PO.CT01.03 · 临床试验

ERY974 在磷脂酰肌醇蛋白聚糖-3（GPC-3）阳性晚期实体瘤患者中的 I 期研究

Phase I study of ERY974 in patients with glypican-3 (GPC-3)-positive advanced solid tumors

编号 CT197 展板 19 时间 4/21 09:00–12:00 区域 Section 50 主讲 Haruyasu Murakami, MD;PhD

分会场 Phase I Clinical Trials

查看 PDF 下载 PDF 🔒 查看 / 下载完整 PDF 需登录并开通下载套餐 · 查看套餐 / 开通 AACR 官方页面

作者与单位 Authors & Affiliations

Haruyasu Murakami¹, Hidetoshi Hayashi², Kensei Yamagushi³, Kei Muro⁴, Taroh Satoh⁵, Tomohiro Nishina⁶, Eisuke Ueda⁷, Chika Ogami⁷, Hitomi Takeshita⁷, Hayato Takahashi⁷, Mikiko Nakamura⁷, Mihiro Toba⁷, Yasutoshi Kuboki⁸

¹Shizuoka Cancer Center, Shizuoka, Japan,²Kindai University Hospital, Osakasayama City, Japan,³The Cancer Institute Hospital of JFCR, Koto City, Tokyo, Japan,⁴Aichi Cancer Center, Nagoya, Japan,⁵The University of Osaka Hospital, Osaka, Japan,⁶National Hospital Organization Shikoku Cancer Center, Shizuoka, Japan,⁷Chugai Pharmaceutical Co. Ltd., Tokyo, Japan,⁸National Cancer Center Hospital East, Chiba, Japan

摘要 Abstract

中文摘要

背景：ERY974 是一种靶向 GPC3 和 CD3 的双特异性抗体，可将 T 细胞重定向至 GPC3+ 肿瘤以增强免疫反应。GPC3 在实体瘤中高表达，在正常组织中极少存在，使其成为一个有前景的靶点。ERY102JP（I 期）评估了 ERY974 在 GPC3+ 晚期/复发性实体瘤患者（pts）中的应用。一项先前研究显示，由于细胞因子释放综合征（CRS），在剂量 ≥0.81 μg/kg 时耐受性有限，促使对预防性策略进行研究。方法：合格患者的肿瘤 GPC3 表达 ≥1%。患者每周一次（QW）经静脉给予 ERY974（0.12-4.0 μg/kg；剂量递增设计）。在 ERY974 之前给予 Tocilizumab（toc），一种 IL-6 受体拮抗剂（所有队列），以缓解 CRS。添加了类固醇（队列 5-10）和递增给药（SUD；队列 6-10）以减少 CRS 和肝毒性。终点包括安全性、PK 和抗肿瘤活性（RECIST 1.1）。结果：38 例患者跨 10 个队列入组。61%（23/38）的患者发生 ≥3 级不良事件（AE）；37%（14/38）出现 ALT 升高，24%（9/38）出现 AST 升高。剂量限制性毒性发生于 0.80 μg/kg QW 队列 3 例中的 1 例、0.80 μg/kg QW + 类固醇队列 6 例中的 1 例，以及 0.5/1.2/4.0 μg/kg QW + 类固醇队列 4 例中的 3 例。最大耐受剂量为 2.7 μg/kg。未见缓解（见表）。ERY974 暴露量随剂量增加；使用 SUD 加类固醇实现了更高的暴露量，包括 4.0 μg/kg。55%（21/38）的患者发生 CRS，最常见于接受 ERY974 ≥0.80 μg/kg 的队列。在 0.24 μg/kg 仅用 toc 时 CRS 发生率为 0%，在初始 ERY974 剂量 0.50 μg/kg 加类固醇时较低（33%）vs 不加时（67%）。较高的 ERY974 血浆浓度与 CRS 风险增加（p=0.01）和 ≥3 级肝毒性（p=0.05）相关。结论：使用 SUD、类固醇预处理和 toc 使得能够递增至更高的 ERY974 剂量（最高至 2.7 μg/kg 可耐受），安全性可控。Toc 可能缓解了 CRS。抗肿瘤活性有限。表 ERY974 剂量（µg/kg）0.12（n=3）0.24（n=4）0.50（n=3）0.80（n=3）0.80 + 类固醇（n=6）0.50/1.20 + 类固醇 a（n=3）0.50/1.80 + 类固醇 a（n=4）0.50/1.20/1.80 + 类固醇 a（n=4）0.50/1.20/2.70 + 类固醇 a（n=4）0.50/1.20/4.0 + 类固醇 a（n=4）相关 AE，n（%）b 所有级别 3（100）1（25）1（33）3（100）6（100）3（100）4（100）4（100）4（100）4（100）3/4 级 c 0 1（25）0 2（67）3（50）2（67）4（100）3（75）4（100）4（100）严重 0 0 0 0 0 0 1（25）2（50）1（25）1（25）导致从任何治疗中退出的 AE 0 0 0 0 0 0 0 1（25）0 0 最佳总体反应，n（%）CR/PR 0 0 0 0 0 0 0 0 0 0 SD 0 1（25）0 0 3（50）0 1（25）0 1（25）2（50）jRCT2031200382。临床截止：2024 年 10 月 18 日 AE，不良事件；CR，完全缓解；PR，部分缓解；SD，疾病稳定；SUD，递增给药。a 每周 SUD 方案。b 同一人多次发生同一 AE 计为一次。c 未报告 5 级 AE。

