohort, 130 out of 157 patients receiving immunotherapy experienced irAE, of which more than half experienced irAE Grade ≥ 3. The most common irAE independent of its grade included cutaneous irAE, colitis, endocrine irAE, and hepatitis. Patients experiencing irAE had significantly longer progression-free survival (PFS) and overall survival (OS) compared to patients who did not experience irAE under ICI therapy. Stratification by irAE groups revealed that musculoskeletal irAEs are associated with the longest, whereas myocarditis is associated with the shortest OS and PFS. IrAE was a significant beneficial prognosticator for PFS in univariate, but not in multivariate Cox regression analysis. With respect to OS, the occurrence of irAE was an independent prognostic factor among ECOG status ≥ 2 and uveal melanoma. ROC analysis demonstrated that D-dimers have moderate predictive capability for irAE occurrence. Cox regression analysis demonstrated that elevated D-dimers and PD-1 monotherapy vs. CTLA-4 and PD-1 combination regimen are the only independent prospective prognostic markers for irAE-free survival.Conclusions: Our study demonstrates that different irAE across the irAE spectrum have a different impact on the PFS and OS of advanced melanoma patients. D-dimers may be used as a blood-based biomarker for irAE prediction, warranting future validation in multi-center studies.
背景：免疫检查点抑制剂（ICI）是晚期黑色素瘤患者的标准治疗方法。尽管与既往治疗方案相比其疗效显著，但免疫相关不良事件（irAE）频繁发生。虽然大多数患者经历轻度至中度irAE，但部分患者在ICI治疗期间出现重度甚至致死性irAE，因此亟需寻找相关生物标志物。 方法：本项回顾性单中心研究纳入了157例在汉堡-埃彭多夫大学医学中心接受ICI治疗的晚期黑色素瘤患者。研究将irAE与临床病理参数、疾病相关结局及无irAE生存期进行关联分析。 结果：在接受免疫治疗的157例患者中，130例出现irAE，其中超过半数患者发生≥3级irAE。各级别中最常见的irAE包括皮肤irAE、结肠炎、内分泌irAE和肝炎。与未发生irAE的患者相比，发生irAE的患者在ICI治疗期间具有显著更长的无进展生存期（PFS）和总生存期（OS）。按irAE类型分层分析显示，肌肉骨骼irAE与最长的OS和PFS相关，而心肌炎则与最短的生存期相关。单变量Cox回归分析表明irAE是PFS的显著有利预后因素，但多变量分析中未显示此关联。对于OS而言，在ECOG评分≥2和葡萄膜黑色素瘤亚组中，irAE的发生是独立预后因素。ROC分析显示D-二聚体对irAE发生具有中等预测能力。Cox回归分析表明，D-二聚体升高以及PD-1单药治疗（相较于CTLA-4与PD-1联合方案）是无irAE生存期仅有的独立前瞻性预后标志物。 结论：本研究证实不同谱系的irAE对晚期黑色素瘤患者的PFS和OS具有差异化影响。D-二聚体可作为预测irAE的血液生物标志物，未来需通过多中心研究进一步验证。
肿瘤(癌症)患者之家