Background

The genomic mutation and immune feature landscape of ERBB2 exon 20 insertion (ERBB2-ex20ins)-driven non-small cell lung cancer and the features associated with the response to chemoimmunotherapy are currently unknown.

Methods

The genomic landscape of ERBB2-ex20ins lung adenocarcinoma (LUAD) patients was characterized by next-generation sequencing (NGS) of 1021 cancer genes. The clinical outcomes of chemoimmunotherapy were evaluated among 13 patients with stage IV ERBB2-ex20ins LUAD, and potential biomarkers of the response to chemoimmunotherapy were explored using NGS and T cell receptor sequencing.

Results

Among 8247 LUAD patients, 207 (2.5%) had ERBB2-ex20ins, of whom 181 (87.4%) harbored more than one comutation. The most common comutations were in TP53. Patients with ERBB2-ex20ins had a low tumor mutational burden (TMB; median, 4.2 mutations/Mb), and most (66.7%) were PD-L1 negative. Thirteen of the 207 patients received chemoimmunotherapy, for whom the objective response rate, disease control rate, and median progression-free survival were 31%, 77%, and 8.0 months, respectively. Responders exhibited a higher TMB and a trend toward lower clonality in tumors compared with nonresponders (p = 0.0067 and p = 0.085, respectively). A high TMB combined with mutations in DNA damage repair pathways and SWI/SNF chromatin remodeling complexes was associated with a benefit from chemoimmunotherapy.

Conclusions

The efficacy and outcome of chemoimmunotherapy were encouraging among ERBB2-ex20ins LUAD patients, who were characterized by low TMB and negative PD-L1 expression. The combination of TMB and comutations is a potential biomarker to identify patients who will benefit from chemoimmunotherapy.

中文翻译：

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具有 ERBB2 外显子 20 插入的肺腺癌：与化学免疫疗法相关的突变和免疫基因组学特征

背景

ERBB2外显子 20 插入 ( ERBB2 -ex20ins) 驱动的非小细胞肺癌的基因组突变和免疫特征景观以及与化学免疫疗法反应相关的特征目前尚不清楚。

方法

ERBB2 -ex20ins 肺腺癌 (LUAD) 患者的基因组景观以 1021 个癌症基因的下一代测序 (NGS) 为特征。在 13 名 IV 期ERBB2 -ex20ins LUAD患者中评估了化学免疫疗法的临床结果，并使用 NGS 和 T 细胞受体测序探索了化学免疫疗法反应的潜在生物标志物。

结果

在 8247 名 LUAD 患者中，207 名 (2.5%) 患有ERBB2- ex20ins，其中 181 名 (87.4%) 患有不止一种突变。最常见的转换发生在TP53 中。ERBB2-患者ex20ins 具有低肿瘤突变负荷（TMB；中位数，4.2 个突变/Mb），并且大多数（66.7%）为 PD-L1 阴性。207 名患者中有 13 名接受了化学免疫治疗，其客观缓解率、疾病控制率和中位无进展生存率分别为 31%、77% 和 8.0 个月。与无反应者相比，反应者表现出更高的 TMB 和肿瘤克隆性降低的趋势（分别为 p = 0.0067 和 p = 0.085）。高 TMB 结合 DNA 损伤修复途径和 SWI/SNF 染色质重塑复合物的突变与化学免疫疗法的益处相关。

结论

在ERBB2- ex20ins LUAD 患者中，化学免疫疗法的疗效和结果令人鼓舞，这些患者的特征是低 TMB 和阴性 PD-L1 表达。TMB 和基因突变的组合是一种潜在的生物标志物，可用于识别将从化学免疫疗法中受益的患者。