PO.CT01.04 · 临床试验

Dirozalkib治疗晚期ALK阳性非小细胞肺癌（NSCLC）患者：一项2期研究的结果

Dirozalkib in patients with advanced ALK-positive non-small cell lung cancer (NSCLC): Results from a phase 2 study

编号 CT243 展板 8 时间 4/21 02:00–05:00 区域 Section 50 主讲 Haifeng Liu

分会场 Phase II 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

Ying Liu¹, Yan Yu², Zhiye Zhang³, Ruiling Ning⁴, Yulan Sun⁵, Meili Sun⁶, Dairong Li⁷, Li Wang⁸, Xianghui Duan⁸, Xuejie Guo⁸, Yan Hu⁸, Weili Liu⁸, Haifeng Liu¹

¹Department of Oncology, Jilin Provincial Cancer Hospital, Changchun, China,²Department of Thoracic Oncology, The Affiliated Cancer Hospital of Harbin Medical University, Harbin, China,³Department of Medical Oncology, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, China,⁴Department of Medical Oncology of Respiratory, The Affiliated Cancer Hospital of Guangxi Medical University, Nanning, China,⁵Department of Internal Medicine Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Science, Jinan, China,⁶Department of Oncology, Jinan Central Hospital, Shandong First Medical University, Jinan, China,⁷Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, China,⁸Department of Clinical Science, Xuanzhu Biopharmaceutical Co., Ltd., Beijing, China

摘要 Abstract

中文摘要

背景：Dirozalkib是一种新型、高选择性的间变性淋巴瘤激酶（ALK）抑制剂。这项在晚期ALK阳性NSCLC中国患者（pts）中开展的2期研究（NCT05482087）旨在评估dirozalkib在具有不同ALK抑制剂治疗史患者中的疗效和耐受性。方法：本研究根据既往ALK抑制剂治疗情况将晚期ALK阳性NSCLC患者纳入三个队列（队列A、B、C）。队列A纳入ALK抑制剂初治患者，队列B纳入既往仅接受过crizotinib治疗的患者，队列C纳入既往接受过其他ALK抑制剂±crizotinib治疗的患者。所有患者接受dirozalkib 500 mg口服每日一次。主要终点为按RECIST 1.1版评估的客观缓解率（ORR）。次要终点包括无进展生存期（PFS）、疾病控制率（DCR）、缓解持续时间（DoR）、颅内客观缓解率（IC-ORR）、总生存期（OS）和安全性等。探索性目的为表征耐药机制以及dirozalkib抗肿瘤疗效与ALK突变之间的分子相关性。结果：截至数据截止（2024年3月27日），队列A（n=31）、B（n=33）和C（n=49）的ORR分别为71.0%、33.3%和22.4%，DCR分别为83.9%、87.9%和65.3%，中位PFS分别为11.07个月（mo）、9.26个月和4.63个月。分析时所有队列的OS数据均不成熟。在三个队列基线时具有可测量脑转移的患者中，IC-ORR为59.1%。对50例患者的配对基线和治疗结束（EOT）循环肿瘤DNA（ctDNA）样本的分析表明：在队列A（n=8）中，dirozalkib治疗后未出现新的ALK耐药突变。在队列B（n=11）中，7例患者检测到基线ALK耐药突变，dirozalkib治疗使6例患者在EOT时突变ctDNA清除或肿瘤缓解，其中包括一些常见的crizotinib耐药突变（如F1174L、G1296A、L1196M、C1156Y、I1171T）。在队列C（n=31）中，5例患者具有基线ALK耐药突变，包括2例G1202R突变。在1例患者中，dirozalkib治疗使EOT时G1202R突变ctDNA清除，相应的最佳总体缓解（BOR）为疾病稳定（SD）。最常见的治疗相关不良事件（TRAE）为胃肠道疾病和转氨酶升高。≥3级TRAE主要包括腹泻（13.3%）、高甘油三酯血症（3.5%）、γ-谷氨酰转移酶升高（3.5%）、低钾血症（2.7%）、贫血（2.7%）和QT间期延长（2.7%）。未观察到新的安全性信号。结论：ctDNA检测结果和临床数据均证明dirozalkib在晚期ALK阳性NSCLC患者中具有有前景的疗效。

查看英文原文 English abstract

Background: Dirozalkib is a novel, highly selective inhibitor of anaplastic lymphoma kinase (ALK). The phase 2 study (NCT05482087) in Chinese patients (pts) with advanced ALK-positive NSCLC was designed to evaluate the efficacy and tolerability of dirozalkib in pts with different ALK inhibitor therapy history. Methods: This study enrolled pts with advanced ALK-positive NSCLC into three cohorts (Cohort A, B, C) based on prior ALK inhibitor therapy. Cohort A enrolled pts with ALK inhibitor-naïve, Cohort B included pts previously treated with only crizotinib, and Cohort C included pts previously treated with other ALK inhibitors ± crizotinib. All pts received dirozalkib 500 mg orally once daily. The primary endpoint was objective response rate (ORR) per RECIST version 1.1. Secondary endpoints included progression-free survival (PFS), disease control rate (DCR), duration of response (DoR), intracranial objective response rate (IC-ORR), overall survival (OS) and safety etc. Exploratory objective was to characterize resistance mechanisms and molecular correlations between the antitumor efficacy of dirozalkib and ALK mutations. Results: At data cutoff (Mar. 27, 2024), the ORR for Cohorts A (n=31), B (n=33), and C (n=49) was 71.0%, 33.3% and 22.4%, respectively, with a DCR of 83.9%, 87.9%, and 65.3%, and a median PFS of 11.07 months (mo), 9.26 mo, and 4.63 mo, respectively. OS data in all cohorts remained immature at the time of analysis. Among pts with measurable brain metastases at baseline across the three cohorts, the IC-ORR was 59.1%. Analysis of paired baseline and end-of-treatment (EOT) circulating tumor DNA (ctDNA) samples from 50 pts demonstrated that: in Cohort A (n=8), no new ALK resistance mutations emerged following dirozalkib treatment. In Cohort B (n=11), baseline ALK resistance mutations were detected in 7 pts, and dirozalkib treatment led to the mutant ctDNA clearance at EOT or tumor response in 6 pts with some common crizotinib resistance mutations (e.g., F1174L, G1296A, L1196M, C1156Y, I1171T). In Cohort C (n=31), 5 pts had baseline ALK resistance mutations, including 2 with the G1202R mutation. In one patient, dirozalkib treatment resulted in the clearance of the G1202R mutant ctDNA at EOT, with a corresponding best overall response (BOR) of stable disease (SD). The most common treatment-related adverse events (TRAEs) were gastrointestinal disorders and transaminase elevations. Grade ≥3 TRAEs mainly included diarrhea (13.3%), hypertriglyceridemia (3.5%), gamma-glutamyltransferase increased (3.5%), hypokalemia (2.7%), anaemia (2.7%), and QT interval prolongation (2.7%). No new safety signal was observed. Conclusions: Both ctDNA testing results and clinical data demonstrated the promising efficacy of dirozalkib in patients with advanced ALK-positive NSCLC.

利益披露 Disclosure

Y. Liu, None.. Y. Yu, None.. Z. Zhang, None.. R. Ning, None.. Y. Sun, None.. M. Sun, None.. D. Li, None.. L. Wang, None.. X. Duan, None.. X. Guo, None.. Y. Hu, None.. W. Liu, None.. H. Liu, None.

← 返回 AACR 2026 检索