PO.CL09.01 · 临床研究

非小细胞肺癌一线免疫检查点抑制剂结局的临床基因组预测因素：来自日本的全国性C-CAT队列

Clinicogenomic predictors of first-line immune checkpoint inhibitor outcomes in non-small cell lung cancer: A nationwide C-CAT cohort from Japan

编号 5338 展板 6 时间 4/21 09:00–12:00 区域 Section 46 主讲 Mika Iwasaki, MD

分会场 Precision Oncology and Real World Data

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作者与单位 Authors & Affiliations

Mika Iwasaki¹, Takahiro Ando¹, Koki Fujii¹, Kousuke Watanabe¹, Katsutoshi Oda², Hidenori Kage¹

¹Department of Respiratory Medicine, The University of Tokyo, Tokyo, Japan,²Division of Integrative Genomics, The University of Tokyo, Tokyo, Japan

摘要 Abstract

中文摘要

背景：免疫检查点抑制剂（ICIs）在非小细胞肺癌（NSCLC）中的疗效存在差异，凸显了对预测性生物标志物的需求。程序性死亡配体1（PD-L1）和肿瘤突变负荷（TMB）被广泛使用，但敏感性和特异性有限。越来越多的证据表明，基因组改变塑造免疫反应并影响ICI结局。然而，来自大规模真实世界队列的数据，特别是在东亚患者中，仍然有限。方法：我们回顾性分析了癌症基因组学与先进治疗中心（C-CAT）数据库，整合了全面基因组分析（CGP）结果与来自日本各地癌症患者的临床信息，涵盖了国家保险计划下99.7%的所有CGP检测。共有1,629例IV期NSCLC患者在2019年至2025年间接受了一线ICI为基础的治疗。主要终点为治疗失败时间（TTF）；次要终点为总生存期（OS）。我们使用按年龄分层并校正协变量的Cox模型。基因组协变量包括KRAS、KEAP1和STK11，以及来自探索性筛查的其他基因。为阐明交互效应，我们进一步将结果表示为以野生型为参照的风险比，针对KRAS单独、KEAP1单独、STK11单独及其共突变（KRAS-KEAP1和KRAS-STK11）。敏感性分析包括一个具有TMB数据的仅福尔马林固定石蜡包埋（FFPE）子集（n = 1,095，分为<10 vs ≥10 mut/Mb），模型还校正了ECOG体能状态（0、1、≥2）。结果：BRAF突变与更长的TTF独立相关（HR 0.77，95% CI 0.59-1.00；p = 0.049），而KRAS、KEAP1和STK11单独均无显著关联（HRs 1.21、1.08和1.09；均p > 0.21）。显著的KRAS-KEAP1交互作用与更短的TTF相关（HR 1.89，95% CI 1.06-3.36；p = 0.032）。与PD-L1 ≥ 50%相比，PD-L1 < 1%与更短的TTF相关（HR 1.17；p = 0.041）。在与野生型的四级比较中，KRAS单独和KEAP1单独均不显著（HRs 1.09和1.21），而KRAS-KEAP1共突变与更高的治疗失败风险相关（HR 2.48，95% CI 1.50-4.10；p < 0.001）。在具有TMB数据的仅FFPE子集中结果一致。KEAP1（p < 0.001）和STK11（p = 0.001）与更差的OS相关，而BRAF未显示出显著差异（p = 0.840）。结论：在一线ICI治疗的IV期NSCLC中，是KRAS-KEAP1共突变（而非单独的KRAS或KEAP1）识别出早期失败的高风险患者，而BRAF与更长的TTF相关。这些发现突显了共突变分析在指导治疗选择中的重要性，并有必要通过纳入PD-L1和TMB的整合模型进行前瞻性验证。

查看英文原文 English abstract

Background: The efficacy of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) varies, underscoring the need for predictive biomarkers. Programmed death-ligand 1 (PD-L1) and tumor mutational burden (TMB) are widely used but have limited sensitivity and specificity. Increasing evidence suggests that genomic alterations shape immune responses and influence ICI outcomes. However, data from large-scale real-world cohorts, particularly in East Asian patients, remain limited. Methods: We retrospectively analyzed the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database, integrating comprehensive genomic profiling (CGP) results with clinical information from cancer patients across Japan, encompassing 99.7% of all CGP tests under the national insurance program. A total of 1,629 patients with stage IV NSCLC received first-line ICI-based therapy between 2019 and 2025. The primary endpoint was time to treatment failure (TTF); the secondary endpoint was overall survival (OS). We used age-stratified Cox models adjusted for covariates. Genomic covariates included KRAS, KEAP1 , and STK11 , with additional genes from an exploratory screening. To clarify interaction effects, we further expressed results as wild-type-referenced hazard ratios for KRAS -only, KEAP1 -only, STK11 -only, and their co-mutations ( KRAS - KEAP1 and KRAS - STK11 ). Sensitivity analyses included a formalin-fixed paraffin-embedded (FFPE)-only subset with TMB available (n = 1,095, categorized as <10 vs ≥10 mut/Mb), and models also adjusting for ECOG performance status (0, 1, ≥ 2). Results: BRAF mutation was independently associated with longer TTF (HR 0.77, 95% CI 0.59-1.00; p = 0.049), whereas KRAS , KEAP1 , and STK11 alone showed no significant associations (HRs 1.21, 1.08, and 1.09; all p > 0.21). A significant KRAS - KEAP1 interaction was associated with shorter TTF (HR 1.89, 95% CI 1.06-3.36; p = 0.032). Compared with PD-L1 ≥ 50%, PD-L1 < 1% was associated with shorter TTF (HR 1.17; p = 0.041). In a four-level comparison versus wild-type, KRAS -only and KEAP1 -only were not significant (HRs 1.09 and 1.21), whereas the KRAS - KEAP1 co-mutation was associated with higher risk of treatment failure (HR 2.48, 95% CI 1.50-4.10; p < 0.001). Results were consistent in FFPE-only subsets with TMB data. KEAP1 ( p < 0.001) and STK11 ( p = 0.001) were associated with worse OS, while BRAF showed no significant difference ( p = 0.840). Conclusions: In first-line ICI-treated stage IV NSCLC, KRAS - KEAP1 co-mutation, not KRAS or KEAP1 alone, identifies patients at high risk of early failure, whereas BRAF was associated with longer TTF. These findings highlight the importance of co-mutation profiling in guiding treatment selection and warrant prospective validation with integrative models incorporating PD-L1 and TMB.

利益披露 Disclosure

M. Iwasaki, None.. T. Ando, None.. K. Fujii, None. K. Watanabe, Konica Minolta, Inc. ), Endowed chair. GenMine Labs Corp. Lecture fees. K. Oda, Konica Minolta, Inc.ca ). GenMine Labo, Inc. Lecture fees. H. Kage, None.

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