PO.CL01.03 · 临床研究

高PRMT5表达与非小细胞肺癌免疫浸润减少及免疫检查点抑制剂疗效较差相关

High PRMT5 expression is associated with decreased immune infiltrate and worse outcomes to immune checkpoint inhibitors in non-small cell lung cancer

编号 2446 展板 16 时间 4/20 09:00–12:00 区域 Section 40 主讲 Natalie Vokes, MD

分会场 Biomarkers Predictive of Therapeutic Benefit 3

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作者与单位 Authors & Affiliations

Natalie Vokes¹, Stamatina Fragkogianni², Pooja A. Shah³, Santiago G. Trevino¹, Konstantinos Leventakos⁴, Lei Deng⁵, Matthew Lee⁶, Tali Azenkot⁷, KAYLA LAYNG², JACOB MERCER², Jyoti Patel², Jordi Rodon Ahnert⁸

¹MD Anderson Cancer Center, Houston, TX,²Tempus, Chicago, IL,³UT MD Anderson Cancer Center, Houston, TX,⁴Mayo Clinic Cancer Center Minnesota, Rochester, MN,⁵Fred Hutchinson Cancer Center, Seattle, WA,⁶City of Hope, Duarte, CA,⁷University of California San Diego - UCSD, San Diego, CA,⁸UT MD Anderson Cancer Center, Conroe, TX

摘要 Abstract

中文摘要

背景：MTAP缺失发生于10-15%的癌症中，并与不良预后相关。MTAP缺失（MTAPdel）导致MTA蓄积，从而部分抑制PRMT5，为PRMT5抑制剂创造了一种合成致死策略。多种在研的MTA协同型PRMT5抑制剂已在MTAPdel NSCLC及其他癌症中显示出早期临床疗效。MTAPdel、PRMT5表达以及对标准治疗免疫检查点抑制剂（ICI）和化疗（chemo）的临床结局尚未得到充分表征。方法：使用Tempus Lens平台（Tempus AI, Inc., 芝加哥, IL）查询Tempus多模态去标识化数据库，建立并随后分析了一个患者队列（pts），这些患者患有NSCLC并接受了DNA（Tempus xT）和RNA（Tempus xR）检测，接受一线（1L）ICI联合或不联合化疗治疗（N=3,676）。PRMT5表达以每百万转录本（TPM）标准化，并报告为log2(TPM + 1)。根据PRMT5表达中位数将患者分为高与低组，并根据MTAP双等位基因缺失分为MTAPdel与完整（MTAPwt）组。使用Quantiseq估计免疫浸润。真实世界总生存期（rwOS）定义为从1L开始至死亡或末次已知随访的时间。真实世界无进展生存期（rwPFS）定义为从1L开始至死亡、进展或末次已知随访的时间。使用Cox比例风险模型计算风险比（HR），并根据年龄、性别、组织学、吸烟状态和PDL1状态进行校正。结果：MTAPdel患者的PRMT5表达适度增加（6.65对6.70，p=0.012）。在MTAPdel和MTAPwt患者中，PRMT5高表达肿瘤均富集MYC、SMARCA4和KEAP1的改变（p<0.03）。PRMT5高表达肿瘤的患者多种免疫细胞浸润减少，包括B细胞、巨噬细胞（M1和M2）、NK细胞、CD4和CD8 T细胞（p<0.001）。当单用ICI治疗时，MTAPdel/PRMT5高表达患者的rwOS较MTAPwt/PRMT5低表达患者更短（HR 1.58，95% CI 1.11-2.24，p=0.011），联用ICI+化疗时亦然（HR 1.65，95% CI 1.34-2.03，p<0.001）。这些关联在多变量分析中依然存在。MTAPdel/PRMT5高表达患者在接受ICI+化疗治疗时，单变量和多变量分析中也与更差的rwPFS相关（HR 1.5，95% CI 1.22-1.86，p<0.001），但在单用ICI治疗的患者中与rwPFS无关（HR=0.97，95% CI 0.66-1.42，p=0.9）。结论：PRMT5表达界定了一个免疫抑制的NSCLC患者亚群。PRMT5表达升高且伴MTAPdel的患者对ICI联合或不联合化疗的结局较差，表明PRMT5 RNA表达水平可用于指导临床试验设计，尤其是那些测试新型联合策略的试验。

