Department of Hematology and Oncology, KIM IV, Faculty of Medicine, University Halle-Wittenberg, Halle, Germany.
Department of Hematology and Oncology, University of Freiburg, Freiburg, Germany.
Thyroid. 2021 Jul;31(7):1076-1085. doi: 10.1089/thy.2020.0322. Epub 2021 Apr 15.
Anaplastic thyroid carcinoma (ATC) and metastatic poorly differentiated thyroid carcinomas (PDTCs) are rare aggressive malignancies with poor overall survival (OS) despite extensive multimodal therapy. These tumors are highly proliferative, with frequently increased tumor mutational burden (TMB) compared with differentiated thyroid carcinomas, and elevated programmed death ligand 1 (PD-L1) levels. These tumor properties implicate responsiveness to antiangiogenic and antiproliferative multikinase inhibitors such as lenvatinib, and immune checkpoint inhibitors such as pembrolizumab. In a retrospective study, we analyzed six patients with metastatic ATC and two patients with PDTC, who received a combination therapy of lenvatinib and pembrolizumab. Lenvatinib was started at 14-24 mg daily and combined with pembrolizumab at a fixed dose of 200 mg every three weeks. Maximum treatment duration with this combination was 40 months, and 3 of 6 ATC patients are still on therapy. Patient tumors were characterized by whole-exome sequencing and PD-L1 expression levels (tumor proportion score [TPS] 1-90%). Best overall response (BOR) within ATCs was 66% complete remissions (4/6 CR), 16% stable disease (1/6 SD), and 16% progressive disease (1/6 PD). BOR within PDTCs was partial remission (PR 2/2). The median progression-free survival was 17.75 months for all patients, and 16.5 months for ATCs, with treatment durations ranging from 1 to 40 months (1, 4, 11, 15, 19, 25, 27, and 40 months). Grade III/IV toxicities developed in 4 of 8 patients, requiring dose reduction/discontinuation of lenvatinib. The median OS was 18.5 months, with three ATC patients being still alive without relapse (40, 27, and 19 months) despite metastatic disease at the time of treatment initiation (UICC and stage IVC). All patients with long-term (>2 years) or complete responses (CRs) had either increased TMB or a PD-L1 TPS >50%. Our results implicate that the combination of lenvatinib and pembrolizumab might be safe and effective in patients with ATC/PDTC and can result in complete and long-term remissions. The combination treatment is now being systematically examined in a phase II clinical trial (Anaplastic Thyroid Carcinoma Lenvatinib Pembrolizumab [ATLEP]) in ATC/PDTC patients.
间变性甲状腺癌（ATC）和转移性低分化甲状腺癌（PDTC）是罕见的侵袭性恶性肿瘤，尽管采用了广泛的多模式治疗，但总体生存率（OS）仍然很差。这些肿瘤具有高度增殖性，与分化型甲状腺癌相比，肿瘤突变负担（TMB）经常增加，程序性死亡配体 1（PD-L1）水平升高。这些肿瘤特性提示对血管生成和抗增殖多激酶抑制剂（如仑伐替尼）以及免疫检查点抑制剂（如 pembrolizumab）有反应。在一项回顾性研究中，我们分析了 6 例转移性 ATC 和 2 例 PDTC 患者，他们接受了仑伐替尼和 pembrolizumab 的联合治疗。仑伐替尼起始剂量为 14-24mg/天，并与固定剂量的 pembrolizumab（每 3 周 200mg）联合使用。该联合治疗的最大治疗持续时间为 40 个月，6 例 ATC 患者中有 3 例仍在接受治疗。患者肿瘤通过全外显子组测序和 PD-L1 表达水平（肿瘤比例评分[TPS]1-90%）进行特征描述。在 ATC 中，最佳总体缓解（BOR）为 66%完全缓解（4/6 CR）、16%疾病稳定（1/6 SD）和 16%疾病进展（1/6 PD）。PDTC 中的 BOR 为部分缓解（PR 2/2）。所有患者的中位无进展生存期为 17.75 个月，ATC 为 16.5 个月，治疗持续时间为 1-40 个月（1、4、11、15、19、25、27 和 40 个月）。8 例患者中有 4 例发生 3/4 级毒性反应，需要减少仑伐替尼剂量或停药。中位总生存期为 18.5 个月，3 例 ATC 患者在治疗开始时（UICC 和 IVC 期）已有转移性疾病，但仍无复发（40、27 和 19 个月）。所有长期（>2 年）或完全缓解（CR）的患者均有 TMB 增加或 PD-L1 TPS>50%。我们的结果提示，仑伐替尼和 pembrolizumab 的联合治疗在 ATC/PDTC 患者中可能是安全有效的，并可导致完全和长期缓解。该联合治疗目前正在 ATC/PDTC 患者中进行一项 II 期临床试验（Anaplastic Thyroid Carcinoma Lenvatinib Pembrolizumab [ATLEP]）中进行系统检查。
Front Endocrinol (Lausanne). 2021
Thyroid. 2017-5-31
J Immunother Cancer. 2018-7-11
Front Endocrinol (Lausanne). 2020
Front Endocrinol (Lausanne). 2024
Gan To Kagaku Ryoho. 2017-8
JCEM Case Rep. 2025-7-28
Front Endocrinol (Lausanne). 2025-6-10
Eur Thyroid J. 2025-7-7
Front Oncol. 2025-5-23
Mol Clin Oncol. 2020-2
Endocr Pract. 2019-3
JCI Insight. 2019-3-21
Zotero 插件