查看英文原文 English abstract

Background: ERY974, a bispecific antibody targeting GPC3 and CD3, redirects T cells to GPC3+ tumors to enhance immune responses. GPC3 is highly expressed in solid tumors and minimally present in normal tissue, making it a promising target. ERY102JP (Phase I) evaluated ERY974 in patients (pts) with GPC3+ advanced/recurrent solid tumors. A prior study showed limited tolerability at doses ≥0.81 µg/kg due to cytokine release syndrome (CRS), prompting investigation of prophylactic strategies. Methods: Eligible pts had tumors with ≥1% GPC3 expression. Pts got ERY974 (0.12-4.0 µg/kg; dose escalation design) by IV once weekly (QW). Tocilizumab (toc), an IL-6 receptor antagonist, was given before ERY974 (all cohorts) to mitigate CRS. Steroids (Cohorts 5-10) and step-up dosing (SUD; Cohorts 6-10) were added to reduce CRS and hepatotoxicity. Endpoints included safety, PK and anti-tumor activity (RECIST 1.1). Results 38 pts were enrolled across 10 cohorts. Grade ≥3 adverse events (AEs) occurred in 61% (23/38) of pts; ALT increased was seen in 37% (14/38) and AST increased in 24% (9/38). Dose-limiting toxicities occurred in 1 of 3 pts in the 0.80 µg/kg QW cohort, 1 of 6 pts in 0.80 µg/kg QW + Steroid cohort, and 3 of 4 pts in 0.5/1.2/4.0 µg/kg QW + Steroid cohort. The maximum tolerated dose was 2.7 µg/kg. No responses were seen (Table). ERY974 exposure increased dose-dependently; higher exposure, including 4.0 µg/kg, was achieved using SUD with steroids. CRS occurred in 55% (21/38) of pts, most often in cohorts receiving ERY974 ≥0.80 µg/kg. CRS incidence was 0% at 0.24 µg/kg with toc alone, and lower at initial ERY974 dose of 0.50 µg/kg with steroids (33%) vs without (67%). Higher ERY974 plasma concentrations were associated with increased risk of CRS (p=0.01) and grade ≥3 liver toxicity (p=0.05). Conclusions: Use of SUD, steroid premedication and toc enabled escalation to higher ERY974 doses (up to 2.7 µg/kg was tolerated) with manageable safety profiles. Toc likely mitigated CRS. Anti-tumor activity was limited. Table ERY974 dose (µg/kg) 0.12 (n=3) 0.24 (n=4) 0.50 (n=3) 0.80 (n=3) 0.80 + Steroid (n=6) 0.50/1.20 + Steroid a (n=3) 0.50/1.80 + Steroid a (n=4) 0.50/1.20/1.80 + Steroid a (n=4) 0.50/1.20/2.70 + Steroid a (n=4) 0.50/1.20/4.0 + Steroid a (n=4) Related AEs, n (%) b All grade 3 (100) 1 (25) 1 (33) 3 (100) 6 (100) 3 (100) 4 (100) 4 (100) 4 (100) 4 (100) Grade 3/4 c 0 1 (25) 0 2 (67) 3 (50) 2 (67) 4 (100) 3 (75) 4 (100) 4 (100) Serious 0 0 0 0 0 0 1 (25) 2 (50) 1 (25) 1 (25) AEs leading to withdrawal from any treatment 0 0 0 0 0 0 0 1 (25) 0 0 Best overall response, n (%) CR/PR 0 0 0 0 0 0 0 0 0 0 SD 0 1 (25) 0 0 3 (50) 0 1 (25) 0 1 (25) 2 (50) jRCT2031200382. Clinical cutoff: Oct 18, 2024 AE, Adverse event; CR, complete response; PR, partial response; SD, stable disease; SUD, step-up dosing. a Weekly SUD regimen. b Multiple occurrences of the same AE in a person is counted once. c No grade 5 AEs were reported.

利益披露 Disclosure

H. Murakami, Chugai Other, The author received medical writing support from Nucleus Global paid for by Chugai. H. Hayashi, Chugai Other, The author received medical writing support from Nucleus Global paid for by Chugai. K. Yamagushi, Chugai Other, The author received medical writing support from Nucleus Global paid for by Chugai. K. Muro, Chugai The author received medical writing support from Nucleus Global paid for by Chugai. T. Satoh, Chugai Other, The author received medical writing support from Nucleus Global paid for by Chugai. T. Nishina, Chugai Other, The author received medical writing support from Nucleus Global paid for by Chugai. E. Ueda, Chugai Employment, Other, The author received medical writing support from Nucleus Global paid for by Chugai. C. Ogami, Chugai Employment, Other, The author received medical writing support from Nucleus Global paid for by Chugai. H. Takeshita, Chugai Employment, Other, The author received medical writing support from Nucleus Global paid for by Chugai. H. Takahashi, Chugai Employment, Other, The author received medical writing support from Nucleus Global paid for by Chugai. M. Nakamura, Chugai Employment, Other, The author received medical writing support from Nucleus Global paid for by Chugai. M. Toba, Chugai Employment, Other, The author received medical writing support from Nucleus Global paid for by Chugai. Y. Kuboki, Chugai Other, The author received medical writing support from Nucleus Global paid for by Chugai.

← 返回 AACR 2026 检索