Kött Julian, Merkle Myriam, Bergmann Lina, Zimmermann Noah, Zell Tim, Heidrich Isabel, Geidel Glenn, Pantel Klaus, Schneider Stefan W, Gebhardt Christoffer, Smit Daniel J
Department of Dermatology and Venereology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Fleur Hiege Center for Skin Cancer Research, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Cancers (Basel). 2025 Aug 27;17(17):2806. doi: 10.3390/cancers17172806.
: 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. : 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. : 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. : 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.
免疫检查点抑制（ICI）是晚期黑色素瘤患者的标准治疗方法。尽管与先前的治疗方案相比其疗效很高，但免疫相关不良事件（irAE）却频繁发生。虽然大多数患者经历轻度至中度irAE，但一些患者在ICI治疗下会出现严重至致命的irAE；因此，迫切需要生物标志物。
在这项回顾性单中心研究中，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。irAE与临床病理参数、疾病相关结局和无irAE生存期相关。
在我们的队列中，157例接受免疫治疗的患者中有130例经历了irAE，其中一半以上经历了≥3级的irAE。最常见的irAE（无论其级别如何）包括皮肤irAE、结肠炎、内分泌irAE和肝炎。与在ICI治疗下未经历irAE的患者相比，经历irAE的患者的无进展生存期（PFS）和总生存期（OS）明显更长。按irAE组分层显示，肌肉骨骼irAE与最长的生存期相关，而心肌炎与最短的OS和PFS相关。在单变量Cox回归分析中，irAE是PFS的显著有益预后指标，但在多变量Cox回归分析中并非如此。关于OS，irAE的发生是ECOG状态≥2和葡萄膜黑色素瘤患者中的独立预后因素。ROC分析表明，D-二聚体对irAE的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单药治疗与CTLA-4和PD-1联合方案相比是无irAE生存期的唯一独立前瞻性预后标志物。
我们的研究表明，整个irAE谱中的不同irAE对晚期黑色素瘤患者的PFS和OS有不同影响。D-二聚体可作为基于血液的irAE预测生物标志物，有待未来在多中心研究中进行验证。
