LBPO.CL01 · 临床研究 · Late-Breaking

3期RATIONALE 305试验的探索性生物标志物分析：一线（1L）替雷利珠单抗（TIS）+化疗（CT）对比安慰剂（PBO）+CT治疗晚期胃癌/胃食管交界处腺癌（GC/GEJC）

Exploratory biomarker analysis of the phase 3 RATIONALE 305 trial: First-line (1L) tislelizumab (TIS) + chemotherapy (CT) vs placebo (PBO) + CT for advanced gastric cancer/gastro-oesophageal junction adenocarcinoma (GC/GEJC)

编号 LB011 展板 11 时间 4/19 02:00–05:00 区域 Section 50 主讲 Ciji Cabrera

分会场 Late-Breaking Research: Clinical Research 1

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作者与单位 Authors & Affiliations

Miaozhen Qiu¹, Kai Wang², Jingwen Shi², Yang Shi², Mingyu Lai¹, Jing Yang¹, Do-Youn Oh³, Yuxian Bai⁴, Ruiqi Huang², David Shames², Rui-Hua Xu¹

¹Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, China,²BeOne Medicines, Ltd., Beijing, China,³Seoul National University Hospital, Seoul, Korea, Republic of,⁴Harbin Medical University Cancer Hospital, Harbin, China

摘要 Abstract

中文摘要

背景：在随机3期RATIONALE 305试验（NCT03777657）中，接受1L TIS + CT治疗的晚期GC/GEJC患者（pts）的总生存期（OS）较PBO + CT显著改善。我们展示了RATIONALE 305利用RNA测序（RNAseq）和全外显子组测序（WES）数据得出的探索性生物标志物和分子分型结果。方法：使用基线（BL）肿瘤组织的RNAseq（507/997，50.9%）评估基因表达特征（GES）。GES亚组按中位数临界值定义。对BL肿瘤组织和匹配的血液样本进行WES（235/997，23.6%），以评估肿瘤突变负荷（TMB）、人类白细胞抗原（HLA）基因分型、显著突变基因和细胞遗传带扩增（amp）。评估了生物标志物状态与OS之间的关联。所有P值均为描述性。结果：GES或WES可评估患者的BL特征与ITT人群相似。高炎症（如细胞毒性T细胞[CTL]）和低免疫抑制（如中性粒细胞）的GES与TIS + CT相较于PBO + CT的OS改善相关（表）。高克隆性TMB与TIS + CT相较于PBO + CT的OS改善相关（表），而总TMB未显示出明确关联。非HLA B27超型、TP53野生型或20q13.13非扩增与TIS + CT相较于PBO + CT的OS获益改善相关（表）。将展示包括免疫组化和分子分型结果在内的其他生物标志物分析。结论：这项探索性生物标志物分析发现，高CTL GES和低中性粒细胞GES，以及克隆性TMB、某些HLA基因型、TP53野生型和细胞遗传带非扩增，均与接受1L TIS + CT对比PBO + CT治疗的晚期GC/GEJC患者的OS获益相关。表 TIS + CT 对比 PBO + CT 人群亚人群 N OS HR（95% CI） P值交互作用P值 GES可评估 507 CTL高 254 0.69（0.52, 0.91）0.009 0.063 CTL低 253 1.00（0.76, 1.32）0.999 中性粒细胞高 254 1.01（0.76, 1.33）0.970 0.044 中性粒细胞低 253 0.67（0.50, 0.89）0.005 WES可评估 235 高cTMB（第90百分位数）24 0.37（0.14, 0.95）0.038 0.125 低cTMB（第90百分位数）211 0.80（0.59, 1.08）0.144 HLA B27 52 1.30（0.70, 2.41）0.401 0.045 HLA非B27 183 0.64（0.46, 0.89）0.007 TP53突变a 148 0.96（0.67, 1.38）0.825 0.025 TP53野生型 84 0.48（0.29, 0.78）0.003 20q13.13非扩增 205 0.64（0.47, 0.88）0.005 0.002 20q13.13扩增 30 2.58（1.15, 5.79）0.021 a 未纳入伴有TP53扩增的患者

查看英文原文 English abstract

Background: In the randomised phase 3 RATIONALE 305 trial (NCT03777657), patients (pts) with advanced GC/GEJC treated with 1L TIS + CT had significantly improved overall survival (OS) vs PBO + CT. We present exploratory biomarker and molecular subtyping results from RATIONALE 305 derived using RNA sequencing (RNAseq) and whole exome sequencing (WES) data. Methods: RNAseq (507/997, 50.9%) of baseline (BL) tumor tissue was used to assess gene expression signatures (GES). GES subgroups were defined by median cutoff. WES (235/997, 23.6%) of BL tumor tissue and matching blood samples was performed to assess tumor mutational burden (TMB), human leukocyte antigen (HLA) genotyping, significantly mutated genes, and cytoband amplifications (amp). Associations between biomarker status and OS were evaluated. All P values are descriptive. Results: BL characteristics in the GES- or WES-evaluable pts were similar to the ITT population. High inflammation (e.g. cytotoxic T cells [CTL]) and low immunosuppression (e.g. neutrophils) GES were associated with improved OS for TIS + CT vs PBO + CT (Table). High clonal TMB was linked to improved OS with TIS + CT vs PBO + CT (Table) while total TMB showed no clear association. Non-HLA B27 supertype or TP53 wildtype or 20q13.13 non-amp were associated with improved OS benefit with TIS + CT vs PBO + CT (Table). Additional biomarker analyses including immunohistochemistry and molecular subtyping results will be presented. Conclusion: This exploratory biomarker analysis found that high CTL GES and low neutrophil GES, as well as clonal TMB, certain HLA genotypes, TP53 wildtype, and cytoband non-amp were all associated with OS benefit in 1L TIS + CT vs PBO + CT treated pts with advanced GC/GEJC. TABLE TIS + CT vs PBO + CT Population Subpopulation N OS HR (95% CI) P value Interaction P value GES evaluable 507 CTL high 254 0.69 (0.52, 0.91) 0.009 0.063 CTL low 253 1.00 (0.76, 1.32) 0.999 Neutrophil high 254 1.01 (0.76, 1.33) 0.970 0.044 Neutrophil low 253 0.67 (0.50, 0.89) 0.005 WES evaluable 235 High cTMB (90 th percentile) 24 0.37 (0.14, 0.95) 0.038 0.125 Low cTMB (90 th percentile) 211 0.80 (0.59, 1.08) 0.144 HLA B27 52 1.30 (0.70, 2.41) 0.401 0.045 HLA non-B27 183 0.64 (0.46, 0.89) 0.007 TP53 mutation a 148 0.96 (0.67, 1.38) 0.825 0.025 TP53 wildtype 84 0.48 (0.29, 0.78) 0.003 20q13.13 non-amp 205 0.64 (0.47, 0.88) 0.005 0.002 20q13.13 amp 30 2.58 (1.15, 5.79) 0.021 a Pts with TP53 amplification not included

利益披露 Disclosure

M. Qiu, None. K. Wang, BeOne Med Ltd Employment, Stock. J. Shi, BeOne Med Ltd Employment, Stock. Y. Shi, BeOne Med Ltd Employment, Stock. M. Lai, None.. J. Yang, None.. D. Oh, None.. Y. Bai, None. R. Huang, BeOne Med Ltd Employment, Stock. D. Shames, BeOne Med Ltd Employment, Stock. R. Xu, None.

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