PO.CL05.06 · 临床研究

单核细胞活化增强与T细胞细胞毒性是新辅助durvalumab联合吉西他滨-顺铂(D+GP)治疗局限性胆道癌(BTC)获益的基础：2期DEBATE研究

Enhanced monocyte activation and T cell cytotoxicity underlie the benefit of neoadjuvant durvalumab plus gemcitabine-cisplatin (D+GP) in localized biliary tract cancer (BTC): Phase 2 DEBATE study

编号 6454 展板 2 时间 4/21 02:00–05:00 区域 Section 41 主讲 Changhoon Yoo, MD;PhD

分会场 Clinical Correlates of Immunotherapy

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作者与单位 Authors & Affiliations

Changhoon Yoo¹, Hyung-Don Kim¹, Chang Yeon Kim², Joon Oh Park³, Hyehyun Jeong¹, Kyu-Pyo Kim¹, Jung Yong Hong⁴, Sang Hyun Shin⁴, Tae Jun Song¹, Dongwook Oh¹, Woohyung Lee¹, Jae Hoon Lee¹, Dae Wook Hwang¹, Jeong Seok Lee⁵

¹University of Ulsan College of Medicine, Seoul, Korea, Republic of,²Seoul National University College of Medicine, Seoul, Korea, Republic of,³Associate Professor, Dept. of Hem./Onc., Samsung Medical Center, Seoul, Korea, Republic of,⁴Samsung Medical Center, Seoul, Korea, Republic of,⁵Korea Advanced Institute of Science and Technology, Daejeon, Korea, Republic of

摘要 Abstract

中文摘要

引言：尽管有手术治疗，局限性BTC的预后仍然较差。新辅助治疗在BTC中的作用尚未得到充分确立。方法：DEBATE是一项多中心、随机、非比较性2期试验，纳入未接受过治疗的局限性BTC患者(pts)。患者按2:1随机分组，接受4个周期的新辅助D+GP或单用GP。接受手术的患者接受6个周期的辅助durvalumab治疗。主要终点为R0切除率。生物标志物分析包括外周血单个核细胞(PBMC)的单细胞RNA测序(scRNA-seq)以及血浆蛋白质组学(基线和第1周期第8天[C1D8])。结果：共纳入45例患者(D+GP，n=31；GP，n=14)。D+GP组与GP组的手术率分别为64.5%对42.9%，R0切除率分别为48.4%对42.9%。在D+GP组中，客观缓解率为38.7%，中位PFS为19个月(单侧80% CI，15-21)，OS为28个月(24-43)；而GP组分别为14.3%、6个月(3-11)和30个月(23-44)。98%(n=44)的患者具有生物标志物数据。scRNA-seq显示D+GP组中具有促炎特征的经典单核细胞显著富集，尤其在缓解者中，同时在scRNA-seq和血浆蛋白质组学中均观察到CXCL10表达升高。D+GP组的缓解者还表现出CD8+ T细胞细胞毒性增强、CD4+终末分化效应记忆T(TEMRA)细胞增多以及IL12RB2表达增加。仅在接受D+GP治疗的缓解者中，CD4+ TEMRA细胞的TIGIT表达从基线到C1D8有所下降。结论：新辅助D+GP治疗可行，并在局限性BTC中显示出令人鼓舞的疗效。综合生物标志物分析表明，单核细胞活化增强和T细胞反应增强有助于durvalumab带来的额外获益。本研究为在BTC中的D+GP基础上加用抗TIGIT提供了理论依据(NCT04308174)。

查看英文原文 English abstract

Introduction: The prognosis of localized BTC remains poor despite surgery. The role of neoadjuvant therapy in BTC has not been well established. Methods: DEBATE is a multicenter, randomized, non-comparative phase 2 trial enrolling treatment-naïve patients (pts) with localized BTC. Pts were randomized (2:1) to receive 4 cycles of neoadjuvant D+GP or GP alone. Those undergoing surgery received 6 cycles of adjuvant durvalumab. The primary endpoint was the R0 resection rate. Biomarker analyses included single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs), and plasma proteomics (baseline and cycle 1 day 8 [C1D8]). Results: A total of 45 pts were enrolled (D+GP, n=31; GP, n=14). Surgery was performed in 64.5% vs. 42.9%, and R0 resection rates were 48.4% vs. 42.9% in the D+GP and GP arms, respectively. In the D+GP group, the objective response rate was 38.7%, median PFS 19 months (1-sided 80% CI, 15-21), and OS 28 months (24-43), versus 14.3%, 6 months (3-11), and 30 months (23-44) in the GP group. Biomarker data were available in 98% (n=44). scRNA-seq showed a significant enrichment of classical monocytes with pro-inflammatory signatures in the D+GP group, especially among responders, along with increased CXCL10 expression in both scRNA-seq and plasma proteomics. Responders in the D+GP group also exhibited increased CD8+ T cell cytotoxicity, CD4+ Terminally differentiated effector memory T (TEMRA) cells, and IL12RB2 expression. TIGIT expression in CD4+ TEMRA cells decreased from baseline to C1D8 only in responders treated with D+GP. Conclusion: Neoadjuvant D+GP was feasible and demonstrated encouraging efficacy in localized BTC. Integrated biomarker analyses suggest that enhanced monocyte activation and T cell responses contribute to the added benefit of durvalumab. Current study provide the rationale of adding anti-TIGIT to D+GP in BTC (NCT04308174).

利益披露 Disclosure

C. Yoo, AstraZeneca ). Servier ). BMS ). MSD ). Boryung ). Servier ). Ipsen ). H. Kim, None.. C. Kim, None.. H. Jeong, None.. K. Kim, None.. J. Hong, None.. S. Shin, None.. T. Song, None.. D. Oh, None.. W. Lee, None.. J. Lee, None.. D. Hwang, None.. J. Lee, None.

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