Frost Nikolaj, Kollmeier Jens, Vollbrecht Claudia, Grah Christian, Matthes Burkhard, Pultermann Dennis, von Laffert Maximilian, Lüders Heike, Olive Elisabeth, Raspe Matthias, Mairinger Thomas, Ochsenreither Sebastian, Blum Torsten, Hummel Michael, Suttorp Norbert, Witzenrath Martin, Grohé Christian
Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Infectious Diseases and Pulmonary Medicine, Berlin, Germany.
Helios Klinikum Emil von Behring, Lungenklinik Heckeshorn, Berlin, Germany.
Transl Lung Cancer Res. 2021 Feb;10(2):737-752. doi: 10.21037/tlcr-20-958.
Pembrolizumab is a standard of care as first line palliative therapy in PD-L1 overexpressing (≥50%) non-small cell lung cancer (NSCLC). This study aimed at the identification of KRAS and TP53-defined mutational subgroups in the PD-L1 high population to distinguish long-term responders from those with limited benefit.
In this retrospective, observational study, patients from 4 certified lung cancer centers in Berlin, Germany, having received pembrolizumab monotherapy as first line palliative treatment for lung adenocarcinoma (LuAD) from 2017 to 2018, with PD-L1 expression status and targeted NGS data available, were evaluated.
A total of 119 patients were included. Rates for KRAS, TP53 and combined mutations were 52.1%, 47.1% and 21.9%, respectively, with no association given between KRAS and TP53 mutations (P=0.24). By trend, PD-L1 expression was higher in KRAS-positive patients (75% 65%, P=0.13). Objective response rate (ORR), median progression-free survival (PFS) and overall survival (OS) in the KRAS group (n=32, 51.6%) were 63.3%, 19.8 months (mo.) and not estimable (NE), respectively. Results in KRAS and wild type patients were similar and by far lower (42.7%, P=0.06; 6.2 mo., P<0.001; 23.4 mo., P=0.08). TP53 mutations alone had no impact on response and survival. However, KRAS/TP53 co-mutations (n=12) defined a subset of long-term responders (ORR 100.0%, PFS 33.3 mo., OS NE). In contrast, patients with KRAS/TP53 mutations showed a dismal prognosis (ORR 27.3%, P=0.002; PFS 3.9 mo., P=0.001, OS 9.7 mo., P=0.02).
A comprehensive assessment of KRAS subtypes and TP53 mutations allows a highly relevant prognostic differentiation of patients with metastatic, PD-L1 high LuAD treated upfront with pembrolizumab.
帕博利珠单抗是程序性死亡受体 1 配体（PD-L1）过表达（≥50%）的非小细胞肺癌（NSCLC）一线姑息治疗的标准疗法。本研究旨在确定 PD-L1 高表达人群中由 KRAS 和 TP53 定义的突变亚组，以区分长期缓解者和获益有限者。
在这项回顾性观察研究中，对 2017 年至 2018 年期间来自德国柏林 4 家认证肺癌中心、接受帕博利珠单抗单药作为肺腺癌（LuAD）一线姑息治疗、有 PD-L1 表达状态和靶向二代测序（NGS）数据的患者进行了评估。
共纳入 119 例患者。KRAS、TP53 和联合突变率分别为 52.1%、47.1%和 21.9%，KRAS 和 TP53 突变之间无关联（P = 0.24）。趋势上，KRAS 阳性患者的 PD-L1 表达较高（75%对 65%，P = 0.13）。KRAS 组（n = 32，51.6%）的客观缓解率（ORR）、中位无进展生存期（PFS）和总生存期（OS）分别为 63.3%、19.8 个月（mo.）和不可估计（NE）。KRAS 突变型和野生型患者的结果相似且远低于此（42.7%，P = 0.06；6.2 个月，P < 0.001；23.4 个月，P = 0.08）。单独的 TP53 突变对缓解和生存无影响。然而，KRAS/TP53 共突变（n = 12）定义了一组长期缓解者（ORR 100.0%，PFS 33.3 个月，OS NE）。相比之下，KRAS/TP53 突变患者预后较差（ORR 27.3%，P = 0.002；PFS 3.9 个月，P = 0.001，OS 9.7 个月，P = 0.02）。
对 KRAS 亚型和 TP53 突变进行全面评估，能够对接受帕博利珠单抗一线治疗的转移性、PD-L1 高表达 LuAD 患者进行高度相关的预后区分。
