PO.CT01.02 · 临床试验

1b/2期Morpheus肝癌研究在不可切除的局部晚期或转移性肝细胞癌（HCC）患者中的结果：Muzastotug（ADG126：掩蔽型抗CTLA-4抗体）联合治疗组

Results from the phase 1b/2 Morpheus liver study in patients with unresectable locally advanced or metastatic hepatocellular carcinoma (HCC): Muzastotug (ADG126: masked anti-CTLA-4 Ab) combination arm

编号 CT054 展板 14 时间 4/20 09:00–12:00 区域 Section 50 主讲 Jiping Zha, MD;PhD

分会场 First-in-Human Phase I Clinical Trials

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作者与单位 Authors & Affiliations

Daneng Li¹, Edward Gane², Chih-Hung Hsu³, Adam Burgoyne⁴, Peter Luo⁵, Songmao Zheng⁵, Yan Li⁵, Xiaohong She⁵, Stanley Frankel⁵, Jiping Zha⁵, Ann-Lii Cheng³

¹City of Hope Comprehensive Cancer Center, Los Angeles, CA,²Auckland City Hospital, Auckland, New Zealand,³National Taiwan University Cancer Center, Taipei, Taiwan,⁴University of California San Diego Medical Center, San Diego, CA,⁵Adagene Inc., San Diego, CA

摘要 Abstract

中文摘要

背景：Muzastotug（ADG126）是一种掩蔽型、肿瘤激活型、Treg耗竭型抗CTLA-4 IgG1抗体，经过工程改造可在肿瘤微环境内通过蛋白酶介导激活。激活后，ADG126结合一个独特的CTLA-4表位，阻断CTLA-4信号传导，对效应T细胞进行温和预激（soft-prime），并选择性耗竭调节性T细胞（Treg），其抗体依赖性细胞毒性（ADCC）约为ipilimumab的10倍。鉴于Treg介导的免疫抑制在HCC中的作用以及阿替利珠单抗（Atezo）和贝伐珠单抗（Bev）的确切获益，ADG126 + Atezo + Bev三药方案可能进一步增强抗肿瘤免疫。我们报告MORPHEUS-Liver平台研究（NCT04524871）中该三药联合随机队列的中期结果。方法：既往未经治疗、不可切除的局部晚期或转移性HCC患者被随机分配至Atezo（1200 mg IV）+ Bev（15 mg/kg IV）Q3W，联合或不联合ADG126（6 mg/kg IV）Q6W。主要终点为研究者评估的客观缓解率（ORR；RECIST v1.1）。次要终点包括缓解持续时间（DOR）、安全性、PFS和OS。结果：截至2025年7月11日，6名患者被随机分配至ADG126 + Atezo + Bev组，40名分配至Atezo + Bev组。ADG126组和对照组的中位随访时间分别为18.8个月和17.2个月。ADG126 + Atezo + Bev的确认ORR为50%[各患者基线靶肿瘤大小及最佳总体缓解（BOR）如下：52 mm至8.5 mm（-84%），65 mm至36 mm（-45%），20 mm至7.4 mm（-63%），76.8 mm至54.8 mm（-28.6%），82.62 mm至83.83 mm（+1.5%），71.2 mm至71.7 mm（+0.7%）]，而Atezo + Bev为17.5%；根据RECIST v1.1，DCR分别为83%和53%。中位DOR未达到（各患者DOR：>18.1个月、>13.8个月和>4个月）。三药联合的PFS和OS更长。≥3级治疗相关不良事件（AE）相似（50% vs 45%），无致命性AE，无ADG126剂量降低（三药组的3级AE：1例高血压、蛋白尿；1例输注相关反应；1例天冬氨酸氨基转移酶升高、发热）。两名患者因毒性而停用Bev，但继续接受ADG126 + Atezo治疗，其中一名仍在治疗中，超过630天。ADG126组严重AE发生率为33%，而对照组为55%。结论：接受ADG126 + Atezo + Bev治疗的最初6名患者与对照组相比，表现出增强的抗肿瘤活性、PFS和OS，以及可比的安全性特征。两名在停用Bev后继续接受ADG126 + Atezo治疗的患者的观察结果，凸显了ADG126 + Atezo双药方案的潜在重要性，该方案本身即为有效方案，并允许在毒性出现后灵活调整治疗。这些发现支持进一步研究基于ADG126的联合方案作为HCC及其他癌症一线免疫治疗策略。

