PO.CT01.05 · 临床试验

agenT-797、botensilimab（BOT）和balstilimab（BAL）治疗PD-1难治性胃食管癌（GEC）的II期研究

A phase II study of agenT-797, botensilimab (BOT) and balstilimab (BAL) in PD-1 refractory gastroesophageal cancer (GEC)

编号 CT166 展板 30 时间 4/20 02:00–05:00 区域 Section 52 主讲 Samuel Cytryn, MD

分会场 Phase II and Phase III Clinical Trials

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作者与单位 Authors & Affiliations

Samuel L. Cytryn, Jeremy Tchack, Charlton Tsai, Yuval Elhanati, Patrick Evans, June Song, Michal Segal, Rory Mcgriskin, Amin Yaqubie, Joyce Lam, Haroon Kanishka, Michael B. Foote, Geoffrey Y. Ku, Steven B. Maron, Yelena Y. Janjigian

Memorial Sloan Kettering Cancer Center, New York, NY

摘要 Abstract

中文摘要

背景：GEC是癌症相关死亡的第二大原因。使用雷莫芦单抗（RAM）和紫杉醇（PAC）的二线治疗结局不佳，客观缓解率（ORR）为28%，中位无进展生存期（PFS）为4.4个月（mo）。方法：这是一项研究者发起的试验（NCT06251793），针对既往接受过一线治疗的GEC患者，评估BOT（Fc增强型抗CTLA-4）、BAL（抗PD-1）和agenT-797（同种异体不变自然杀伤T[iNKT]细胞）联合RAM/PAC。主要终点为ORR。次要终点为安全性、PFS和总生存期（OS）。整个治疗期间连续采集组织和血液用于多重免疫荧光（IF）、流式细胞术、T细胞受体（TCR）测序和细胞因子分析。结果：从2024年2月至2025年4月共入组17名患者：2名接受了agenT-797诱导周期，5名接受了agenT-797/BOT/BAL诱导，10名同时启动所有治疗。所有患者既往均接受过含抗PD-1/氟嘧啶/铂类的方案。中位随访20.7个月（范围11.9-22.2个月）。在15名可测量疾病的患者中，0名（0%）达到完全或部分缓解，11名（73%）疾病稳定，4名（27%）以疾病进展作为最佳缓解。中位PFS和OS分别为4.4个月（95% CI 3.4-6.9个月）和7.7个月（95% CI 4.9-NR）。3名患者OS≥20个月，其中1名在22.5个月后仍无进展。接受诱导周期治疗的患者相较于同时启动所有治疗的患者具有更优的PFS（6.9对3.5个月，p=0.008）。有肝转移与无肝转移的患者之间无差异（4.0对4.3个月，p=0.4）。17名（100%）患者发生不良事件（AE）；9名（53%）为3级及以上。最常见的为乏力（82%）、发热（59%）和腹泻（47%）。9名（53%）患者发生免疫相关AE；4名（24%）为3级及以上。最常见的为结肠炎（24%）、皮炎（24%）和胃炎（18%）。治疗中组织分析（n=10）显示，与基线样本相比，增殖性CD8+ T细胞浸润增加（3.3倍变化[FC] p=0.037）和活化的抗原呈递细胞增加（5.7 FC p=0.006）。外周血分析显示CD8+效应记忆T细胞增加（p=0.022）和IFNγ增加（p=0.001），这是iNKT细胞活性的标志。结论：这是首个评估agenT-797/BOT/BAL治疗GEC的研究。尽管观察到强健的全身和肿瘤内免疫激活，但与历史对照相比，ORR和中位PFS/OS并未改善。部分患者的长期生存以及诱导队列中更优的PFS提示患者选择和治疗顺序是获益的关键决定因素。所有17名患者的mIF、流式和TCR分析以及这些亚组之间的比较正在进行中，可能为治疗顺序和患者选择提供依据，支持对这些疗法的进一步研究。

