从 FUZE 多中心、开放标签、II 期篮子试验中评估 Debio 1347 在表皮生长因子受体融合阳性晚期实体瘤患者中的应用。

IF 10 1区 医学 Q1 ONCOLOGY Clinical Cancer Research Pub Date : 2024-10-15 DOI:10.1158/1078-0432.CCR-24-0012
Petros Grivas, Elena Garralda, Funda Meric-Bernstam, Ingo K Mellinghoff, Lipika Goyal, James J Harding, E Claire Dees, Rastislav Bahleda, Nilofer S Azad, Asha Karippot, Razelle Kurzrock, Josep Tabernero, Juha Kononen, Matthew C H Ng, Rutika Mehta, Nataliya V Uboha, Frédéric Bigot, Valentina Boni, Samantha E Bowyer, Valeriy Breder, Andrés Cervantes, Nancy Chan, James M Cleary, Mallika Dhawan, Rikke L Eefsen, James Ewing, Donna M Graham, Tormod K Guren, Jin Won Kim, Krassimir Koynov, Do-Youn Oh, Rebecca Redman, Chia-Jui Yen, David Spetzler, Marie-Claude Roubaudi-Fraschini, Valerie Nicolas-Metral, Rafik Ait-Sarkouh, Claudio Zanna, Abdallah Ennaji, Anna Pokorska-Bocci, Keith T Flaherty
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引用次数: 0

摘要

目的:这项多中心II期篮子试验研究了Debio 1347的疗效、安全性和药代动力学,Debio 1347是一种口服、高选择性、ATP竞争性、小分子FGFR1-3抑制剂,适用于携带功能性FGFR1-3融合的实体瘤患者:符合条件的成人患者均曾接受过局部晚期(不可切除)或转移性胆道癌(群组 1)、尿路癌(群组 2)或其他组织学类型癌症(群组 3)的治疗。Debio 1347的用药剂量为80毫克,每天一次,连续用药28天为一个周期。主要终点是客观反应率(ORR)。次要终点包括应答持续时间、无进展生存期、总生存期、药代动力学和不良事件发生率:2019年3月22日至2020年1月8日期间,63名患者入组并接受治疗,其中队列1中有30名患者,队列2中有4名患者,队列3中有29名患者。一项计划外的初步统计审查显示,Debio 1347 的疗效低于预期,因此终止了试验。在58名可评估的患者中,有3名患者出现部分反应,ORR为5%,另有26名患者(45%)病情稳定(病程≥6周)。63名患者中有22名(35%)发生了≥3级的治疗相关不良反应,其中最常见的是高磷血症(13%)和口腔炎(5%)。两名患者(3%)因不良反应停止了治疗:结论:Debio 1347的毒性可控,但对FGFR融合肿瘤患者的疗效并不支持在这种情况下进行进一步的临床评估。我们基于转录组学的分析详细描述了FGFR融合在实体瘤中的发生率和性质。
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Evaluating Debio 1347 in Patients with FGFR Fusion-Positive Advanced Solid Tumors from the FUZE Multicenter, Open-Label, Phase II Basket Trial.

Purpose: This multicenter phase II basket trial investigated the efficacy, safety, and pharmacokinetics of Debio 1347, an investigational, oral, highly selective, ATP-competitive, small molecule inhibitor of FGFR1-3, in patients with solid tumors harboring a functional FGFR1-3 fusion.

Patients and methods: Eligible adults had a previously treated locally advanced (unresectable) or metastatic biliary tract (cohort 1), urothelial (cohort 2), or another histologic cancer type (cohort 3). Debio 1347 was administered at 80 mg once daily, continuously, in 28-day cycles. The primary endpoint was the objective response rate. Secondary endpoints included duration of response, progression-free survival, overall survival, pharmacokinetics, and incidence of adverse events.

Results: Between March 22, 2019, and January 8, 2020, 63 patients were enrolled and treated, 30 in cohort 1, 4 in cohort 2, and 29 in cohort 3. An unplanned preliminary statistical review showed that the efficacy of Debio 1347 was lower than predicted, and the trial was terminated. In total, 3 of 58 evaluable patients had partial responses, representing an objective response rate of 5%, with a further 26 (45%) having stable disease (≥6 weeks duration). Grade ≥3 treatment-related adverse events occurred in 22 (35%) of 63 patients, with the most common being hyperphosphatemia (13%) and stomatitis (5%). Two patients (3%) discontinued treatment due to adverse events.

Conclusions: Debio 1347 had manageable toxicity; however, the efficacy in patients with tumors harboring FGFR fusions did not support further clinical evaluation in this setting. Our transcriptomic-based analysis characterized in detail the incidence and nature of FGFR fusions across solid tumors. See related commentary by Hage Chehade et al., p. 4549.

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来源期刊
Clinical Cancer Research
Clinical Cancer Research 医学-肿瘤学
CiteScore
20.10
自引率
1.70%
发文量
1207
审稿时长
2.1 months
期刊介绍: Clinical Cancer Research is a journal focusing on groundbreaking research in cancer, specifically in the areas where the laboratory and the clinic intersect. Our primary interest lies in clinical trials that investigate novel treatments, accompanied by research on pharmacology, molecular alterations, and biomarkers that can predict response or resistance to these treatments. Furthermore, we prioritize laboratory and animal studies that explore new drugs and targeted agents with the potential to advance to clinical trials. We also encourage research on targetable mechanisms of cancer development, progression, and metastasis.
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