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先前基于抗血管生成酪氨酸激酶抑制剂的治疗作为转移性肾细胞癌患者中纳武单抗介导的复发性甲状腺疾病不良事件的潜在诱发因素:病例系列

Prior Anti-Angiogenic TKI-Based Treatment as Potential Predisposing Factor to Nivolumab-Mediated Recurrent Thyroid Disorder Adverse Events in mRCC Patients: A Case Series.

作者信息

Liguori Luigi, Luciano Angelo, Polcaro Giovanna, Ottaiano Alessandro, Cascella Marco, Perri Francesco, Pepe Stefano, Sabbatino Francesco

机构信息

Oncology Unit, Department of Clinical Medicine and Surgery, University of Naples "Federico II", 80131 Naples, Italy.

Oncology Unit, Department of Medicine, Surgery and Dentistry, University of Salerno, 84081 Baronissi, Italy.

出版信息

Biomedicines. 2023 Nov 4;11(11):2974. doi: 10.3390/biomedicines11112974.

Abstract

Immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1) or its ligand 1 (PD-L1) have revolutionized the management of many types of solid tumors, including metastatic renal cell carcinoma (mRCC). Both sequential and combinatorial therapeutic strategies utilizing anti-PD-1 monoclonal antibodies (mAbs) and anti-angiogenic tyrosine kinase inhibitors (TKIs) have demonstrated to improve the survival of patients with mRCC as compared to standard therapies. On the other hand, both ICIs and TKIs are well known to potentially cause thyroid disorder adverse events (TDAEs). However, in the context of sequential therapeutic strategy, it is not clear whether prior anti-angiogenic TKI may increase the risk and/or the severity of ICI-related TDAEs. In this work, by describing and analyzing a case series of mRCC patients treated sequentially with prior TKIs and then with ICIs, we investigated the role of prior anti-angiogenic TKI-based treatment as a potential predisposing factor to anti-PD-1-mediated recurrent TDAEs, as well as its potential impact on the clinical characteristics of nivolumab-mediated recurrent TDAEs. Fifty mRCC patients were included in the analysis. TKI-mediated TDAEs were reported in ten out of fifty patients. TKI-mediated TDAEs were characterized by hypothyroidism in all ten patients. Specifically, 40%, 40% and 20% of patients presented grade 1, 2 and 3 hypothyroidisms, respectively. Following tumor progression and during anti-PD-1 nivolumab treatment, five out of ten patients developed anti-PD-1 nivolumab-mediated recurrent TDAEs. Anti-PD-1 nivolumab-mediated recurrent TDAEs were characterized by an early transient phase of thyrotoxicosis and a late phase of hypothyroidism in all five patients. The TDAEs were grade 1 and 2 in four and one patients, respectively. Prior anti-angiogenic TKI did not modify the clinical characteristics of nivolumab-mediated recurrent TDAEs. However, all five patients required an increased dosage of levothyroxine replacement therapy. In conclusion, our work suggests that prior anti-angiogenic TKI-based treatment significantly increases the risk of ICI-mediated recurrent TDAEs in patients with mRCC without modifying their clinical characteristics. The most relevant effect for these patients is the need to increase the dosage of lifelong levothyroxine replacement therapy.

摘要

靶向程序性细胞死亡蛋白1(PD-1)或其配体1(PD-L1)的免疫检查点抑制剂(ICI)彻底改变了包括转移性肾细胞癌(mRCC)在内的多种实体瘤的治疗方式。与标准疗法相比,使用抗PD-1单克隆抗体(mAb)和抗血管生成酪氨酸激酶抑制剂(TKI)的序贯和联合治疗策略均已证明可提高mRCC患者的生存率。另一方面,众所周知,ICI和TKI都可能导致甲状腺疾病不良事件(TDAE)。然而,在序贯治疗策略的背景下,尚不清楚先前使用的抗血管生成TKI是否会增加ICI相关TDAE的风险和/或严重程度。在这项研究中,通过描述和分析一系列先接受TKI治疗然后接受ICI治疗的mRCC患者病例,我们研究了先前基于抗血管生成TKI的治疗作为抗PD-1介导的复发性TDAE潜在诱发因素的作用,以及其对纳武单抗介导的复发性TDAE临床特征的潜在影响。分析纳入了50例mRCC患者。50例患者中有10例报告了TKI介导的TDAE。所有10例患者的TKI介导的TDAE均表现为甲状腺功能减退。具体而言,分别有40%、40%和20%的患者出现1级、2级和3级甲状腺功能减退。在肿瘤进展后以及抗PD-纳武单抗治疗期间,10例患者中有5例出现了抗PD-1纳武单抗介导的复发性TDAE。所有5例患者的抗PD-1纳武单抗介导的复发性TDAE均表现为早期短暂的甲状腺毒症期和晚期甲状腺功能减退期。TDAE在4例和1例患者中分别为1级和2级。先前的抗血管生成TKI并未改变纳武单抗介导的复发性TDAE的临床特征。然而,所有5例患者都需要增加左甲状腺素替代治疗的剂量。总之,我们的研究表明,先前基于抗血管生成TKI 的治疗显著增加了mRCC患者中ICI介导的复发性TDAE的风险,而未改变其临床特征。对这些患者最相关的影响是需要增加终身左甲状腺素替代治疗的剂量。

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