Sehgal Kartik, Pappa Theodora, Shin Kee-Young, Schiantarelli Julia, Liu Mofei, Ricker Cora, Besson Naomi R, Jones Stephanie M, Welsh Emma L, Pfaff Kathleen L, Barletta Justine A, Park Jihye, Reardon Brendan, Doherty Gerard M, Alexander Erik K, Rodig Scott J, Barbie David A, O'Neill Anne, Van Allen Eliezer, Haddad Robert I, Lorch Jochen H
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Thyroid Cancer Center, Dana-Farber Cancer Institute, Boston, Massachusetts.
JAMA Oncol. 2024 Dec 1;10(12):1663-1671. doi: 10.1001/jamaoncol.2024.4019.
Aggressive 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.
To 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 PARTICIPANTS: This 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.
Intravenous 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.
The 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.
A 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.
This 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.
ClinicalTrials.gov Identifier: NCT03246958.
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）、髓样甲状腺癌（MTC）和间变性甲状腺癌（ATC），与显著的发病率和死亡率相关，且治疗选择有限。已在甲状腺癌亚型中鉴定出不同的免疫特征，提示它们可能对免疫检查点抑制敏感。
评估抗程序性细胞死亡蛋白1纳武单抗和抗细胞毒性淋巴细胞相关蛋白4伊匹单抗在侵袭性甲状腺癌患者中的疗效。
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月在单一中心纳入RAIR DTC患者，并在MTC和ATC中设立探索性队列。于2021年6月至2023年9月对数据进行分析。
静脉注射纳武单抗，3mg/kg，每2周一次；伊匹单抗，1mg/kg，每6周一次，直至疾病进展、出现无法耐受的不良事件或最长持续2年。
该研究的主要终点是RAIR DTC中的客观缓解率（ORR），根据实体瘤疗效评价标准（RECIST）1.1版进行评分。关键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。
共登记51例患者，49例患者可进行分析。中位（范围）年龄为65岁（30 - 88岁），25名参与者（51%）为女性。DTC队列中的ORR为9.4%（3/32 [95% CI，2.8% - 28.5%]），所有部分缓解均出现在嗜酸细胞癌（2/6 [33.0%]）或低分化甲状腺癌（1/5 [20.0%]）中。整个DTC队列的临床获益率为62.5%（20/32），其中嗜酸细胞癌为83.3%（5/6），低分化甲状腺癌为40%（2/5）。探索性ATC队列中的ORR为30.0%（3/10 [95% CI，6.7% - 65.2%]），临床获益率为50.0%（5/10）。探索性MTC队列中未观察到缓解。安全性概况与先前关于双重免疫检查点抑制的报告相似（瘙痒、皮疹、腹泻、疲劳以及脂肪酶和肝酶升高）。NRAS肿瘤基因序列变异的存在而非BRAF V600E与较差的结局相关。
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的主要人群中未达到其终点，不支持在未进行生物标志物选择的DTC中进行进一步研究。然而，在ATC中观察到的信号可能值得进一步评估。
ClinicalTrials.gov标识符：NCT03246958。
