Medical Oncology Department, Institut de Cancérologie Gustave Roussy, Université Paris-Saclay, Villejuif, France.
Genitourinary Oncology, Yale School of Medicine, New Haven.
Ann Oncol. 2024 Apr;35(4):392-401. doi: 10.1016/j.annonc.2024.01.002. Epub 2024 Jan 18.
BACKGROUND: Sacituzumab govitecan (SG) is a Trop-2-directed antibody-drug conjugate containing cytotoxic SN-38, the active metabolite of irinotecan. SG received accelerated US Food and Drug Administration approval for locally advanced (LA) or metastatic urothelial carcinoma (mUC) previously treated with platinum-based chemotherapy and a checkpoint inhibitor, based on cohort 1 of the TROPHY-U-01 study. Mutations in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene are associated with increased adverse events (AEs) with irinotecan-based therapies. Whether UGT1A1 status could impact SG toxicity and efficacy remains unclear. PATIENTS AND METHODS: TROPHY-U-01 (NCT03547973) is a multicohort, open-label, phase II registrational study. Cohort 1 includes patients with LA or mUC who progressed after platinum- and checkpoint inhibitor-based therapies. SG was administered at 10 mg/kg intravenously on days 1 and 8 of 21-day cycles. The primary endpoint was objective response rate (ORR) per central review; secondary endpoints included progression-free survival, overall survival, and safety. Post hoc safety analyses were exploratory with descriptive statistics. Updated analyses include longer follow-up. RESULTS: Cohort 1 included 113 patients. At a median follow-up of 10.5 months, ORR was 28% (95% CI 20.2% to 37.6%). Median progression-free survival and overall survival were 5.4 months (95% CI 3.5-6.9 months) and 10.9 months (95% CI 8.9-13.8 months), respectively. Occurrence of grade ≥3 treatment-related AEs and treatment-related discontinuation were consistent with prior reports. UGT1A1 status was wildtype (∗1|∗1) in 40%, heterozygous (∗1|∗28) in 42%, homozygous (∗28|∗28) in 12%, and missing in 6% of patients. In patients with ∗1|∗1, ∗1|∗28, and ∗28|∗28 genotypes, any grade treatment-related AEs occurred in 93%, 94%, and 100% of patients, respectively, and were managed similarly regardless of UGT1A1 status. CONCLUSIONS: With longer follow-up, the ORR remains high in patients with heavily pretreated LA or mUC. Safety data were consistent with the known SG toxicity profile. AE incidence varied across UGT1A1 subgroups; however, discontinuation rates remained relatively low for all groups.
背景：Sacituzumab govitecan（SG）是一种 Trop-2 定向抗体药物偶联物，含有细胞毒性 SN-38，是伊立替康的活性代谢物。SG 在美国食品和药物管理局（FDA）加速批准用于先前接受过铂类化疗和检查点抑制剂治疗的局部晚期（LA）或转移性尿路上皮癌（mUC），这基于 TROPHY-U-01 研究的队列 1。尿苷二磷酸葡萄糖醛酸基转移酶 1A1（UGT1A1）基因的突变与伊立替康为基础的治疗相关的不良反应（AE）增加有关。UGT1A1 状态是否会影响 SG 的毒性和疗效尚不清楚。 患者和方法：TROPHY-U-01（NCT03547973）是一项多队列、开放标签、II 期注册研究。队列 1包括铂类和检查点抑制剂治疗后进展的 LA 或 mUC 患者。SG 以 10mg/kg 剂量静脉注射，每 21 天为一个周期，第 1 天和第 8 天给药。主要终点为中心评估的客观缓解率（ORR）；次要终点包括无进展生存期、总生存期和安全性。事后安全性分析是探索性的，采用描述性统计。更新分析包括更长的随访。 结果：队列 1纳入了 113 名患者。在中位随访 10.5 个月时，ORR 为 28%（95%CI 20.2%至 37.6%）。中位无进展生存期和总生存期分别为 5.4 个月（95%CI 3.5-6.9 个月）和 10.9 个月（95%CI 8.9-13.8 个月）。≥3 级治疗相关不良事件和治疗相关停药的发生与既往报告一致。UGT1A1 状态为野生型（∗1|∗1）占 40%，杂合型（∗1|∗28）占 42%，纯合型（∗28|∗28）占 12%，缺失型占 6%。在∗1|∗1、∗1|∗28 和∗28|∗28 基因型的患者中，任何级别治疗相关 AE 分别发生在 93%、94%和 100%的患者中，无论 UGT1A1 状态如何，AE 的管理均相似。 结论：在接受过大量预处理的 LA 或 mUC 患者中，随着随访时间的延长，ORR 仍然较高。安全性数据与已知的 SG 毒性特征一致。AE 发生率在 UGT1A1 亚组之间存在差异；然而，所有组的停药率仍然相对较低。
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