查看英文原文 English abstract

Background: Muzastotug (ADG126) is a masked, tumor-activated, Treg-depleting anti-CTLA-4 IgG1 antibody engineered for protease-mediated activation within the tumor microenvironment. Upon activation ADG126 binds a unique CTLA-4 epitope, blocks CTLA-4 signaling, soft-primes effector T cells, and selectively depletes regulatory T cells (Tregs) with ~10-fold greater antibody-dependent cellular cytotoxicity (ADCC) than ipilimumab. Given the role of Treg-mediated immunosuppression in HCC and the established benefit of atezolizumab (Atezo) and bevacizumab (Bev), the triplet regimen ADG126 + Atezo + Bev may further amplify antitumor immunity. We report interim results from a randomized cohort of the MORPHEUS-Liver platform study (NCT04524871) for the triple combo. Methods: Patients with previously untreated, unresectable locally advanced or metastatic HCC were randomized to Atezo (1200 mg IV) + Bev (15 mg/kg IV) Q3W with or without ADG126 (6 mg/kg IV) Q6W. The primary endpoint was investigator-assessed objective response rate (ORR; RECIST v1.1). Secondary endpoints included duration of response (DOR), safety, PFS and OS. Results: As of July 11, 2025, 6 patients were randomized to ADG126 + Atezo + Bev arm and 40 to Atezo + Bev. Median follow-up was 18.8 and 17.2 months for the ADG126 and control arm, respectively. Confirmed ORR was 50% with ADG126 + Atezo + Bev [individual patient target tumor size at baseline and BOR as follows: 52 mm to 8.5 mm (-84%), 65 mm to 36 mm (-45%), 20 mm to 7.4 mm (-63%), 76.8 mm to 54.8 mm (-28.6%), 82.62 mm to 83.83 mm (+1.5%), 71.2 mm to 71.7 mm (+0.7%)] versus 17.5% with Atezo + Bev; DCR was 83% versus 53% per RECIST v1.1. Median DOR was not reached (individual DORs: >18.1 months, >13.8 months, and >4 months). PFS and OS were longer for the triple combo. Grade ≥3 treatment-related adverse events (AEs) were similar (50% vs 45%), with no fatal AEs and no ADG126 dose reduction (G3 AEs for triplet arm: 1 hypertension, proteinuria; 1 infusion related reaction; 1 aspartate aminotransferase increased, pyrexia). Two patients discontinued Bev due to toxicity yet remained on ADG126 + Atezo with one remaining on treatment >630 days. Serious AEs occurred in 33% of cases for the ADG126 arm compared to 55% for control. Conclusions: The initial 6 patients treated with ADG126 + Atezo + Bev demonstrated enhanced antitumor activity, PFS and OS, and comparable safety profile compared to the control arm. Observations from two patients for which ADG126 + Atezo therapy continued following Bev discontinuation underscores the potential importance of the ADG126 + Atezo doublet, which is an effective regimen on its own and allows flexibility in treatment after toxicity. These findings support further investigation of ADG126-based combinations for first-line immunotherapy strategies for HCC and beyond.

利益披露 Disclosure

D. Li, None.. E. Gane, None.. C. Hsu, None.. A. Burgoyne, None. P. Luo, Adagene, Inc. Employment, g., Board of Directors, non-salaried role), Stock, Stock Option, Patent. S. Zheng, Adagene, Inc. Employment. Y. Li, Adagene, Inc. Employment. X. She, Adagene, Inc. Employment. S. Frankel, Adagene, Inc. Independent Contractor. J. Zha, Adagene, Inc. Employment. A. Cheng, None.

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