抗 PD-1 免疫相关不良反应与晚期黑色素瘤的生存结局。
Anti-PD1-Induced Immune-Related Adverse Events and Survival Outcomes in Advanced Melanoma.
机构信息
Department of Oncology, University of Calgary, Calgary, Alberta, Canada.
Department of Gastroenterology, University of Calgary, Calgary, Alberta, Canada.
出版信息
Oncologist. 2020 May;25(5):438-446. doi: 10.1634/theoncologist.2019-0674. Epub 2020 Feb 12.
INTRODUCTION
Objective response rates (ORR) appear to be higher in melanoma patients who develop immune-related adverse events (irAEs), but whether there is a similar association between irAEs and survival remains unknown.
MATERIALS AND METHODS
Patients with advanced melanoma treated with single-agent pembrolizumab or nivolumab in the province of Alberta from June 2014 to May 2017 were identified through the provincial pharmacy database. Chart review identified and categorized all irAEs that occurred while on anti-programmed cell death protein 1 (PD-1) checkpoint inhibitors. The primary objective was to compare overall survival (OS) with patients who developed any irAEs versus those who did not. Secondary outcomes included progression-free survival (PFS) and ORR.
RESULTS
Among 186 patients, any-grade and grade ≥3 irAEs occurred in 88 (47%) and 27 (15%) patients, respectively; one patient died of pneumonitis. In a landmark analysis excluding patients who died within the first 12 weeks, the median follow-up was 24 months, 20 months in patients without any irAEs and 26 months in patients with irAEs (p = .006). Median OS was 39 versus 23 months (hazard ratio [HR], 0.46; p = .001) for any irAE and no irAE, respectively, and median OS not reached versus 29 months for grade ≥3 irAEs and no grade ≥3 irAEs, respectively. In multivariate analysis, elevated lactate dehydrogenase correlated with reduced OS (HR, 2.34; p = .001), whereas each additional cycle of treatment received (HR, 0.94; p < .001) and development of grade ≥3 irAEs (HR, 0.29, p = .024) were significantly associated with longer OS.
CONCLUSION
Anti-PD-1-associated grade ≥3 irAEs in patients with advanced melanoma is associated with better patient outcomes, including overall survival.
IMPLICATIONS FOR PRACTICE
Previous prospective randomized clinical trials demonstrate improved response rates in patients with melanoma who develop select adverse events. The current population-based real-world study in advanced melanoma reports an association with anti-programmed cell death protein 1 (PD-1)-induced grade ≥3 immune-related adverse events (irAEs) and better patient outcomes, including overall survival. These results suggest that irAEs may be a manifestation of a patient's ability to mount a systemic immune response from PD-1-directed therapies, which may be associated with therapeutic benefit. The finding of irAEs coinciding with clinical benefit from these therapies supposes that these events are, by and large, unavoidable, and the critical management of irAEs remains essential for optimizing patient outcomes.
简介
客观缓解率（ORR）似乎在发生免疫相关不良事件（irAE）的黑色素瘤患者中更高，但 irAE 与生存之间是否存在类似的关联尚不清楚。
材料和方法
通过省级药房数据库，确定了 2014 年 6 月至 2017 年 5 月在艾伯塔省接受单药 pembrolizumab 或 nivolumab 治疗的晚期黑色素瘤患者。图表审查确定并分类了所有在接受抗程序性细胞死亡蛋白 1（PD-1）检查点抑制剂治疗时发生的 irAE。主要目的是比较发生任何 irAE 的患者与未发生任何 irAE 的患者的总生存期（OS）。次要结局包括无进展生存期（PFS）和 ORR。
结果
在 186 名患者中，分别有 88 名（47%）和 27 名（15%）患者发生任何级别和≥3 级 irAE；1 名患者死于肺炎。在排除前 12 周内死亡患者的里程碑分析中，中位随访时间为 24 个月，无任何 irAE 的患者为 20 个月，有 irAE 的患者为 26 个月（p=0.006）。任何 irAE 和无任何 irAE 的中位 OS 分别为 39 个月和 23 个月（风险比[HR]，0.46；p=0.001），而≥3 级 irAE 和无≥3 级 irAE 的中位 OS 分别为未达到和 29 个月。多变量分析显示，乳酸脱氢酶升高与 OS 降低相关（HR，2.34；p=0.001），而接受的每增加一个周期的治疗（HR，0.94；p<0.001）和发生≥3 级 irAE（HR，0.29，p=0.024）与 OS 延长显著相关。
结论
晚期黑色素瘤患者的抗 PD-1 相关≥3 级 irAE 与更好的患者结局相关，包括总生存期。
意义
先前的前瞻性随机临床试验表明，在发生特定不良事件的黑色素瘤患者中，反应率提高。目前在晚期黑色素瘤中进行的基于人群的真实世界研究报告了与抗程序性细胞死亡蛋白 1（PD-1）诱导的≥3 级免疫相关不良事件（irAE）和更好的患者结局之间的关联，包括总生存期。这些结果表明，irAE 可能是患者从 PD-1 靶向治疗中产生全身免疫反应的表现，这可能与治疗益处相关。irAE 与这些治疗的临床获益同时发生的发现表明，这些事件在很大程度上是不可避免的，因此，irAE 的关键管理对于优化患者结局仍然至关重要。
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