PO.CT01.03 · 临床试验

首例接受 LP-118（一种新型 Bcl-2/Bcl-xL 双重抑制剂）治疗的实体瘤患者报告

The first report of patients with solid tumors treated with LP-118, a novel Bcl-2/Bcl-xL dual inhibitor

编号 CT192 展板 14 时间 4/21 09:00–12:00 区域 Section 50 主讲 Qing Zhou

分会场 Phase I Clinical Trials

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作者与单位 Authors & Affiliations

Qing Zhou¹, Xiaorong Dong², Jianya Zhou³, Duidui Hong⁴, Yue Shen⁴, Fenlai Tan⁴, Xiang Xiao⁴, Yejiang Lou⁴, Jiemin Xie⁴, Yilong Wu¹

¹Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China,²Cancer Center, Union Hospital Tongji Medical College Huazhong University of Science and Technology, Wuhan, China,³Department of Respiratory Disease, Thoracic Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China,⁴Guangzhou Lupeng Pharmaceutical Co., Ltd., Guangzhou, China

摘要 Abstract

中文摘要

背景：Bcl-2 家族蛋白在肿瘤中常常过表达，这会阻断凋亡并促进不受控制的细胞增殖。Navitoclax 已在多种恶性肿瘤中显示出抗肿瘤活性，但因抑制 Bcl-xL 而引起剂量限制性血小板减少。LP-118 是一种新型 Bcl-2/Bcl-xL 抑制剂，对 Bcl-2 具有强效活性，对 Bcl-xL 具有精细调节的活性，旨在最大限度地减少血小板毒性，同时保持强劲的抗肿瘤活性。方法：这是一项 LP-118 治疗实体瘤或血液系统恶性肿瘤患者的开放标签 I 期研究（NCT05025358）。合格受试者为标准治疗失败且有可测量疾病者。LP-118 口服给药，剂量范围为 50 至 700 mg/天，采用 3+3 设计。研究终点包括安全性、药代动力学（PK）和初步疗效。在此，我们报告实体瘤队列的结果。结果：截至 2025 年 7 月 9 日，共入组 52 例实体瘤患者，包括 42 例小细胞肺癌（SCLC）患者。SCLC 队列的基线特征总结于表 1。患者接受了跨越 10 个剂量水平的 LP-118。PK 分析显示，LP-118 暴露量随剂量从 50-500 mg 增加，然后在 600-700 mg 时似乎达到平台。每日一次（QD）给予 500 mg 后，平均 Cmax,ss 为 420.5 ng/mL，AUCτ 为 5138.1 ng·h/mL，平均半衰期为 7.9 小时，支持 QD 给药。未报告剂量限制性毒性（DLT），尚未达到最大耐受剂量（MTD）。常见的治疗相关不良事件包括白细胞减少（53.8%）、中性粒细胞减少（48.1%）、淋巴细胞减少（32.7%）、血肌酸磷酸激酶 MB 升高（30.8%）、食欲下降（30.8%）和贫血（30.8%），其中大多数为 1-2 级。值得注意的是，血小板减少的发生率为 15.4%，4 例受试者（7.7%）经历了 3-4 级事件。在以 ≥300 mg QD 治疗的 32 例可评估疗效的 SCLC 受试者中，5 例观察到部分缓解，18 例为疾病稳定，包括一例受试者持续治疗超过 22 个月。客观缓解率（ORR）为 15.6%，疾病控制率（DCR）为 71.9%。中位总生存期（OS）为 8.15 个月。结论：LP-118 是一种新型 Bcl-2/Bcl-xL 双重抑制剂，具有良好的安全性和 PK 特征。在 SCLC 患者中观察到的初步疗效令人鼓舞，支持进一步的临床评估。表 1. SCLC 患者的基线特征（N=42）中位年龄（范围），岁 62.5（39-77）男性，n（%）37（88.1）ECOG 体能状态，n（%）0 5（11.9）1 37（88.1）疾病分期，n（%）III 3（7.1）IV 39（92.9）既往治疗中位线数（范围）2（1-6）既往治疗数，n（%）1 18（42.9）2 15（35.7）≥3 9（21.4）既往治疗方案，n（%）化疗 42（100）免疫治疗 38（90.5）靶向治疗 9（21.4）

查看英文原文 English abstract

Background: Bcl-2 family proteins are often overexpressed in tumors, which blocks apoptosis and promotes uncontrolled cell proliferation. Navitoclax has shown anti-tumor activity in various malignancies but induces dose-limiting thrombocytopenia due to Bcl-xL inhibition. LP-118 is a novel Bcl-2/Bcl-xL inhibitor with potent activity against Bcl-2 and fine-tuned activity against Bcl-xL, designed to minimize platelet toxicity while maintaining robust anti-tumor activity. Methods: This is an open-label, phase I study of LP-118 in patients with solid tumors or hematological malignancies (NCT05025358). Eligible subjects had failed standard therapies and had measurable disease. LP-118 was administrated orally, with doses ranging from 50 to 700 mg/day using the 3+3 design. The study endpoints included safety, pharmacokinetic (PK) and preliminary efficacy. Here, we report results from the solid tumor cohort. Results: As of July 09, 2025, a total of 52 patients with solid tumors, including 42 with small cell lung cancer (SCLC) were enrolled. Baseline characteristics of the SCLC cohort are summarized in Table 1. Patients received LP-118 across 10 dose levels. PK analysis showed that LP-118 exposure increases with doses from 50-500 mg, then appears to plateau at 600-700 mg. Following once-daily (QD) administration of 500 mg, the mean C max,ss was 420.5 ng/mL, with AUCτ of 5138.1 ng·h/mL and the mean half-life was 7.9 hours, supporting QD dosing. No dose-limiting toxicity (DLT) was reported, and the maximum tolerated dose (MTD) has not yet been reached. Common treatment related adverse events included leukopenia (53.8%), neutropenia (48.1%), lymphopenia (32.7%), blood creatine phosphokinase MB increased (30.8%), decreased appetite (30.8%), and anemia (30.8%), most of which were grade 1-2. Notably, the incidence of thrombocytopenia was 15.4%, with 4 subjects (7.7%) experienced grade 3 - 4 events. Of 32 efficacy-evaluable SCLC subjects treated at ≥300 mg QD, partial response was observed in 5 subjects and stable disease in 18 subjects, including one subject remaining on treatment for over 22 months. The objective response rate (ORR) was 15.6%, and the disease control rate (DCR) was 71.9%. The median overall survival (OS) was 8.15 months. Conclusion: LP-118 is a novel Bcl-2/Bcl-xL dual inhibitor with favorable safety and PK profiles. Preliminary efficacy observed in patients with SCLC is encouraging, supporting further clinical evaluations. Table 1. Baseline characteristics of SCLC patients (N=42) Median age (range), years 62.5 (39-77) Male, n (%) 37 (88.1) ECOG performance status, n (%) 0 5 (11.9) 1 37 (88.1) Disease stage, n (%) III 3 (7.1) IV 39 (92.9) Median line of prior therapies (range) 2 (1-6) No. of prior therapies, n (%) 1 18 (42.9) 2 15 (35.7) ≥3 9 (21.4) Prior therapeutic regimens, n (%) Chemotherapy 42 (100) Immunotherapy 38 (90.5) Targeted therapy 9 (21.4)

利益披露 Disclosure

Q. Zhou, None.. X. Dong, None.. J. Zhou, None.. D. Hong, None.. Y. Shen, None.. F. Tan, None.. X. Xiao, None.. Y. Lou, None.. J. Xie, None.. Y. Wu, None.

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