Department of Oncology, Comprehensive Cancer Center Eugène Marquis, Rennes, France.
Department of Dermatology, University Hospital, Marseille, France.
JAMA Dermatol. 2020 Sep 1;156(9):982-986. doi: 10.1001/jamadermatol.2020.2149.
Since 2011, many patients with metastatic melanoma have been treated with ipilimumab therapy and have developed severe immune-related adverse events (AEs). Because several immune therapies are now available to treat metastatic melanoma, a better knowledge of mechanisms and recurrence risks of immune-related AEs is needed before reintroduction of immunotherapies.
To evaluate the risk of a recurrence of immune toxic effects associated with anti-programmed cell death 1 antibody (anti-PD-1) therapy after discontinuation of ipilimumab monotherapy because of severe AEs.
DESIGN, SETTINGS, AND PARTICIPANTS: This cohort study conducted at 19 French melanoma referral centers included patients with metastatic melanoma who experienced severe immune-related AEs after ipilimumab therapy and then were treated with anti-PD-1 therapy between February 1, 2013, and December 31, 2016. The study cutoff was June 1, 2017. Statistical analysis was performed from June 1, 2016, to August 31, 2017.
Monotherapy with at least 1 cycle of ipilimumab that was associated with a grade 3 or 4 immune-related AE and subsequent treatment with at least 1 cycle of an anti-PD-1 (nivolumab or pembrolizumab) therapy.
The primary outcome was the rate of immune-related AEs associated with anti-PD-1 therapy. Secondary outcomes were characteristics of ipilimumab-related and anti-PD-1 immune-related AEs and overall response rate and overall survival associated with anti-PD-1 therapy.
Of 56 patients with metastatic melanoma included in the study, all of whom experienced severe immune-related AEs after ipilimumab therapy (31 [55%] male; mean [SD] age, 64 [14.9] years), 20 (36%) experienced at least 1 immune-related AE associated with pembrolizumab (6 of 20 [30%]) or nivolumab (14 of 20 [70%]) therapy. A total of 12 patients (21%) experienced grade 3 or 4 immune-related AEs, and among these patients, 4 (33%) presented with the same immune-related AE as with ipilimumab therapy. Severe immune-related AEs were resolved with use of systemic corticosteroids (7 [58%]) and/or anti-tumor necrosis factor (1 [8%]), and no grade 5 toxic effects were reported. Five patients discontinued anti-PD-1 therapy because of immune-related AEs. The overall response rate was 43%, with a median overall survival of 21 months (interquartile range, 18 to ongoing).
The findings suggest that anti-PD-1 therapy may be associated with reduced risk of toxic effects and improved survival among patients who have experienced severe toxic effects after ipilimumab therapy.
自 2011 年以来，许多转移性黑色素瘤患者接受了伊匹单抗治疗，并出现了严重的免疫相关不良事件（AE）。由于现在有几种免疫疗法可用于治疗转移性黑色素瘤，因此在重新引入免疫疗法之前，需要更好地了解免疫相关 AE 的机制和复发风险。
评估抗程序性死亡 1 抗体（抗 PD-1）治疗因严重 AE 而停用伊匹单抗单药治疗后，与抗 PD-1 治疗相关的免疫毒性作用复发的风险。
设计、地点和参与者：这项在 19 家法国黑色素瘤转诊中心进行的队列研究纳入了在接受伊匹单抗治疗后出现严重免疫相关 AE 且在 2013 年 2 月 1 日至 2016 年 12 月 31 日期间接受抗 PD-1 治疗的转移性黑色素瘤患者。研究截止日期为 2017 年 6 月 1 日。统计分析于 2016 年 6 月 1 日至 2017 年 8 月 31 日进行。
至少接受过 1 个周期的伊匹单抗单药治疗，其相关的免疫相关 AE 为 3 级或 4 级，随后至少接受过 1 个周期的抗 PD-1（纳武单抗或帕博利珠单抗）治疗。
主要结局是与抗 PD-1 治疗相关的免疫相关 AE 发生率。次要结局是与伊匹单抗相关的和抗 PD-1 相关免疫相关 AE 的特征，以及与抗 PD-1 治疗相关的总反应率和总生存期。
在这项研究中，共纳入了 56 名患有转移性黑色素瘤的患者，他们均在接受伊匹单抗治疗后出现了严重的免疫相关 AE（31 名[55%]为男性；平均[SD]年龄为 64[14.9]岁），其中 20 名（36%）至少经历过 1 次与 pembrolizumab（6/20[30%]）或 nivolumab（14/20[70%]）治疗相关的免疫相关 AE。共有 12 名（21%）患者出现了 3 级或 4 级免疫相关 AE，在这些患者中，有 4 名（33%）出现了与伊匹单抗治疗相同的免疫相关 AE。严重的免疫相关 AE 经全身性皮质类固醇（7 [58%]）和/或抗肿瘤坏死因子（1 [8%]）的使用得到解决，没有报道 5 级毒性作用。有 5 名患者因免疫相关 AE 而停止抗 PD-1 治疗。总反应率为 43%，中位总生存期为 21 个月（四分位距，18 至持续）。
这些发现表明，对于在接受伊匹单抗治疗后出现严重毒性反应的患者，抗 PD-1 治疗可能与毒性反应风险降低和生存改善相关。
