PO.CL05.08 · 临床研究
表型定制的预防性免疫调节使高危患者在发生严重irAEs后能够安全地再次使用免疫检查点抑制剂
Phenotype-tailored prophylactic immunomodulation enables safe immune checkpoint inhibitor rechallenge after severe irAEs in high-risk patients
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：严重的免疫相关不良事件（irAEs）常导致免疫检查点抑制剂（ICIs）永久停药。表型定制的预防性免疫调节（PTPI）能否使此类高危患者安全地再次使用ICI尚不清楚。
方法：我们在一家三级免疫肿瘤学毒性管理项目中，回顾性研究了因至少一次≥2级irAE而中断ICI、随后在预防性生物免疫调节下再次接受ICI治疗的患者。预防措施根据首次irAE的主导炎症表型进行选择，可联合或不联合低剂量类固醇。主要终点为3个月和6个月时因irAEs导致的ICI停药以及再次治疗期间≥3级irAEs的发生率。次要终点包括复发性irAEs的时间和表型、“免疫耐受使能策略”（ITES；6个月时仍在使用ICI且无≥3级irAEs）、疾病控制率（DCR）以及按预防措施类别的探索性比较。
结果：38例患者在预防措施下再次接受治疗。irAEs包括风湿性（39%）、结肠炎（32%）和葡萄膜炎（8%）；66%为多器官受累。12例患者（32%）曾接受联合治疗，26例（68%）接受抗PD-(L)1治疗。主要肿瘤类型为肺癌（39%）、黑色素瘤（32%）、肾细胞癌（13%）。预防措施中61%为IL-6R阻断，26%为TNF阻断。再次治疗期间，26%发生≥3级irAEs。因irAE导致的ICI停药在3个月和6个月时分别发生于16%和24%的患者；在15例因irAEs停药的患者中，至停药的中位时间为130天。至复发性irAE的中位时间为108天，其中50%发生于>90天。55%的患者实现了ITES，中位ICI持续时间为201天。在结肠炎中，基于TNF的预防与罕见的结肠炎复发（11%）相关，且比非TNF策略导致更少的irAE相关停药。在风湿性表型中，IL-6R阻断显示出比最少/非IL-6R预防更低的复发率（14%）和更少的irAE相关停药。仅1例患者（3%）因感染性并发症停用ICI，未发生4级irAEs。3、6、9和12个月时的DCR分别为52%、63%、62%和65%。
结论：在高危患者中，PTPI使ICI暴露得以延长，高级别毒性可接受，irAE驱动的停药率低，疾病控制得以维持，支持将器官定制的预防措施作为一种策略在前瞻性试验中进行检验。
查看英文原文 English abstract
Background: Severe immune-related adverse events (irAEs) frequently lead to permanent discontinuation of immune checkpoint inhibitors (ICIs). Whether phenotype-tailored prophylactic immunomodulation (PTPI) can safely enable ICI rechallenge in such high-risk patients is unknown.
Methods: We retrospectively studied patients with ICI interruption after at least one grade ≥2 irAE who were subsequently rechallenged under prophylactic biologic immunomodulation in a tertiary immuno-oncology toxicity program. Prophylaxis was selected according to the dominant inflammatory phenotype of the index irAE, with or without low-dose steroids. Primary endpoints were ICI discontinuation due to irAEs at 3 and 6 months and incidence of grade ≥3 irAEs during rechallenge. Secondary endpoints included timing and phenotype of recurrent irAEs, an “immune tolerance enabling strategy” (ITES; on ICI at 6 months without grade ≥3 irAEs), disease control rates (DCR) and exploratory comparisons by prophylaxis class
Results: Thirty-eight patients were rechallenged under prophylaxis. irAEs were rheumatologic (39%), colitis (32%) and uveitis (8%); 66% were multi-organ. Twelve patients (32%) had received combination and 26 (68%) anti-PD-(L)1. The main tumour types were lung (39%), melanoma (32%), renal cell carcinoma (13%). Prophylaxis consisted of IL-6R blockade in 61% and TNF blockade in 26%. During rechallenge, 26% developed grade ≥3 irAEs. IrAE-related ICI discontinuation occurred in 16% and 24% at 3 and 6 months, respectively; among 15 patients who discontinued for irAEs, median time to discontinuation was 130 days. Median time to recurrent irAE was 108 days with 50% occurring >90 days. ITES was achieved in 55% of patients, with median ICI duration 201 days. In colitis, TNF-based prophylaxis was associated with rare colitis recurrences (11%) and fewer irAE-related discontinuations than non-TNF strategies. In rheumatologic phenotypes, IL-6R blockade showed lower recurrence (14%) and fewer irAE-related discontinuations than minimal/non-IL-6R prophylaxis. Only one patient (3%) discontinued ICI for an infectious complication, no grade 4 irAEs occurred. DCR at 3, 6, 9 and 12 months were 52%, 63%, 62% and 65%, respectively.
Conclusions: In high-risk patients, PTPI enabled prolonged ICI exposure with acceptable high-grade toxicity, low irAE-driven discontinuation, preserved disease control, supporting organ-tailored prophylaxis as a strategy to be tested in prospective trials.
利益披露 Disclosure
L. Mencarelli, None..
P. Van Mol, None..
D. Daoudlarian, None..
S. Latifyan, None..
N. Mederos, None..
H. Bouchaab, None..
M. Torsello, None..
A. Stamatiou, None..
N. Etienne, None..
K. Abdelhamid, None..
N. Ferahta, None..
A. Stravodimou, None..
K. Shabafrouz, None..
S. Peters, None..
M. Obeid, None.