EGFR 或 HER2 外显子 20 插入的非小细胞肺癌患者的免疫微环境特征和 PD-1/PD-L1 阻断疗效。

Immune microenvironment features and efficacy of PD-1/PD-L1 blockade in non-small cell lung cancer patients with EGFR or HER2 exon 20 insertions.

机构信息

The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China.

Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China.

出版信息

Thorac Cancer. 2021 Jan;12(2):218-226. doi: 10.1111/1759-7714.13748. Epub 2020 Nov 18.

BACKGROUND

Insertions in exon 20 (Ex20ins) of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) are relatively insensitive to first- and second-generation EGFR-tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). This study aimed to investigate the immune microenvironment features and efficacy of PD-1/PD-L1 blockade of NSCLC with EGFR and HER2 Ex20ins.

METHODS

Clinical characteristics, coexisting mutations, and outcomes to EGFR-TKIs and immune checkpoint blockade were reviewed for NSCLC patients with exon 20 mutations of EGFR or HER2. Data obtained included the molecular spectrum (extended genotyping for mutations in 324 cancer-related genes), as well as tumor mutational burden (TMB), PD-L1 protein expression, and the abundance of CD4+ and CD8+ tumor-infiltrating lymphocytes (TILs).

RESULTS

A total of 1270 NSCLC patients were identified. Of these, 504 (39.7%) cases had EGFR mutations and 6.9% (35/504) of them had EGFR Ex20ins. Meanwhile, 21 (1.7%) cases with HER2 Ex20ins were detected. Comprehensive genomic profiling identified A767_V769dup variant (25.0%) was the most common type in tumors with EGFR Ex20ins. Co-occurring mutations were not uncommon including TP53 (45%), PIK3CA (20%), CDKN2A (10%), and EGFR amplification (20%). The average TMB was 3.3 mutations/megabase. PD-L1 expression in patients with EGFR Ex20ins was significantly higher than for those with HER2 mutations (48.6% vs. 19.0%, P = 0.027). High TMB and PD-L1 expression was independently associated with significantly poor prognosis (P = 0.025, P = 0.045, respectively) while there was no association between CD4+/CD8+ TILs and prognosis in EGFR or HER2 mutant NSCLC. Finally, patients harboring EGFR Ex20ins seemed to be sensitive to PD-1/PD-L1 blockage whereas it showed limited efficacy in patients with HER2 Ex20ins.

CONCLUSIONS

NSCLC patients with EGFR/HER2 Ex20ins had similar genomic characteristics and distinct immune features. Patients with EGFR Ex20ins had significantly higher PD-L1 expression than those with HER2 mutations, which may be the potential reason for the different responses to PD-1/PD-L1 blockage.

背景

表皮生长因子受体（EGFR）和人表皮生长因子受体 2（HER2）外显子 20 插入（Ex20ins）对非小细胞肺癌（NSCLC）的第一代和第二代 EGFR 酪氨酸激酶抑制剂（TKI）相对不敏感。本研究旨在探讨 EGFR 和 HER2 Ex20ins 肺癌的 PD-1/PD-L1 阻断的免疫微环境特征和疗效。

方法

对 EGFR 或 HER2 外显子 20 突变的 NSCLC 患者的临床特征、共存突变以及对 EGFR-TKIs 和免疫检查点阻断的疗效进行了回顾性分析。获得的数据包括分子谱（对 324 种与癌症相关的基因进行扩展基因分型），以及肿瘤突变负担（TMB）、PD-L1 蛋白表达以及 CD4+和 CD8+肿瘤浸润淋巴细胞（TIL）的丰度。

结果

共鉴定了 1270 例 NSCLC 患者。其中，504 例（39.7%）有 EGFR 突变，其中 6.9%（35/504）有 EGFR Ex20ins。同时，检测到 21 例（1.7%）HER2 Ex20ins 病例。综合基因组分析确定 A767_V769dup 变异（25.0%）是 Ex20ins 肿瘤中最常见的类型。共存突变并不少见，包括 TP53（45%）、PIK3CA（20%）、CDKN2A（10%）和 EGFR 扩增（20%）。平均 TMB 为 3.3 个突变/Mb。与 HER2 突变患者相比，EGFR Ex20ins 患者的 PD-L1 表达明显更高（48.6% vs. 19.0%，P=0.027）。高 TMB 和 PD-L1 表达与预后显著不良独立相关（P=0.025，P=0.045），而 CD4+/CD8+TILs 与 EGFR 或 HER2 突变型 NSCLC 的预后无关。最后，携带 EGFR Ex20ins 的患者似乎对 PD-1/PD-L1 阻断敏感，而对 HER2 Ex20ins 患者则显示出有限的疗效。