Background/Objectives: Immune checkpoint inhibitors have significantly transformed the treatment paradigm of advanced melanoma, leading to substantial improvements in survival outcomes. However, this therapeutic success is accompanied by a spectrum of treatment-related adverse events, some of which are increasingly recognised as enduring and non-reversible. Whilst early-onset immune-related toxicities have been well characterized, late-onset toxicities, often emerging in patients with long-term disease control, remain understudied and are frequently overlooked. Methods: To address this knowledge gap, we conducted a retrospective multicentre study in three UK tertiary referral centres, exploring immune-related adverse events in 246 patients with melanoma who received immune checkpoint inhibitors in the advanced setting. We defined late-onset immune-related adverse events as those occurring at least 3 months after the last cycle of immune checkpoint inhibitors. Results: Although most patients experienced early-onset toxicity, almost 15% of patients developed late-onset immune-related adverse events, including skin rash, colitis, hepatitis, and arthritis, among others. These were often challenging to manage and necessitated the use of systemic steroids. Up to 2% of patients presented ultra-late-onset toxicities, defined as those events occurring at least 12 months after treatment completion. Conclusions: This study provides valuable insights into the characteristics of late-onset immune-related adverse events. To further advance our understanding of these late-onset toxicities, dedicated prospective studies are needed to assess risk factors associated with their development and their impact on quality of life. Additionally, translational research focused on finding predictive biomarkers is essential to identify patients at a higher risk of developing delayed adverse events and to understand how best to manage them.
背景/目的：免疫检查点抑制剂显著改变了晚期黑色素瘤的治疗模式，使患者生存结局获得实质性改善。然而，这一治疗成功伴随着一系列治疗相关不良事件，其中部分事件正日益被认识到具有持久性和不可逆性。虽然早发性免疫相关毒性已得到充分描述，但迟发性毒性（常见于获得长期疾病控制的患者）仍缺乏深入研究且常被忽视。方法：为填补这一知识空白，我们在英国三家三级转诊中心开展了一项多中心回顾性研究，对246例接受晚期免疫检查点抑制剂治疗的黑色素瘤患者的免疫相关不良事件进行分析。我们将迟发性免疫相关不良事件定义为末次免疫检查点抑制剂治疗周期结束后至少3个月发生的事件。结果：尽管多数患者出现早发性毒性，但近15%的患者发生迟发性免疫相关不良事件，包括皮疹、结肠炎、肝炎和关节炎等。这些事件通常难以处理，需使用全身性类固醇治疗。高达2%的患者出现超迟发性毒性（定义为治疗结束后至少12个月发生的事件）。结论：本研究为迟发性免疫相关不良事件的特征提供了重要见解。为进一步深化对这些迟发性毒性的认识，需要开展专门的前瞻性研究以评估其发生的相关风险因素及对生活质量的影响。此外，应重点开展转化医学研究以寻找预测性生物标志物，这对识别迟发性不良事件高风险患者及探索最佳管理策略至关重要。
Late-Onset Immune-Related Adverse Events in Patients with Advanced Melanoma: The LATENT Study
肿瘤(癌症)患者之家