Anti-PD1-Induced Immune-Related Adverse Events and Survival Outcomes in Advanced Melanoma
Anti-PD1-Induced Immune-Related Adverse Events and Survival Outcomes in Advanced Melanoma
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DOI：
10.1634/theoncologist.2019-0674
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发表时间：
2020-02-12
期刊：
影响因子：
5.8
通讯作者：
Cheng, Tina
中科院分区：
文献类型：
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作者：
Suo, Aleksi;Chan, Yin;Cheng, Tina
引言客观反应率（ORR）似乎是更高的黑色素瘤患者谁发展免疫相关的不良事件（irAE），但是否有一个类似的关联irAE和survival.Materials和方法与晚期黑色素瘤患者治疗单药派姆单抗或纳武单抗在阿尔伯塔省从2014年6月至2017年5月通过省级药房数据库进行了确定。图表审查确定并分类了在抗程序性细胞死亡蛋白1（PD-1）检查点抑制剂治疗期间发生的所有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）。结果在186例患者中，88例（47%）和27例（15%）患者分别发生了任何级别和≥ 3级的irAE; 1例患者死于肺炎。在排除前12周内死亡的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，发生irAE的患者为26个月（p = .006）。任何irAE和无irAE的中位OS分别为39个月和23个月（风险比[HR]，0.46; p = .001），未达到的中位OS分别为≥ 3级irAE和无≥ 3级irAE的中位OS为29个月。在多变量分析中，乳酸脱氢酶升高与OS降低相关（HR，2.34; p = .001），而每增加一个治疗周期，（HR，0.94; p < .001）和≥ 3级irAE的发生（HR，0.29，p = 0.024）与较长OS显著相关。结论在晚期黑色素瘤患者中，抗PD-1相关等级>= 3的irAE与较好的患者结局相关，包括总生存期。实践的意义以前的前瞻性随机临床试验表明，在发生选择性不良事件的黑色素瘤患者中，反应率有所提高。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）与更好的患者结局（包括总生存期）之间的相关性。这些结果表明，irAE可能是患者通过PD-1导向治疗产生全身免疫应答的能力的表现，这可能与治疗获益相关。irAE的发现与这些治疗的临床获益一致，这意味着这些事件基本上是不可避免的，irAE的关键管理对于优化患者结局至关重要。
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.