Department of Pharmacy, Vanderbilt University Medical Center, Nashville, USA.
Department of Pharmacy, Vanderbilt Ingram Cancer Center, Nashville, USA.
Ann Oncol. 2018 Jan 1;29(1):250-255. doi: 10.1093/annonc/mdx642.
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.
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.
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).
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.
联合使用细胞毒性 T 淋巴细胞相关抗原 4（CTLA-4）和程序性死亡受体 1（PD-1）抑制剂可引发高频率的免疫相关不良事件（irAEs）。对于因 irAEs 而停止联合治疗的患者，重新使用 PD-1 抑制剂的安全性尚不清楚。
我们评估了在四家学术中心因 irAEs 而停止联合 CTLA-4 和 PD-1 阻断治疗的患者。我们根据复发性和不同的 irAEs 评估了重新使用 PD-1 抑制剂的安全性。
80 例患者因 irAEs 而停止了联合治疗，包括结肠炎（41%）、肝炎（36%）和肺炎（4%）。其中，96%的患者接受了皮质类固醇治疗，21%的患者接受了额外的免疫抑制治疗（如英夫利昔单抗）。所有患者均重新接受了 PD-1 抑制剂治疗，14 例（18%）在重新开始治疗后 14 天内出现复发性 irAEs（6 例 1-2 级，7 例 3-4 级，1 例 5 级史蒂文斯-约翰逊综合征）。结肠炎的复发率低于其他 irAEs（6%对 28%，P=0.01）。另外还有 17 例（21%）患者出现了新的但具有临床意义的毒性（11 例 1-2 级，6 例 3-4 级）。皮质类固醇减量的持续时间、初始 irAEs 的严重程度和是否使用额外的免疫抑制剂并不能预测重新使用时的毒性，但在重新开始使用 PD-1 抑制剂时仍在使用皮质类固醇治疗的患者毒性发生率更高（55%对 31%，P=0.03）。
因严重 irAEs 而停止 CTLA-4/PD-1 阻断治疗的患者，在重新使用 PD-1 抑制剂时，复发或新发毒性的发生率相对较高。然而，许多患者，特别是因联合治疗引起的结肠炎患者，能够很好地耐受 PD-1 抑制剂的再次使用，这种方法可以在某些患者中考虑。
