Background Combined cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1) blockade induces high rates of immune-related adverse events (irAEs). The safety of resuming anti-PD-1 in patients who discontinue combination therapy due to irAEs is not known. Patients and methods We assessed patients who experienced clinically significant irAEs from combined CTLA-4 and PD-1 blockade leading to treatment discontinuation at four academic centers. We assessed the safety of resuming anti-PD-1 in terms of recurrent and distinct irAEs. Results Eighty patients discontinued combination therapy due to irAEs, including colitis (41%), hepatitis (36%), and pneumonitis (4%). Of these, 96% received corticosteroids and 21% received additional immunosuppression (e.g. infliximab). All were rechallenged with anti-PD-1, and 14 (18%) had recurrent irAEs at a median of 14 days after therapy resumption (six grade 1-2, seven grade 3-4, and one grade 5 Steven-Johnson Syndrome). Colitis was less likely to recur than other irAEs (6% versus 28%, P = 0.01). Clinically significant but distinct toxicities occurred in an additional 17 (21%) patients (11 grade 1-2 and 6 grade 3-4). Duration of steroid taper, severity of initial irAEs and use of additional immunosuppressants did not predict for toxicity on rechallenge, although patients remaining on steroid therapy at anti-PD-1 resumption had higher rates of toxicities (55% versus 31%, P = 0.03). Conclusions Patients who discontinued CTLA-4/PD-1 blockade for severe irAEs had relatively high rates of recurrent or distinct toxicities with anti-PD-1 resumption. However, many patients, particularly with combination-induced colitis, tolerated anti-PD-1 rechallenge well, and this approach can be considered in selected patients.

中文翻译：

---

在转移性黑色素瘤联合抗 CTLA-4 和抗 PD1 治疗期间，免疫相关不良事件 (irAEs) 患者恢复抗 PD-1 治疗的安全性。

背景 细胞毒性 T 淋巴细胞抗原 4 (CTLA-4) 和程序性死亡 1 (PD-1) 联合阻断会导致高发生率的免疫相关不良事件 (irAE)。因 irAEs 而停止联合治疗的患者恢复抗 PD-1 治疗的安全性尚不清楚。患者和方法 我们评估了在四个学术中心因 CTLA-4 和 PD-1 联合阻断导致治疗中断而经历临床显着 irAE 的患者。我们根据复发和不同的 irAE 评估了恢复抗 PD-1 的安全性。结果 80 名患者因 irAEs 停止联合治疗，包括结肠炎 (41%)、肝炎 (36%) 和肺炎 (4%)。其中，96% 接受了皮质类固醇，21% 接受了额外的免疫抑制（例如英夫利昔单抗）。所有人都再次接受了抗 PD-1 抗体的攻击，14 名 (18%) 在治疗恢复后的中位数 14 天出现复发性 irAE（6 名 1-2 级、7 名 3-4 级和 1 名 5 级 Steven-Johnson 综合症）。与其他 irAE 相比，结肠炎不太可能复发（6% 对 28%，P = 0.01）。另外 17 名 (21%) 患者（11 名 1-2 级和 6 名 3-4 级）发生了临床显着但明显的毒性。类固醇逐渐减量的持续时间、初始 irAE 的严重程度和额外免疫抑制剂的使用并不能预测再次挑战时的毒性，尽管在抗 PD-1 恢复时继续接受类固醇治疗的患者有更高的毒性发生率（55% 对 31%，P = 0.03 ). 结论 因严重 irAE 而停用 CTLA-4/PD-1 阻断剂的患者在恢复抗 PD-1 治疗后具有相对较高的复发率或明显的毒性反应。然而，许多患者，