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Brief Report: Not Created Equal: Survival Differences by KRAS Mutation Subtype in NSCLC Treated with Immunotherapy

Lova Sun, Yunyun Zhou, Elizabeth A. Handorf,Hossein Borghaei,Jessica Bauman,Charu Aggarwal

JTO Clinical and Research Reports(2025)

Univ Penn | Fox Chase Canc Ctr

Cited 0|Views1
Abstract
Introduction The predictive and prognostic implications of different KRAS mutation (KRASm) subtypes in metastatic NSCLC have not been clearly defined. We used a nationwide observational database to investigate whether KRASm subtypes differ in their association with survival in metastatic NSCLC treated with immune checkpoint inhibitor (ICI)-based therapy, across programmed death-ligand 1 (PD-L1) levels. Methods Patients with advanced nonsquamous NSCLC who initiated first-line ICI-based therapy from 2016 to 2021 and had known PD-L1 expression and comprehensive genomic profiling including KRAS, STK11, KEAP1, and TP53 were included. Within PD-L1 expression subgroups (<1%, 1%-49%, >= 50%), Cox multivariable regression was used to evaluate the association between KRASm subtypes (G12C, G12V, G12D, other KRASm) and overall survival, estimated using Kaplan-Meier methodology. Results Among the 1539 patients, 819 patients were KRAS wild type (KRASwt) and 720 were KRASm (296 KRAS G12C, 143 KRAS G12V, 97 KRAS G12D, 184 other KRASm). In the 50% or higher PD-L1 subgroup, patients with KRAS G12V had worse survival (median overall survival [mOS] = 8.2 mo) compared with KRASwt (mOS = 13.3 mo) and other KRAS subgroups (mOS ranging from 13.4 to 19.9 mo). On adjusted Cox multivariable regression in the 50% or higher PD-L1 subgroup, the hazard ratio for death for KRAS G12V ranged from 1.53 to 1.78 compared with KRASwt and other KRASm subtypes (all p < 0.05). Conclusions Although patients with 50% or higher PD-L1 with KRAS G12C, G12D, and other subtypes exhibited similar survival to KRASwt, KRAS G12V was associated with significantly worse survival than KRASwt and other KRASm subtypes. All KRASm should not be regarded as uniform predictors of ICI responsiveness, even with high PD-L1 expression; KRAS G12V tumors may have worse outcomes with ICI-based therapy and benefit from treatment intensification. (c) 2024 The Authors. Published by Elsevier Inc. on behalf of the International Association for the Study of Lung Cancer. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/ 4.0/).
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NSCLC,Immunotherapy,KRAS mutation
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要点】:研究通过全国观察数据库分析不同KRAS突变亚型在免疫治疗下的生存差异,发现KRAS G12V亚型与显著较差的生存率相关,表明所有KRAS突变不应被视为同质的免疫检查点抑制剂响应预测因子。

方法】:使用Cox多变量回归分析KRAS突变亚型与总体生存率之间的关联,通过Kaplan-Meier方法估计生存率。

实验】:纳入2016至2021年间开始一线免疫检查点抑制剂治疗且已知PD-L1表达和综合基因组分析(包括KRAS、STK11、KEAP1和TP53)的晚期非鳞状NSCLC患者,共1539例,分析其生存数据。结果显示,在PD-L1表达≥50%的患者中,KRAS G12V亚型患者的总生存期显著较差。