Westmead Hospital WNH, Westmead, New South Wales, Australia.
Melanoma Institute Australia, North Sydney, New South Wales, Australia.
J Immunother Cancer. 2024 Jan 31;12(1):e008232. doi: 10.1136/jitc-2023-008232.
Immune checkpoint inhibitor (ICI) gastrointestinal toxicity (gastritis, enteritis, colitis) is a major cause of morbidity and treatment-related death. Guidelines agree steroid-refractory cases warrant infliximab, however best management of infliximab-refractory ICI gastrointestinal toxicity (IRIGItox) is unknown.
We conducted an international multicenter retrospective case series. IRIGItox was defined as failure of symptom resolution ≤grade 1 (Common Terminology Criteria for Adverse Events V.5.0) following ≥2 infliximab doses failure of symptom resolution ≤grade 2 after one dose. Data were extracted regarding demographics, steroid use, response to treatment, and survival outcomes. Toxicity was graded at symptom onset and time of infliximab failure. Efficacy of infliximab refractory therapy was assessed by symptom resolution, time to resolution and steroid wean duration. Survival outcomes were examined based on immunosuppressive therapy received.
78 patients were identified: median age 60 years; 56% men; majority melanoma (N=70, 90%); 60 (77%) received anti-cytotoxic T-lymphocyte-associated protein 4 alone or in combination with anti-programmed cell death protein-1 and most had colitis (N=74, 95%). 106 post-infliximab treatments were given: 31 calcineurin inhibitors (CNIs); 27 antimetabolites (mycophenolate, azathioprine); 16 non-systemic immunomodulatory agents (eg, mesalazine or budesonide); 15 vedolizumab; 5 other biologics (anti-interleukin-12/23, 16, Janus kinase inhibitors) and 7 interventional procedures (including colectomy); 5 did not receive post-infliximab therapy. Symptom resolution was achieved in most (N=23/31, 74%) patients treated with CNIs; 12/27 (44%) with antimetabolites; 7/16 (44%) with non-systemic immunomodulation, 8/15 (53%) with vedolizumab and 5/7 (71%) with interventional procedures. No non-vedolizumab biologics resulted in toxicity resolution. CNIs had the shortest time to symptom resolution (12 days) and steroid wean (43 days); however, were associated with poorer event-free survival (6.3 months) and overall survival (26.8 months) than other agents. Conversely, vedolizumab had the longest time to toxicity resolution and steroid wean, 66 and 124 days, but most favorable survival data: EFS 24.5 months; median OS not reached. Six death occurred (three due to IRIGItox or management of toxicity; three with persisting IRIGItox progressive disease).
IRIGItox causes major morbidity and mortality. Management is heterogeneous. CNIs appear most likely to result in toxicity resolution in the shortest time period, however, are associated with poorer oncological outcomes in contrast to vedolizumab.
免疫检查点抑制剂（ICI）胃肠道毒性（胃炎、肠炎、结肠炎）是发病率和治疗相关死亡的主要原因。指南一致认为类固醇难治性病例需要使用英夫利昔单抗，但英夫利昔单抗难治性 ICI 胃肠道毒性（IRIGItox）的最佳治疗方法尚不清楚。
我们进行了一项国际多中心回顾性病例系列研究。IRIGItox 定义为在接受≥2 剂英夫利昔单抗后症状缓解≤1 级（不良事件通用术语标准 V.5.0），或在接受 1 剂后症状缓解≤2 级。提取有关人口统计学、类固醇使用、治疗反应和生存结果的数据。在症状出现时和英夫利昔单抗失败时对毒性进行分级。通过症状缓解、缓解时间和类固醇减药时间评估英夫利昔单抗难治性治疗的疗效。根据接受的免疫抑制治疗检查生存结果。
共确定了 78 例患者：中位年龄 60 岁；56%为男性；大多数为黑色素瘤（N=70，90%）；60 例（77%）单独或联合接受抗细胞毒性 T 淋巴细胞相关蛋白 4 治疗，大多数患有结肠炎（N=74，95%）。共给予 106 种英夫利昔单抗后治疗：31 种钙调神经磷酸酶抑制剂（CNIs）；27 种抗代谢物（霉酚酸酯、硫唑嘌呤）；16 种非全身性免疫调节剂（如美沙拉嗪或布地奈德）；15 种维得利珠单抗；5 种其他生物制剂（抗白细胞介素-12/23、16、Janus 激酶抑制剂）和 7 种介入性手术（包括结肠切除术）；5 例未接受英夫利昔单抗后治疗。接受 CNIs 治疗的大多数患者（N=23/31，74%）症状缓解；12/27（44%）接受抗代谢物治疗；7/16（44%）接受非全身性免疫调节治疗，8/15（53%）接受维得利珠单抗治疗，7/7（71%）接受介入性手术治疗。非维得利珠单抗生物制剂均未导致毒性缓解。CNIs 达到症状缓解的时间最短（12 天）和类固醇减药时间最短（43 天）；然而，与其他药物相比，无事件生存（6.3 个月）和总生存（26.8 个月）较差。相反，维得利珠单抗达到毒性缓解和类固醇减药的时间最长，分别为 66 天和 124 天，但生存数据最有利：EFS 24.5 个月；中位 OS 未达到。6 例死亡（3 例死于 IRIGItox 或毒性管理；3 例因 IRIGItox 持续存在且进展性疾病）。
IRIGItox 导致严重的发病率和死亡率。管理方法存在差异。CNIs 似乎最有可能在最短的时间内导致毒性缓解，但与维得利珠单抗相比，与较差的肿瘤学结果相关。
