Genomic and immune characteristics of HER2‐mutated non‐small‐cell lung cancer and response to immune checkpoint inhibitor‐based therapy

• Published in: Molecular oncology Vol. 17; no. 8; pp. 1581 - 1594
• Main Authors: Tu, Hai‐Yan, Yin, Kai, Zhao, Xiaotian, Ke, E‐E, Wu, Si‐Pei, Li, Yang‐Si, Zheng, Mei‐Mei, Liu, Si‐Yang Maggie, Xu, Chong‐Rui, Sun, Yue‐Li, Lin, Jia‐Xin, Bai, Xiao‐Yan, Zhang, Yi‐Chen, Zhou, Qing, Yang, Jin‐Ji, Zhong, Wen‐Zhao, Wang, Bing‐Chao, Zhang, Xu‐Chao, Zhu, Dongqin, Yang, Lingling, Ou, Qiuxiang, Wu, Yi‐Long
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.08.2023; John Wiley and Sons Inc; Wiley
• Subjects: advanced NSCLC; Apoptosis; Cancer therapies; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Committees; Epidermal growth factor; ErbB-2 protein; exon 20 insertion; FDA approval; Genes; Genomes; Genomics; human epidermal growth factor receptor 2; Humans; immune checkpoint inhibitor; Immune checkpoint inhibitors; Immune Checkpoint Inhibitors - pharmacology; Immune Checkpoint Inhibitors - therapeutic use; Immunotherapy; Kinases; Leukocytes; Ligands; Lung Cancer; Lung diseases; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Medical prognosis; Mutation; Mutation - genetics; Non-small cell lung carcinoma; non‐exon 20 insertion; Patients; PD-L1 protein; Plasma; Retrospective Studies; Small cell lung carcinoma; Tumor Microenvironment; United States > US; immune checkpoint inhibitor; human epidermal growth factor receptor 2; advanced NSCLC; exon 20 insertion; non-exon 20 insertion
• ISSN: 1574-7891; 1878-0261; 1878-0261
• DOI: 10.1002/1878-0261.13439

The efficacy of immunotherapy in advanced HER2‐mutated non‐small‐cell lung cancer (NSCLC) remains incomprehensively studied. A total of 107 NSCLC patients with de novo HER2 mutations were retrospectively studied at Guangdong Lung Cancer Institute [GLCI cohort, exon 20 insertions (ex20ins): 71.0%] to compare clinical/molecular features and immune checkpoint inhibitor (ICI)‐based therapy efficacy between patients with ex20ins and non‐ex20ins. Two external cohorts (TCGA, n = 21; META‐ICI, n = 30) were used for validation. In the GLCI cohort, 68.2% of patients displayed programmed death‐ligand 1 (PD‐L1) expression < 1%. Compared with ex20ins patients, non‐ex20ins patients had more concurrent mutations in the GLCI cohort (P < 0.01) and a higher tumour mutation burden in the TCGA cohort (P = 0.03). Under ICI‐based therapy, advanced NSCLC patients with non‐ex20ins had potentially superior progression‐free survival [median: 13.0 vs. 3.6 months, adjusted hazard ratio (HR): 0.31, 95% confidence interval (CI): 0.11–0.83] and overall survival (median: 27.5 vs. 8.1 months, adjusted HR: 0.39, 95% CI: 0.13–1.18) to ex20ins patients, consistent with findings in the META‐ICI cohort. ICI‐based therapy may serve as an option for advanced HER2‐mutated NSCLC, with potentially better efficacy in non‐ex20ins patients. Further investigations are warranted in clinical practice. HER2‐mutated non‐small‐cell lung cancer (NSCLC) patients with HER2 mutations other than exon 20 insertions (non‐ex20ins) had higher tumour mutation burden than patients with HER2 ex20ins, whereas similar programmed death‐ligand 1 expression was observed. Under immune checkpoint inhibitor‐based therapy, advanced NSCLC patients with HER2 non‐ex20ins had potentially superior progression‐free survival and overall survival compared with patients with HER2 ex20ins.