Department of Endocrinology, Royal North Shore Hospital, NSW 2065, Sydney, Australia.
Northern Clinical School, Faculty of Medicine and Health, University of Sydney, NSW 2006, Australia.
J Clin Endocrinol Metab. 2022 Aug 18;107(9):e3824-e3829. doi: 10.1210/clinem/dgac337.
Metastatic medullary thyroid carcinoma (MTC) and radioactive iodine-refractory differentiated thyroid carcinoma (RAI-R DTC) have poor prognosis and limited treatment options. Selpercatinib (LOXO-292), a selective kinase inhibitor targeting the RET gene, has shown a 69% to 79% objective response rate in this cohort with benefits in other tumors including lung cancer harboring the same oncogenic driver. Published reports describe only 17% of patients experiencing gastrointestinal (GI) adverse effects (AEs), which is in contrast to our local experience.
Here we characterize the AEs and correlate them with radiological and histopathological findings.
Sequential patients enrolled in LIBRETTO-001 at Royal North Shore Hospital, Sydney, Australia, with available imaging (n = 22) were recruited. Patients had regular visits with AEs documented and computed tomography (CT) scans every 3 months. CT at screening, at time of GI AE, and at most recent follow-up were reviewed and scored. Endoscopic examination was performed in 5 patients.
Of 22 patients in this cohort, the majority had somatic RET alterations (n = 18), most commonly p.Met918Thr (n = 14). Ten patients (50%) developed GI AEs. Dose reduction was required in 8 of the 10 patients, but none discontinued therapy. The majority had stable disease (n = 17). Gastric and small-bowel edema was evident in symptomatic patients after a median time of 67 weeks' treatment. Histological correlation in 5 patients revealed mucosal edema correlating with radiological evidence of congestion and edema.
GI AEs with selpercatinib may be more common than previously described. Most are self-limiting but often require dose adjustments. Histological evidence of mucosal edema observed in conjunction with the radiological findings of congestion and wall thickening suggest bowel-wall edema is a predominant mechanism of abdominal pain in these patients.
转移性甲状腺髓样癌（MTC）和放射性碘难治性分化型甲状腺癌（RAI-R DTC）预后较差，治疗选择有限。选择性激酶抑制剂 Selpercatinib（LOXO-292）针对 RET 基因，在这一人群中的客观缓解率为 69%至 79%，并且在包括携带相同致癌驱动因素的肺癌在内的其他肿瘤中也有获益。已发表的报告仅描述了 17%的患者出现胃肠道（GI）不良事件（AE），这与我们的本地经验形成对比。
本研究旨在描述 AE 并将其与影像学和组织病理学发现相关联。
在澳大利亚悉尼皇家北岸医院参与 LIBRETTO-001 研究且有可用影像学资料的连续患者（n=22）被招募。定期记录 AE 并每 3 个月进行 CT 扫描。对筛查时、出现 GI AE 时和最近一次随访时的 CT 进行回顾和评分。对 5 例患者进行了内镜检查。
在这组 22 例患者中，大多数患者存在体细胞 RET 改变（n=18），最常见的是 p.Met918Thr（n=14）。10 例患者（50%）出现 GI AE。10 例患者中有 8 例需要减少剂量，但没有患者停止治疗。大多数患者疾病稳定（n=17）。中位治疗时间为 67 周后，有症状的患者出现胃和小肠水肿。5 例患者的组织学相关性研究显示，黏膜水肿与影像学上充血和水肿的证据相关。
Selpercatinib 相关的 GI AE 可能比之前描述的更为常见。大多数是自限性的，但通常需要调整剂量。在观察到的黏膜水肿与影像学上的充血和壁增厚提示肠壁水肿是这些患者腹痛的主要机制的同时，也观察到了组织学证据。
