Department of Hematology Oncology, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
Department of Hematology Oncology, UTMDACC, Houston, Texas, USA.
ESMO Open. 2020 Oct;5(5):e000799. doi: 10.1136/esmoopen-2020-000799.
The receptor tyrosine kinase rearranged during transfection (RET) can be oncogenically activated by gene fusions or point mutations. Multikinase inhibitors such as cabozantinib, lenvatinib and vandetanib have demonstrated activity in RET-dependent malignancies, and selective RET inhibitors (Selpercatinib and Pralsetinib) are in clinical trials. However, the responsiveness of RET-dependent malignancies to immune checkpoint inhibitors (ICIs) is unknown. We compared the time to treatment discontinuation (TTD) for ICI versus non-ICI therapy in patients with malignancies harbouring activating RET mutations or fusions (RET+).
A retrospective review of all RET+ patients who were referred to the phase I clinical trials programme at the University of Texas MD Anderson Cancer Center was conducted. TTD was estimated using Kaplan-Meier analysis. Multivariate analysis using the Cox proportional hazard model was performed to identify independent risk factors of treatment discontinuation.
Of 70 patients who received systemic therapy for RET+ malignancies, 20 (28.6%) received ICI and 50 (71.4%) received non-ICI therapy. Non-ICI therapy was associated with decreased risk for treatment discontinuation compared with ICI in the overall population (HR=0.31; 95% CI 0.16-0.62; p=0.000834) and in patients with RET point mutations (HR=0.13; 95% CI 0.04-0.45; p=0.00134). In patients with RET fusions, non-ICI therapy was associated with a non-statistically significant decreased risk of treatment discontinuation (HR=0.59; 95% CI 0.25-1.4; p=0.24). ICI therapy and a diagnosis other than medullary thyroid cancer (MTC) were independent risk factors for treatment discontinuation.
Our study supports the prioritisation of non-ICI over ICI therapy in patients with RET+ tumours.
受体酪氨酸激酶重排在转染过程中（RET）可通过基因融合或点突变致癌激活。多激酶抑制剂，如卡博替尼、仑伐替尼和凡德他尼，已在依赖 RET 的恶性肿瘤中显示出活性，而选择性 RET 抑制剂（Selpercatinib 和 Pralsetinib）正在临床试验中。然而，依赖 RET 的恶性肿瘤对免疫检查点抑制剂（ICIs）的反应尚不清楚。我们比较了在携带激活的 RET 突变或融合（RET+）的恶性肿瘤患者中，ICI 与非 ICI 治疗的治疗终止时间（TTD）。
对在德克萨斯大学 MD 安德森癌症中心进行的 I 期临床试验计划中被转诊的所有携带 RET+的患者进行了回顾性审查。使用 Kaplan-Meier 分析估计 TTD。使用 Cox 比例风险模型进行多变量分析，以确定治疗终止的独立危险因素。
在 70 名接受 RET+恶性肿瘤系统治疗的患者中，20 名（28.6%）接受了 ICI，50 名（71.4%）接受了非 ICI 治疗。与 ICI 相比，非 ICI 治疗与总体人群（HR=0.31；95%CI 0.16-0.62；p=0.000834）和 RET 点突变患者（HR=0.13；95%CI 0.04-0.45；p=0.00134）的治疗终止风险降低相关。在 RET 融合患者中，非 ICI 治疗与治疗终止风险降低相关，但无统计学意义（HR=0.59；95%CI 0.25-1.4；p=0.24）。ICI 治疗和非甲状腺髓样癌（MTC）诊断是治疗终止的独立危险因素。
我们的研究支持在携带 RET+肿瘤的患者中优先考虑非 ICI 治疗而非 ICI 治疗。
