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AMG 193(一种MTA协同PRMT5抑制剂)在MTAP缺失实体瘤患者中的首次人体研究:I期剂量探索结果

First-in-human study of AMG 193, an MTA-cooperative PRMT5 inhibitor, in patients with MTAP-deleted solid tumors: results from phase I dose exploration.

作者信息

Rodon J, Prenen H, Sacher A, Villalona-Calero M, Penel N, El Helali A, Rottey S, Yamamoto N, Ghiringhelli F, Goebeler M E, Doi T, Postel-Vinay S, Lin C-C, Liu C, Chuang C-H, Keyvanjah K, Eggert T, O'Neil B H

机构信息

MD Anderson Cancer Center, Houston, USA.

University Hospital Antwerp, Edegem, Belgium.

出版信息

Ann Oncol. 2024 Dec;35(12):1138-1147. doi: 10.1016/j.annonc.2024.08.2339. Epub 2024 Sep 16.

Abstract

BACKGROUND

Homozygous deletion of methylthioadenosine phosphorylase (MTAP) occurs in ∼10%-15% of solid tumors. AMG 193, a CNS-penetrant methylthioadenosine-cooperative protein arginine methyltransferase 5 (PRMT5) inhibitor, selectively induces synthetic lethality in MTAP-deleted tumor cells. Here, we report results of the completed monotherapy dose exploration evaluating AMG 193 in patients with MTAP-deleted solid tumors.

PATIENTS AND METHODS

In this first-in-human, multicenter, open-label, phase I study, patients with advanced CDKN2A-deleted and/or MTAP-deleted solid tumors received AMG 193 orally [once (o.d.) or twice (b.i.d.) daily] continuously in 28-day cycles. Primary objectives were safety and tolerability assessed by dose-limiting toxicities and determination of the maximum tolerated dose; secondary objectives included pharmacokinetics and preliminary antitumor activity measured by RECIST v1.1.

RESULTS

As of 23 May 2024, 80 patients in dose exploration received AMG 193 at doses 40-1600 mg o.d. or 600 mg b.i.d. The most common treatment-related adverse events were nausea (48.8%), fatigue (31.3%), and vomiting (30.0%). Dose-limiting toxicities were reported in eight patients at doses ≥240 mg, including nausea, vomiting, fatigue, hypersensitivity reaction, and hypokalemia. The maximum tolerated dose was determined to be 1200 mg o.d. Mean exposure of AMG 193 increased in a dose-proportional manner from 40 mg to 1200 mg. Among the efficacy-assessable patients treated at the active and tolerable doses of 800 mg o.d., 1200 mg o.d., or 600 mg b.i.d. (n = 42), objective response rate was 21.4% (95% confidence interval 10.3% to 36.8%). Responses were observed across eight different tumor types, including squamous/non-squamous non-small-cell lung cancer, pancreatic adenocarcinoma, and biliary tract cancer. At doses ≥480 mg, complete intratumoral PRMT5 inhibition was confirmed in paired MTAP-deleted tumor biopsies, and molecular responses (circulating tumor DNA clearance) were observed.

CONCLUSIONS

AMG 193 demonstrated a favorable safety profile without clinically significant myelosuppression. Encouraging antitumor activity across a variety of MTAP-deleted solid tumors was observed based on objective response rate and circulating tumor DNA clearance.

摘要

背景

甲硫腺苷磷酸化酶(MTAP)的纯合缺失发生在约10%-15%的实体瘤中。AMG 193是一种可穿透中枢神经系统的甲硫腺苷协同蛋白精氨酸甲基转移酶5(PRMT5)抑制剂,可在MTAP缺失的肿瘤细胞中选择性诱导合成致死。在此,我们报告了评估AMG 193治疗MTAP缺失实体瘤患者的单药剂量探索研究的完整结果。

患者与方法

在这项首次人体、多中心、开放标签的I期研究中,晚期CDKN2A缺失和/或MTAP缺失的实体瘤患者接受AMG 193口服给药(每日一次或每日两次),每28天为一个周期。主要目标是通过剂量限制性毒性评估安全性和耐受性,并确定最大耐受剂量;次要目标包括药代动力学以及通过RECIST v1.1测量的初步抗肿瘤活性。

结果

截至2024年5月23日,80名剂量探索阶段的患者接受了40-1600mg每日一次或600mg每日两次剂量的AMG 193治疗。最常见的治疗相关不良事件为恶心(48.8%)、疲劳(31.3%)和呕吐(30.0%)。8名剂量≥240mg的患者报告了剂量限制性毒性,包括恶心、呕吐、疲劳、过敏反应和低钾血症。确定最大耐受剂量为1200mg每日一次。AMG 193的平均暴露量在40mg至1200mg之间呈剂量比例增加。在接受800mg每日一次、1200mg每日一次或600mg每日两次有效且可耐受剂量治疗的疗效可评估患者中(n = 42),客观缓解率为21.4%(95%置信区间10.3%至36.8%)。在八种不同肿瘤类型中观察到了缓解,包括鳞状/非鳞状非小细胞肺癌、胰腺腺癌和胆管癌。在剂量≥480mg时,在配对的MTAP缺失肿瘤活检中证实了肿瘤内PRMT5的完全抑制,并观察到了分子反应(循环肿瘤DNA清除)。

结论

AMG 193显示出良好的安全性,无临床显著的骨髓抑制。基于客观缓解率和循环肿瘤DNA清除,在多种MTAP缺失的实体瘤中观察到了令人鼓舞的抗肿瘤活性。

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