查看英文原文 English abstract

Background: Deletions in MTAP occur in 10-15% of cancers and are associated with poor prognosis. MTAP deletion (MTAPdel) leads to accumulation of MTA which causes partial inhibition of PRMT5, creating a synthetic lethality approach with PRMT5 inhibitors. Multiple investigational MTA-cooperative PRMT5 inhibitors have demonstrated early clinical efficacy in MTAPdel NSCLC and other cancers. MTAPdel, PRMT5 expression, and clinical outcomes to standard of care immune checkpoint inhibitors (ICI) and chemotherapy (chemo) have not been well characterized. Methods: The Tempus Lens Platform (Tempus AI, Inc., Chicago, IL) was used to query the Tempus multimodal de-identified database and establish and subsequently analyze a cohort of patients (pts)with NSCLC and DNA (Tempus xT) and RNA (Tempus xR) testing, treated with front-line (1L) ICI with or without chemo (N=3,676). PRMT5 expression was normalized as transcripts per million (TPM) and reported as log2(TPM + 1). Pts were classified into high vs low groups based on median PRMT5 expression and into MTAPdel vs intact (MTAPwt) based on MTAP biallelic loss. Immune infiltration was estimated using Quantiseq. Real-world overall survival (rwOS) was defined as the time from 1L start to death or last known follow-up. Real-world progression-free survival (rwPFS) was defined as the time from 1L start to death, progression or last known follow-up. Hazard ratios (HR) were calculated using Cox proportional hazards models and adjusted for age, sex, histology, smoking status and PDL1 status. Results: PRMT5 expression was moderately increased in pts with MTAPdel (6.65 v 6.70, p=0.012). Alterations in MYC , SMARCA4 and KEAP1 were enriched in PRMT5-high tumors in both MTAPdel and MTAPwt pts (p<0.03). Pts with PRMT5-high tumors had decreased infiltrate of multiple immune cells, including B cells, macrophages (M1 and M2), NK cells, CD4 and CD8 T cells (p<0.001). Pts with MTAPdel/PRMT5-high expression had shorter rwOS compared to MTAPwt/PRMT5-low when treated with ICI alone (HR 1.58, 95% CI 1.11-2.24, p=0.011) or with ICI + chemo (HR 1.65, 95% CI 1.34-2.03, p<0.001). These associations persisted on multivariate analysis. Pts with MTAPdel/PRMT5-high expression were also associated with worse rwPFS when treated with ICI + chemo (HR 1.5, 95% CI 1.22-1.86, p<0.001) on univariate and multivariate analysis, but did not associate with rwPFS in pts treated with ICI alone (HR=0.97, 95% CI 0.66-1.42, p=0.9). Conclusion: PRMT5 expression defines an immune suppressed subpopulation of pts with NSCLC. Pts with elevated PRMT5 expression and MTAPdel have poor outcomes with ICI+/- chemo, indicating PRMT5 RNA expression levels can be used to inform clinical trial designs, particularly those that are testing novel combinatorial strategies.

利益披露 Disclosure

N. Vokes, Boehringer Ingelheim Independent Contractor, Travel. Tango Independent Contractor, Travel. Catalyst pharmaceuticals Independent Contractor. Astra Zeneca Independent Contractor. ImmunityBio Independent Contractor. Guardant Independent Contractor, ). OncoHost Independent Contractor, ). Summit Therapeutics Independent Contractor, ). Pfizer Independent Contractor. Tempus Independent Contractor, ). Xencor Independent Contractor. Amgen Independent Contractor. Sanofi ). BMS ). IDEAYA ). Regeneron Independent Contractor, ). L. Deng, BMS Independent Contractor. Regeneron Independent Contractor. Merck ), Travel. BridgeBio ). Revolution Medicines ). M. Lee, None.

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