PO.CTP01.01 · 进行中的临床试验
ADG126（muzastotug，一种抗CTLA-4遮蔽抗体）联合pembrolizumab（Pembro）的IO双药方案再联合fruquintinib（Fruq）治疗晚期和转移性微卫星稳定型结直肠癌的Ph1b期评估
Ph1b evaluation of ADG126 (muzastotug, an anti-CTLA-4 masking antibody) pembrolizumab (Pembro) IO doublet in combination with fruquintinib (Fruq) in advanced and metastatic microsatellite stable colorectal cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：ADG126是一种经遮蔽的抗CTLA-4 IgG1抗体，具有拓宽的治疗指数（TI），旨在通过蛋白酶介导的裂解实现肿瘤选择性激活。激活后，ADG126结合独特的CTLA-4表位，部分阻断CTLA-4信号传导，轻度激活效应T细胞，并选择性清除肿瘤内调节性T细胞。Fruquintinib是目前MSS CRC的3/4L标准治疗，而在此背景下，ADG126 + Pembro对无肝转移（NLM）患者显示出令人鼓舞的疗效1。ADG126 + Pembro + Fruq三药联合可能通过在MSS CRC患者（包括伴有肝转移[LM]的患者）中利用这些通路的潜在协同作用，进一步改善治疗结局。在此，我们介绍评估该三药联合方案治疗4L MSS CRC的初步剂量递增结果（NCT05405595）。
方法：无NLM的4L MSS CRC患者接受ADG126（10或15 mg/kg Q6W静脉注射）+ Pembro（400 mg Q6W静脉注射）+ Fruq（5 mg/日口服，服药3周停药1周）。主要终点包括安全性和耐受性，以及ORR/DOR。次要终点包括PK、ADA、PFS和OS。
结果：截至2025年11月29日，9例MSS CRC患者接受了ADG126 + Pembro + Fruq治疗，中位随访时间为5个月。观察到早期疗效信号，在10和15 mg/kg ADG126剂量水平下，可评估疗效的患者的PR率分别为25%（1/4）和50%（2/4），DCR分别为75%（3/4）和75%（3/4）。10 mg/kg和15 mg/kg队列的G3 TRAE分别为25%（1/4）和40%（2/5），可评估安全性的患者中无G4/5 TRAE和DLT。未达到MTD。67%（6/9）的患者对Fruq进行了减量。两个剂量水平均无因安全性原因导致的停药。将报告更新数据。
结论：ADG126 + Pembro IO双药的良好安全性特征使其能够安全地与Fruq联合，ADG126剂量约为其他适应症中某些已获批ipilimumab联合剂量（例如1 mpk Q6W，仅IO双药）的10-15倍。尽管Fruq存在安全性特征，与IO双药相比，该三药联合显示出可控的安全性，未发现新的安全性信号。该三药联合方案通过撤除单个组分（如Fruq）提供了管理安全性的选择。鉴于Fruq适用于LM患者，并可能使此类患者维持治疗足够长时间以使IO治疗诱导持久疗效，因此有必要开展包括伴LM的MSS CRC患者在内的未来研究，以进一步探讨该三药联合的治疗效果。
参考文献：1. Daneng Li等，摘要#3579，ASCO，2025年6月
查看英文原文 English abstract
Background : ADG126 is a masked anti-CTLA-4 IgG1 antibody with a widened therapeutic index (TI), designed for tumor-selective activation via protease-mediated cleavage. Upon activation, ADG126 binds a unique CTLA-4 epitope, partially blocks CTLA-4 signaling, slightly primes effector T cells, and selectively depletes intratumoral regulatory T cells. Fruquintinib is a current 3/4L standard of care treatment for MSS CRC, while ADG126 + Pembro showed promising efficacy for those with no liver metastasis (NLM) in this setting 1 . Triple combo of ADG126 + Pembro + Fruq may further improve therapeutic outcomes by leveraging potential synergy of these pathways in MSS CRC patients, including those with liver metastasis (LM). Here we present the initial dose escalation results evaluating this triple combo in 4L MSS CRC (NCT05405595).
Methods: 4L MSS CRC patients with NLM received ADG126 (10 or 15 mg/kg Q6W IV) + Pembro (400 mg Q6W IV) + Fruq (5 mg/day PO, 3 weeks on and 1 week off). Primary endpoints include safety and tolerability, and ORR/DOR. Secondary endpoints include PK, ADA, PFS and OS.
Results: As of Nov. 29, 2025, 9 MSS CRC Pts were treated with ADG126 + Pembro + Fruq, with median follow up of 5 months. Early efficacy signals were observed, with 25% (1/4) and 50% (2/4) PRs, and 75% (3/4) and 75% (3/4) DCR for efficacy evaluable patients at 10 and 15 mg/kg ADG126 dose levels, respectively. G3 TRAEs were 25% (1/4) for 10 mg/kg and 40% (2/5) for 15 mg/kg cohorts, respectively, with no G4/5 TRAEs and DLT for safety evaluable patients. MTD was not reached. Fruq was dose-reduced in 67% (6/9) of patients. There were no discontinuations due to safety at either dose level. Updated data will be presented.
Conclusions: The favorable safety profile of ADG126 + Pembro IO doublet allows its safe combination with Fruq, with ADG126 dosage ~10-15 fold higher than some approved ipilimumab combination dosages (e.g., 1 mpk Q6W, IO doublet only) in other indications. Despite the safety profile of Fruq, this triple combo shows manageable safety with no new safety signals identified compared with IO doublet. The triple combo provides options to manage safety by dropping individual components, such as Fruq. Given that Fruq is indicated for LM Pts and may allow such Pts to remain on treatment long enough for IO therapy to induce durable efficacy, future studies including MSS CRC patients with LM are warranted to further investigate the therapeutic effects of the triplet.
Reference: 1. Daneng Li et al., Abstract #3579, ASCO, Jun. 2025
利益披露 Disclosure
M. Fakih, None..
S. Sharma, None..
M. R. Patel, None..
D. Li, None.
Y. Li,
Adagene, Inc. Employment.
L. Chung,
Adagene, Inc. Employment.
S. Zheng,
Adagene, Inc. Employment.
X. She,
Adagene, Inc. Employment.
S. Frankel,
Adagene, Inc. Independent Contractor.
M. J. Chisamore,
Merck & Co., Inc. Employment.
P. Luo,
Adagene, Inc. Employment, g., Board of Directors, non-salaried role), Stock, Stock Option, Patent.
J. Zha,
Adagene, Inc. Employment.