局部晚期或转移性非鳞状非小细胞肺癌伴KRAS突变的生存及预后差异分析

摘要(中文译文)

在东亚人群中，非小细胞肺癌（NSCLC）中Kirsten大鼠肉瘤病毒癌基因（KRAS）突变的发生率约为10%至15%。尽管靶向药物已获批上市，但中国临床肿瘤学会（CSCO）指南仅将其推荐为二线选择，一线治疗方案的选取仍有待验证。本研究旨在探讨真实世界背景下KRAS突变NSCLC各种初始治疗方案的有效性。研究回顾性分析了中国人民解放军总医院过去十年间收治的180例KRAS突变阳性的局部晚期或转移性非鳞状NSCLC患者的临床资料。根据初始治疗方案对患者进行分组，比较疗效与预后，并分析相关影响因素。180例患者的中位无进展生存期（mPFS）为8.60个月，中位总生存期（mOS）为17.47个月。免疫检查点抑制剂联合化疗（ICIs+CHE）显示出最佳疗效，mPFS为11.30个月，mOS为21.24个月，客观缓解率（ORR）为39.29%，疾病控制率（DCR）为89.29%。ICIs包括标准的程序性细胞死亡蛋白1（PD-1）/程序性死亡配体1（PD-L1）抗体，化疗为铂类双药方案，抗血管生成治疗仅限于贝伐珠单抗（BEV）。本研究直接比较了ICIs+CHE与三药联合方案（ICIs+CHE+BEV），填补了现有研究空白。ICIs+CHE组的无进展生存期（PFS）显著优于单用ICIs或单用CHE，总生存期（OS）优于单用CHE。在ICIs+CHE基础上加用抗血管生成治疗未提供显著的额外获益。不同水平的PD-L1表达未影响以免疫治疗为基础方案的PFS或OS。在单因素和多因素分析中，年龄和性别未影响PFS；较高的美国东部肿瘤协作组（ECOG）体能状态评分和骨转移与OS相关。各组基线特征总体可比，仅在年龄、脑转移和PD-L1表达方面存在微小差异（P<0.05），但这些因素并未独立预测生存。ICIs+CHE是局部晚期/转移性KRAS突变非鳞状NSCLC患者的首选一线治疗方案，加用抗血管生成药物并未提高疗效。临床治疗方案应根据患者特征进行个体化选择，PD-L1表达水平未作为以免疫治疗为基础治疗方案的生存分层因素。

Abstract

Among Eastern populations, the occurrence of Kirsten rat sarcoma viral oncogene (KRAS) mutations in non-small cell lung cancer (NSCLC) is around 10% to 15%. Despite being approved for marketing, targeted drugs are recommended by the Chinese Society of Clinical Oncology (CSCO) Guidelines only as a second-line option, and the selection of first-line treatment regimens remains to be verified. The purpose of this study is to explore the effectiveness of various initial treatment plans for NSCLC with KRAS mutations in real-world settings. The study reviewed the clinical data of 180 patients with KRAS mutation-positive locally advanced or metastatic non-squamous NSCLC treated at the Chinese People's Liberation Army (PLA) General Hospital over the previous decade. The patients were categorized based on their initial treatment plans to compare therapeutic efficacy and prognosis, and the relevant influencing factors were analyzed. In the 180 patients, median progression-free survival (mPFS) was 8.60 months and median overall survival (mOS) was 17.47 months. Immune checkpoint inhibitors plus chemotherapy (ICIs + CHE) showed the best efficacy, with mPFS 11.30 months, mOS 21.24 months, objective response rate (ORR) 39.29%, and disease control rate (DCR) 89.29%. ICIs included standard programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) antibodies, chemotherapy was platinum-based doublet therapy, and anti-angiogenic therapy was limited to bevacizumab (BEV). This study directly compared ICIs + CHE with the triple combination (ICIs + CHE + BEV) to fill an existing research gap. The ICIs + CHE group had significantly better progression-free survival (PFS) than ICIs or CHE alone, and better overall survival (OS) than CHE alone. Adding anti-angiogenic therapy to ICIs + CHE provided no significant additional benefit. Different level of PD-L1 expression did not affect PFS or OS in immunotherapy-based regimens. In univariate and multivariate analyses, age and gender did not influence PFS; high Eastern Cooperative Oncology Group (ECOG) performance status and bone metastasis were associated with OS. Baseline characteristics were generally comparable across groups, with only minor differences in age, brain metastasis, and PD-L1 expression (P<0.05), which did not independently predict survival. ICIs + CHE is the preferred first-line treatment regimen for patients with locally advanced/metastatic KRAS-mutant non-squamous NSCLC, and the addition of anti-angiogenic agents does not improve therapeutic efficacy. Clinical treatment regimens should be selected individually based on patient characteristics and PD-L1 expression level did not serve as a survival stratification factor for immunotherapy-based treatment regimens.

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