Overt Thyroid Dysfunction and Anti-Thyroid Antibodies Predict Response to Anti-PD-1 Immunotherapy in Cancer Patients
Overt Thyroid Dysfunction and Anti-Thyroid Antibodies Predict Response to Anti-PD-1 Immunotherapy in Cancer Patients
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DOI：
10.1089/thy.2019.0726
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发表时间：
2020-04-23
期刊：
影响因子：
6.6
通讯作者：
Medici, Marco
中科院分区：
文献类型：
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作者：
Basak, Edwin A.;van der Meer, Jan W. M.;Medici, Marco
背景：甲状腺功能障碍是抗程序性细胞死亡1 （PD-1）免疫治疗中最常见的不良反应之一，除了与抗甲状腺抗体（ATAb）升高相关外，研究还发现与生存相关。然而，确切的关系仍有待澄清。因此，我们旨在阐明抗pd -1治疗的癌症患者甲状腺功能障碍、ATAbs和生存之间的关系。方法：我们纳入了168例接受纳武单抗或派姆单抗治疗的非小细胞肺癌、肾细胞癌和转移性黑色素瘤患者。每次抗pd -1输注前检测促甲状腺素和游离T4 （fT4）水平。在基线和治疗两个月后测量ATAb水平（抗甲状腺过氧化物酶[TPO]和抗甲状腺球蛋白[Tg]）。虽然绝大多数患者的ATABs水平可检测到，但只有少数患者在使用常规切断时ATABs呈阳性。为了研究可检测到的ATABs的后果，将截止水平先验地设定为研究人群基线时的中位数浓度。肿瘤进展按照RECIST v1.1分级。结果：治疗期间获得明显甲状腺功能障碍患者的总生存期（OS）（风险比[HR] = 0.18，可信区间[CI: 0.04-0.76]; p = 0.020）和无进展生存期（PFS） （HR = 0.39 [0.15-0.998]; p = 0.050）明显高于无甲状腺功能障碍患者，1年OS率为94%比59%，1年PFS率为64%比34%。在治疗期间，ATAb水平高于中位数的患者的OS （HR = 0.39 [0.21-0.72]; p = 0.003）和PFS （HR = 0.52 [0.33-0.81]; p = 0.004）高于ATAb水平低于中位数的患者，1年OS率分别为83%对49%，PFS率为54%对20%。当分析ATAb水平随时间的变化时，与持续ATAb水平低于中位数的患者相比，持续ATAb水平高于中位数的患者具有更高的OS （HR = 0.41 [0.19-0.89], p = 0.025）和PFS （HR = 0.54 [0.31-0.95], p = 0.032）。与ATAb水平低于中位数的患者相比，治疗期间ATAb水平高于中位数的患者的OS （HR = 0.27 [0.06-1.22], p = 0.088）和PFS （HR = 0.24 [0.07-0.77], p = 0.017）均有改善。结论：抗pd -1治疗期间获得的明显甲状腺毒性和高于中位ATAb水平与PFS和OS的改善相关。此外，我们的研究结果表明，基线ATAb水平与PFS和OS具有临床相关性。
Background: Thyroid dysfunction is among the most common adverse effects during anti-programmed cell death 1 (PD-1) immunotherapy, and alongside correlations with elevated anti-thyroid antibodies (ATAb), studies have found correlations with survival. However, the exact relations remain to be clarified. We, therefore, aimed at clarifying the relationship between thyroid dysfunction, ATAbs, and survival in anti-PD-1 treated cancer patients.Methods: We included 168 patients with nonsmall-cell lung carcinoma, renal cell carcinoma, and metastatic melanoma treated with nivolumab or pembrolizumab. Thyrotropin and free T4 (fT4) levels were measured before each anti-PD-1 infusion. ATAb levels (anti-thyroid peroxidase [TPO] and anti-thyroglobulin [Tg]) were measured at baseline and after two months of treatment. Although the vast majority of patients had detectable levels of ATABs, only a few patients had positive ATAbs when using conventional cut-offs. To study the consequences of detectable ATABs, the cut-off levels were a priori set at the median concentrations at baseline in the study population. Tumor progression was classified according to RECIST v1.1.Results: Patients who acquired overt thyroid dysfunction during treatment had significantly higher overall survival (OS) (hazard ratio [HR] = 0.18 confidence interval [CI: 0.04-0.76]; p = 0.020) and progression-free survival (PFS) (HR = 0.39 [0.15-0.998]; p = 0.050) than patients without thyroid dysfunction with 1-year OS rates of 94% vs. 59% and 1-year PFS rates of 64% vs. 34%. During treatment, patients with ATAb levels above the median had a higher OS (HR = 0.39 [0.21-0.72]; p = 0.003) and PFS (HR = 0.52 [0.33-0.81]; p = 0.004) than patients with ATAb levels below the median, with 1-year OS rates of 83% vs. 49% and PFS rates of 54% vs. 20%, respectively. When analyzing ATAb levels over time, patients with a persistent ATAb level above the median had a higher OS (HR = 0.41 [0.19-0.89], p = 0.025) and PFS (HR = 0.54 [0.31-0.95], p = 0.032) compared with patients with a persistent ATAb level below the median. Patients whose ATAb levels increased above the median during treatment had an improved OS (HR = 0.27 [0.06-1.22], p = 0.088) and PFS (HR = 0.24 [0.07-0.77], p = 0.017) compared with patients whose ATAb levels decreased below the median.Conclusions: Acquired overt thyroid toxicity and above median ATAb levels during anti-PD-1 treatment are associated with improved PFS and OS. In addition, our results suggest that ATAb levels at baseline are of clinical relevance for PFS and OS.