LBPO.CL04 · 临床研究 · Late-Breaking

RELATIVITY-104第2部分：程序性死亡配体1（PD-L1）≥1%和非鳞状（NSQ）非小细胞肺癌（NSCLC）亚组的转化分析

RELATIVITY-104 Part 2: translational analyses in the programmed death ligand 1 (PD-L1) ≥ 1% and non-squamous (NSQ) non-small cell lung cancer (NSCLC) subgroup

编号 LB418 展板 8 时间 4/22 09:00–12:00 区域 Section 51 主讲 Jaclyn Neely, PhD

分会场 Late-Breaking Research: Clinical Research 4

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作者与单位 Authors & Affiliations

Jaclyn Neely¹, Annie Yu¹, Nicolas Girard², Manuel Cobo-Dols³, Mauricio Burotto⁴, Luis Paz-Ares⁵, Vamsidhar Velcheti⁶, Martin Reck⁷, Srijata Samanta¹, Anila Qureshi¹, Priyanka Kasbekar¹, Charlie Garnett-Benson¹

¹Bristol Myers Squibb, Princeton, NJ,²Institut du Thorax Curie-Montsouris, Institut Curie, Paris, France,³Hospital Regional Universitario de Málaga, Malaga, Spain,⁴Bradford Hill Centro de Investigaci ón Clínica, Santiago, Chile,⁵Hospital Universitario 12 de Octubre, Universidad Complutense de Madrid, Madrid, Spain,⁶Mayo Clinic Comprehensive Cancer Center, Jacksonville, FL,⁷Airway Research Center North, German Center for Lung Research, Grosshansdorf, Germany

摘要 Abstract

中文摘要

背景：在RELATIVITY-104二期研究的第2部分中，一线nivolumab（NIVO）加relatlimab（RELA）联合铂类双药化疗（PDCT）对比NIVO+PDCT用于转移性NSCLC患者，NIVO+RELA+PDCT在预设的肿瘤PD-L1表达≥1%亚组中显示出改善的临床获益（包括总生存），该获益在NSQ肿瘤组织学中进一步富集。基线淋巴细胞激活基因3（LAG-3）表达与NIVO+RELA+PDCT和NIVO+PDCT两者的疗效富集均相关。在一项比较转录组学分析中，NSQ和鳞状肿瘤显示出不同的免疫特征，NSQ肿瘤表现出更高的LAG-3配体表达，并按PD-L1表达对联合治疗获益具有更大富集。为进一步阐明NIVO+RELA+PDCT的作用机制，我们报告RELATIVITY-104第2部分PD-L1≥1% NSQ亚组的额外探索性转化数据。方法：未经治疗的转移性NSCLC患者按1:1随机分配至NIVO 360 mg+RELA 360 mg+PDCT或NIVO 360 mg+PDCT，每3周一次（Q3W）。探索性终点包括PD-L1≥1% NSQ亚组的转化分析。对治疗前肿瘤RNA测序的基因表达数据进行标准化，并分析其与临床结局的关联。收集治疗前和治疗中外周血样本，使用经过验证的24标志物LAG-3特异性组合进行高维流式细胞术免疫表型分析，该组合对LAG-3、PD-1和CTLA-4采用耐药、非竞争性克隆。使用逻辑回归和Cox比例风险模型评估生物标志物与临床结局之间的统计学关联。数据来自2025年5月2日的数据库锁定。结果：在NIVO+RELA+PDCT组中，免疫特征在PD-L1≥1% NSQ亚组中显示出显著更低的风险比（HR），而基质特征显示出显著更高的HR。基线时T耗竭祖细胞特征亚群以及ICOS+ CD4+ T细胞被证明富集于NIVO+RELA+PDCT的生存获益。在所有基线LAG-3表达水平（<1%和≥1%）中均观察到临床获益；然而，NIVO+RELA+PDCT治疗中LAG-3+ T细胞的增加与更长的无进展生存和更高的客观缓解率相关。在NIVO+PDCT组中，LAG-3细胞群的增加与更低的缓解相关。结论：在RELATIVITY-104研究中，LAG-3+ T细胞的治疗中免疫动态与PD-L1表达≥1%和NSQ NSCLC患者中NIVO+RELA+PDCT对比NIVO+PDCT的获益相关。包括祖细胞T耗竭特征在内的免疫特征与NIVO+RELA+PDCT改善的结局相关。这些数据支持在PD-L1≥1% NSQ NSCLC中向抗PD-1+PDCT添加抗LAG-3的机制学理论依据。

