Sun Lova, Zhou Yunyun, Handorf Elizabeth A, Borghaei Hossein, Bauman Jessica, Aggarwal Charu
Division of Hematology and Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Fox Chase Cancer Center, Philadelphia, Pennsylvania.
JTO Clin Res Rep. 2024 Oct 24;6(1):100755. doi: 10.1016/j.jtocrr.2024.100755. eCollection 2025 Jan.
The predictive and prognostic implications of different mutation (m) subtypes in metastatic NSCLC have not been clearly defined. We used a nationwide observational database to investigate whether m 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.
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 , , , and were included. Within PD-L1 expression subgroups (<1%, 1%-49%, ≥50%), Cox multivariable regression was used to evaluate the association between m subtypes (G12C, G12V, G12D, other m) and overall survival, estimated using Kaplan-Meier methodology.
Among the 1539 patients, 819 patients were wild type (wt) and 720 were m (296 G12C, 143 G12V, 97 G12D, 184 other m). In the 50% or higher PD-L1 subgroup, patients with G12V had worse survival (median overall survival [mOS] = 8.2 mo) compared with wt (mOS = 13.3 mo) and other 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 G12V ranged from 1.53 to 1.78 compared with wt and other m subtypes (all < 0.05).
Although patients with 50% or higher PD-L1 with G12C, G12D, and other subtypes exhibited similar survival to wt, G12V was associated with significantly worse survival than wt and other m subtypes. All m should not be regarded as uniform predictors of ICI responsiveness, even with high PD-L1 expression; G12V tumors may have worse outcomes with ICI-based therapy and benefit from treatment intensification.
转移性非小细胞肺癌（NSCLC）中不同突变（m）亚型的预测和预后意义尚未明确界定。我们使用了一个全国性的观察数据库，以研究在接受基于免疫检查点抑制剂（ICI）治疗的转移性NSCLC中，m亚型与生存的关联是否因程序性死亡配体1（PD-L1）水平而异。
纳入2016年至2021年开始一线基于ICI治疗、已知PD-L1表达且进行了包括 、 、 及 在内的全面基因组分析的晚期非鳞状NSCLC患者。在PD-L1表达亚组（<1%、1%-49%、≥50%）中，采用Cox多变量回归评估m亚型（G12C、G12V、G12D、其他m）与总生存的关联，总生存采用Kaplan-Meier方法估算。
在1539例患者中，819例患者为 野生型（wt），720例为m（296例G12C、143例G12V、97例G12D、184例其他m）。在PD-L1 50%或更高的亚组中，G12V患者的生存情况（中位总生存[mOS]=8.2个月）比wt（mOS=13.3个月）及其他 亚组（mOS为13.4至19.9个月）更差。在PD-L1 50%或更高的亚组中进行校正后的Cox多变量回归分析，与wt及其他m亚型相比，G12V的死亡风险比为1.53至1.78（所有 均<0.05）。
尽管PD-L1 50%或更高的G12C、G12D及其他亚型患者的生存情况与wt相似，但G12V与比wt及其他m亚型显著更差的生存相关。即使PD-L1高表达，所有m也不应被视为ICI反应性的统一预测指标；G12V肿瘤接受基于ICI的治疗可能预后更差，且可能从强化治疗中获益。
