ImportanceAggressive thyroid carcinoma, including radioiodine refractory (RAIR) differentiated thyroid carcinoma (DTC), medullary thyroid carcinoma (MTC), and anaplastic thyroid carcinoma (ATC), are associated with significant morbidity and mortality and have limited therapeutic options. Distinct immune profiles have been identified in thyroid cancer subtypes suggesting they may be susceptible to immune checkpoint inhibition.ObjectiveTo evaluate the efficacy of anti–programmed cell death 1 nivolumab and anti–cytotoxic lymphocyte–associated protein 4 ipilimumab in patients with aggressive thyroid carcinoma.Design, Setting, and ParticipantsThis phase 2 nonrandomized clinical trial enrolled patients with RAIR DTC in a single center from October 2017 to May 2019, with exploratory cohorts in MTC and ATC. The data were analyzed between June 2021 and September 2023.InterventionIntravenous nivolumab, 3 mg/kg, every 2 weeks and ipilimumab, 1 mg/kg, every 6 weeks until disease progression, intolerable adverse events, or a maximum duration of 2 years.Main Outcomes and MeasuresThe primary end point of the study was objective response rate (ORR) in RAIR DTC, which was scored according to RECIST (Response Evaluation Criteria in Solid Tumours), version 1.1. Key secondary end points included safety, progression-free survival, overall survival, and biomarker analyses.ResultsA total of 51 patients were registered, and 49 patients were evaluable for analysis. The median (range) age was 65 years (30-88 years), and 25 participants (51%) were female. ORR in the DTC cohort was 9.4% (3/32 [95% CI, 2.8%-28.5%]), with all partial responses in either oncocytic carcinoma (2/6 [33.0%]) or poorly differentiated thyroid carcinoma (1/5 [20.0%]). Clinical benefit rates were 62.5% (20/32) in the overall DTC cohort, including 83.3% (5/6) in oncocytic carcinoma and 40% (2/5) in poorly differentiated thyroid carcinoma. ORR in the exploratory ATC cohort was 30.0% (3/10 [95% CI, 6.7%-65.2%]), with a clinical benefit rates of 50.0% (5/10). No responses were observed in the exploratory MTC cohort. The safety profile was similar to prior reports with dual immune checkpoint inhibition (pruritus, rash, diarrhea, fatigue, and elevation of lipase and liver enzymes). The presence of NRAS tumor genetic sequence variations, but not BRAF V600E, was associated with worse outcomes.Conclusions and RelevanceThis phase 2 nonrandomized clinical trial reported clinical activity of dual immune checkpoint inhibition in aggressive thyroid cancer. The study did not meet its end point in the primary population of RAIR DTC and does not support further investigation in non–biomarker-selected DTC. However, the signal observed in ATC may merit further evaluation.Trial RegistrationClinicalTrials.gov Identifier: NCT03246958

中文翻译：

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侵袭性甲状腺癌患者的双重免疫检查点抑制


重要性侵袭性甲状腺癌，包括放射性碘难治性 （RAIR） 分化型甲状腺癌 （DTC）、甲状腺髓样癌 （MTC） 和甲状腺间变性癌 （ATC），与显着的发病率和死亡率相关，并且治疗选择有限。在甲状腺癌亚型中已鉴定出不同的免疫特征，表明它们可能易受免疫检查点抑制。目的评价抗程序性细胞死亡 1 纳武利尤单抗和抗细胞毒性淋巴细胞相关蛋白 4 伊匹木单抗对侵袭性甲状腺癌患者的疗效。设计、设置和参与者这项 2 期非随机临床试验于 2017 年 10 月至 2019 年 5 月在一个中心招募了 RAIR DTC 患者，并在 MTC 和 ATC 中进行了探索性队列。干预静脉注射纳武利尤单抗，3 mg/kg，每 2 周一次，伊匹木单抗，1 mg/kg，每 6 周一次，直至疾病进展、无法耐受的不良事件或最长持续时间为 2 年。主要结局和措施该研究的主要终点是 RAIR DTC 的客观缓解率 （ORR），根据 RECIST（实体瘤反应评估标准）1.1 版进行评分。关键的次要终点包括安全性、无进展生存期、总生存期和生物标志物分析。结果共登记 51 例患者，其中 49 例患者可评估用于分析。中位 （范围） 年龄为 65 岁 （30-88 岁），25 名参与者 （51%） 为女性。DTC 队列的 ORR 为 9.4% （3/32 [95% CI， 2.8%-28.5%]），嗜酸细胞癌 （2/6 [33.0%]） 或低分化甲状腺癌 （1/5 [20.0%]） 全部部分缓解。临床获益率为 62。5% （20/32） 在整个 DTC 队列中，包括 83.3% （5/6） 的肿瘤细胞癌和 40% （2/5） 的低分化甲状腺癌。探索性 ATC 队列的 ORR 为 30.0% （3/10 [95% CI，6.7%-65.2%]），临床获益率为 50.0% （5/10）。在探索性 MTC 队列中未观察到反应。安全性特征与先前报道的双重免疫检查点抑制 （瘙痒、皮疹、腹泻、疲劳以及脂肪酶和肝酶升高） 相似。NRAS 肿瘤基因序列变异的存在，而不是 BRAF V600E 的存在，与较差的结果相关。结论和相关性这项 2 期非随机临床试验报告了双重免疫检查点抑制在侵袭性甲状腺癌中的临床活性。该研究在 RAIR DTC 的主要人群中没有达到终点，并且不支持对非生物标志物选择的 DTC 进行进一步调查。然而，在 ATC 中观察到的信号可能值得进一步评估。试验注册临床试验。gov 标识符： NCT03246958