查看英文原文 English abstract

Background: In Part 2 of the phase 2 RELATIVITY-104 study of first-line nivolumab (NIVO) plus relatlimab (RELA) with platinum-doublet chemotherapy (PDCT) vs NIVO + PDCT in patients with metastatic NSCLC, NIVO + RELA + PDCT demonstrated improved clinical benefit, including overall survival, in the prespecified subgroup of tumor PD-L1 expression ≥ 1%, which was further enriched in NSQ tumor histology. Baseline lymphocyte-activation gene 3 (LAG-3) expression was associated with enriched efficacy for both NIVO + RELA + PDCT and NIVO + PDCT. In a comparative transcriptomic analysis, NSQ and squamous tumors demonstrated distinct immune signatures, with NSQ tumors exhibiting higher expression of LAG-3 ligands and greater enrichment for combination therapy benefit by PD-L1 expression. To further elucidate the mechanism of action of NIVO + RELA + PDCT, we report additional exploratory translational data in the PD-L1 ≥ 1% NSQ subgroup for Part 2 of RELATIVITY-104. Methods: Patients with untreated metastatic NSCLC were randomized 1:1 to NIVO 360 mg + RELA 360 mg + PDCT or NIVO 360 mg + PDCT Q3W. Exploratory endpoints included translational analyses in the PD-L1 ≥ 1% NSQ subgroup. Gene expression data from pretreatment tumor RNA sequencing were normalized and analyzed for associations with clinical outcomes. Pre- and on-treatment peripheral blood samples were collected for high-dimensional flow cytometry immunophenotyping using a validated 24-marker LAG-3-specific panel that used drug-tolerant, noncompeting clones for LAG-3, PD-1, and CTLA-4. Statistical associations between biomarkers and clinical outcomes were assessed using logistic regression and Cox proportional hazards models. Data are from the May 2, 2025, database lock. Results: In the NIVO + RELA + PDCT arm, immune signatures demonstrated a significantly lower hazard ratio (HR) in the PD-L1 ≥ 1% NSQ subgroup, while stromal signatures demonstrated a significantly higher HR. T exhausted progenitor signature subsets, as well as ICOS+ CD4+ T cells, at baseline were shown to enrich for survival with NIVO + RELA + PDCT. Clinical benefit was observed across all baseline LAG-3 expression levels (< 1% and ≥ 1%); however, on-treatment increases in LAG-3+ T cells were associated with longer progression-free survival and a higher objective response rate with NIVO + RELA + PDCT. In the NIVO + PDCT arm, increases in LAG-3 cell populations were associated with lower response. Conclusions: In the RELATIVITY-104 study, the on-treatment immune dynamics of LAG-3+ T cells correlated with the benefit of NIVO + RELA + PDCT vs NIVO + PDCT in patients with PD-L1 expression ≥ 1% and NSQ NSCLC. Immune signatures including progenitor T exhausted signatures associated with improved outcomes with NIVO + RELA + PDCT. These data support the mechanistic rationale for adding anti-LAG-3 to anti-PD-1 + PDCT in PD-L1 ≥ 1% NSQ NSCLC.

利益披露 Disclosure

J. Neely, Bristol Myers Squibb Employment, Stock. A. Yu, Bristol Myers Squibb Employment, Stock. N. Girard, None.. M. Cobo-Dols, None.. M. Burotto, None. L. Paz-Ares, MSD Other, Grants or contracts, consulting fees. AstraZeneca Other, Grants or contracts, consulting fees, and payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events. Pfizer Other, Grants or contracts, consulting fees. BMS Other, Grants or contracts, consulting fees. Lilly Other, Consulting fees. Roche Other, Consulting fees. PharmaMar Other, Consulting fees. Merck Other, Consulting fees and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events. Novartis Other, Consulting fees. Servier Other, Consulting fees. Bayer Other, Consulting fees. Amgen Other, Consulting fees. Sanofi Other, Consulting fees. Mirati Other, Consulting fees and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events. GSK Other, Consulting fees. Janssen Other, Consulting fees and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events. Takeda Other, Consulting fees. Daichii Sankyo Other, Consulting fees. V. Velcheti, BMS, Merck, Astrazenca, BI Oncology, Abbott Independent Contractor, Other, Consulting, Advisory Role. M. Reck, Amgen Other, Consulting fees; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events; and support for attending meetings and/or travel. AstraZeneca Consulting fees; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events; and support for attending meetings and/or travel. Beigene Other, Consulting fees; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events; and support for attending meetings and/or travel. Boehringer-Ingelheim Other, Consulting fees; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events; and support for attending meetings and/or travel. BMS Other, Consulting fees; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events; and support for attending meetings and/or travel. Lilly Other, Consulting fees; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events; and support for attending meetings and/or travel. Merck Other, Consulting fees; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events; and support for attending meetings and/or travel. MSD Other, Consulting fees; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events; and support for attending meetings and/or travel. Mirati Other, Consulting fees; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events; and support for attending meetings and/or travel. Novartis Other, Consulting fees; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events; and support for attending meetings and/or travel. GSK Other, Consulting fees; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events; and support for attending meetings and/or travel. Pfizer Other, Consulting fees; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events; and support for attending meetings and/or travel. Roche Other, Consulting fees; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events; and support for attending meetings and/or travel. Regeneron Other, Consulting fees; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events; and support for attending meetings and/or travel. Sanofi Other, Consulting fees; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events; support for attending meetings and/or travel; and participation on a data safety monitoring board or advisory board. Daiichi-Sankyo Other, Consulting fees; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events; support for attending meetings and/or travel; and participation on a data safety monitoring board or advisory board. Janssen Other, Consulting fees; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events; and support for attending meetings and/or travel. S. Samanta, Bristol Myers Squibb Employment. A. Qureshi, Bristol Myers Squibb Company Employment. P. Kasbekar, Bristol Myers Squibb Employment. C. Garnett-Benson, Bristol Myers Squibb Employment, Stock.

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