Neuroendocrine Unit, Massachusetts General Hospital, Boston, Massachusetts.
Center for Melanoma, Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
Cancer. 2018 Sep 15;124(18):3706-3714. doi: 10.1002/cncr.31629. Epub 2018 Jul 5.
It remains unclear whether high doses of glucocorticoids have a negative impact on the efficacy of checkpoint inhibitors. To control for the potential association between immune-related adverse events (irAEs) and improved survival, this study examined a unique cohort of patients who had the same irAE treated with varying glucocorticoid doses.
In total, 98 patients with melanoma who had ipilimumab-induced hypophysitis were identified retrospectively in the Partners Healthcare system using an automated electronic medical record query tool. Patients with melanoma who received ipilimumab at Massachusetts General Hospital without developing hypophysitis were listed in an actively maintained institutional patient database. Glucocorticoid doses for patients with hypophysitis were categorized as low dose (LD) or high dose (HD). Survival analyses were performed for patients who received ipilimumab monotherapy.
Both overall survival (OS) and the time to treatment failure were significantly longer in the LD group compared with the HD group (hazard ratio, 0.24; P = .002 and 0.28, P = .001, respectively). Median OS and the time to treatment failure were not reached in the LD group and were 23.3 and 14.5 months, respectively, in the HD group. All patients who had hypophysitis had improved OS compared with patients who did not have hypophysitis (median, 28.2 vs 9.5 months; P = .0003). This advantage was maintained in the HD group versus the nonhypophysitis group (P = .02). Radiologic and endocrinologic outcomes and symptom resolution did not differ in the LD group versus the HD group.
Among patients with melanoma who had ipilimumab-induced hypophysitis, those who received higher doses of glucocorticoids had reduced survival. This is the first study to demonstrate a potential negative effect of high glucocorticoid doses on the efficacy of checkpoint inhibitors after an irAE. These findings have potential implications for the management of other irAEs.
目前尚不清楚大剂量糖皮质激素是否会对检查点抑制剂的疗效产生负面影响。为了控制免疫相关不良事件（irAE）与生存改善之间的潜在关联，本研究检查了一个独特的队列，这些患者发生了相同的 irAE，并用不同剂量的糖皮质激素进行了治疗。
本研究通过使用自动电子病历查询工具，在 Partners Healthcare 系统中回顾性地确定了 98 例接受 ipilimumab 诱导性垂体炎的黑色素瘤患者。在马萨诸塞州综合医院接受 ipilimumab 治疗但未发生垂体炎的黑色素瘤患者被列入机构内患者数据库。垂体炎患者的糖皮质激素剂量分为低剂量（LD）或高剂量（HD）。对接受 ipilimumab 单药治疗的患者进行生存分析。
与 HD 组相比，LD 组的总生存（OS）和治疗失败时间均显著延长（风险比，0.24；P = .002 和 0.28，P = .001）。LD 组的中位 OS 和治疗失败时间均未达到，分别为 23.3 个月和 14.5 个月，而 HD 组则分别为 23.3 个月和 14.5 个月。所有发生垂体炎的患者与未发生垂体炎的患者相比，OS 均得到改善（中位值，28.2 个月比 9.5 个月；P = .0003）。在 HD 组与非垂体炎组之间也存在这种优势（P = .02）。在 LD 组与 HD 组之间，影像学和内分泌学结局以及症状缓解并无差异。
在接受 ipilimumab 诱导性垂体炎的黑色素瘤患者中，接受高剂量糖皮质激素治疗的患者生存率降低。这是第一项表明 irAE 后高剂量糖皮质激素对检查点抑制剂疗效产生潜在负面影响的研究。这些发现对管理其他 irAE 具有潜在意义。