查看英文原文 English abstract

Background: GEC is the second leading cause of cancer related mortality. Second line treatment with ramucirumab (RAM) and paclitaxel (PAC) has poor outcomes with an objective response rate (ORR) of 28% and median progression free survival (PFS) of 4.4 months (mo). Methods: This was an investigator initiated trial (NCT06251793) of patients with GEC who received one prior line of therapy evaluating BOT (Fc-enhanced anti-CTLA-4), BAL (anti-PD-1), and agenT-797 (allogeneic invariant natural killer T [iNKT] cells) with RAM/PAC. The primary endpoint was ORR. Secondary endpoints were safety, PFS, and overall survival (OS). Serial tissue and blood were collected throughout treatment for multiplex immunofluorescence (IF), flow cytometry, T cell receptor (TCR) sequencing, and cytokine analysis. Results: From Feb 2024 to Apr 2025 17 patients were enrolled: 2 received an induction cycle of agenT-797, 5 received induction with agenT-797/BOT/BAL, and 10 initiated all therapies simultaneously. All had received prior anti-PD-1/fluoropyrimidine/platinum containing regimens. Median follow up was 20.7mo (range 11.9 - 22.2mo). Of 15 patients with measurable disease, 0 (0%) had a complete or partial response, 11 (73%) had stable disease, and 4 (27%) had progressive disease as best response. Median PFS and OS were 4.4mo (95% CI 3.4 - 6.9mo) and 7.7mo (95% CI 4.9 - NR) respectively. Three patients had an OS ≥ 20mo, including one who remains progression free after 22.5mo. Patients treated with an induction cycle had superior PFS compared to those who started all therapies together (6.9 v 3.5mo, p=0.008). There was no difference in those with liver metastases versus those without (4.0 v 4.3mo, p=0.4). 17 (100%) patients had an adverse event (AE); 9 (53%) were grade (G) 3+. The most common were fatigue (82%), fever (59%), and diarrhea (47%). Nine (53%) patients had an immune related AE; 4 (24%) were G3+. The most common were colitis (24%), dermatitis (24%) and gastritis (18%). Analysis of on-treatment tissue (n=10) showed increased infiltration of proliferating CD8 + T cells (3.3 fold change [FC] p=0.037) and activated antigen presenting cells (5.7 FC p=0.006) compared to baseline samples. Peripheral blood analysis showed increased CD8+ effector memory T cells (p=0.022) and IFNgamma (p=0.001), a hallmark of iNKT cell activity. Conclusions: This is the first study to evaluate agenT-797/BOT/BAL in GEC. Although robust systemic and intratumoral immune activation was observed, ORR and median PFS/OS were not improved compared to historical controls. Long term survival in a subset of patients and superior PFS in the induction cohort suggest patient selection and therapeutic sequencing are key determinants of benefit. Ongoing mIF, flow, and TCR analyses of all 17 patients and comparisons of these subgroups are in process and may inform sequencing and patient selection, supporting further investigation of these therapies.

利益披露 Disclosure

S. L. Cytryn, Amgen Independent Contractor. Astellas Independent Contractor. Bristol Myers Squibb Independent Contractor. Henlius Independent Contractor. Astrazeneca Independent Contractor. Gilead Independent Contractor. MEDACORP Independent Contractor. HMP Education Independent Contractor. PeerView Independent Contractor. GI Oncology Now Independent Contractor. J. Tchack, None.. C. Tsai, None.. Y. Elhanati, None.. P. Evans, None.. J. Song, None.. M. Segal, None.. R. Mcgriskin, None.. A. Yaqubie, None.. J. Lam, None.. H. Kanishka, None. M. B. Foote, Abbott Laboratories Independent Contractor. Axiom healthcare Strategies Independent Contractor. Bristol Myers Squibb Independent Contractor. Cancer Network Independent Contractor. Genzyme Independent Contractor. Horizon CME Independent Contractor. Intera Oncology, Inc Independent Contractor. OMNI Oncology Independent Contractor. OncLive Independent Contractor. G. Y. Ku, Astellas Independent Contractor. Astrazeneca Independent Contractor. Bayer Independent Contractor. Bristol Myers Squibb Independent Contractor. I-Mab Biopharma Independent Contractor. Jazz Pharmaceuticals Independent Contractor. Merck and Co Inc. Independent Contractor. Zymerwork Independent Contractor. S. B. Maron, 1CellBio Inc. Other Securities. Academy for Continued Healthcare Learning Independent Contractor. Amgen Independent Contractor. Batten, LLC Independent Contractor. Bolt Biotherapeutics Independent Contractor. Elevation Oncology, Inc. Independent Contractor. Guidepoint Global Advisors Independent Contractor. McKesson Stock. MDoutlook, LLC Independent Contractor. OMNI Oncology Independent Contractor. Purple Biotech Ltd. Independent Contractor. Total Health Conferencing Independent Contractor. Y. Y. Janjigian, Arcus Biosciences Inc Independent Contractor. AskGene Pharma, Inc. Independent Contractor. Astrazeneca Independent Contractor. BeiGene USA, Inc. Independent Contractor. Boehringer Ingelheim Independent Contractor. Bristol Myers Squibb Independent Contractor. Chinese American Hematology and Oncology Network Independent Contractor. Clinical Education Alliance, LLC Independent Contractor. COR2ED GmbH Independent Contractor. Creative Education Concepts Independent Contractor. Curio Science LLC Independent Contractor. Daiichi Sankyo Independent Contractor. Eisai Independent Contractor. ED Medresources Inc Independent Contractor. Gilead Independent Contractor. Guardant Health, Inc. Independent Contractor. H.C. Wainwright & Co., LLC Independent Contractor. HMP Global, LLC Independent Contractor. IDEOlogy Health, LLC Independent Contractor. Imidex Inc. Independent Contractor.

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