Efficacy of immune checkpoint inhibitors in patients with non–small cell lung cancer harboring ERBB2 exon 20 insertions and non-ERBB2 exon 20 insertions.
Authors: Tu Hai-Yan , Yin Kai , Ke E-E , Wu Si-Pei , Zhao Xiaotian , Li Yang-Si , Zheng Mei-Mei , Liu Si-Yang Maggie , Sun Yue-Li , Lin Jia-Xin , Bai Xiao-Yan , Zhang Yi-Chen , Zhou Qing , Yang Jin-Ji , Zhong Wenzhao , Wang Bin-Chao , Zhu Dongqin , Yang Lingling , Ou Qiuxiang , Wu Yi-Long 
Published: June 2022

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Background: Immune checkpoint inhibitors (ICIs) have suboptimal efficacy in non-small cell lung cancer (NSCLC) patients with ERBB2 mutations, including ERBB2 exon 20 insertions. This study aims to investigate the efficacy of ICIs and immune characteristics in NSCLC patients harboring ERBB2 ex20ins and non-ex20ins mutations. Methods: Advanced NSCLC patients harboring ERBB2 mutations were recruited from January 2016 to December 2020. Pre-ICI tumor tissue samples were collected and performed with targeted next-generation sequencing. Patients received ICIs were followed up every 3 months until November 2021. Genomic features were compared between patients with ERBB2 ex20ins and non-ex20ins mutations. Progression-free survival (PFS), overall survival (OS), and tumor immune microenvironment (TIME) features characterized by multiplex immunohistochemistry (IHC) were further analyzed in patients receiving ICIs. Two-sample T-tests were performed to compare means; Cox models were fitted to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Two external datasets of ERBB2-mutant NSCLC patients, including TCGA (n = 23) and META (n = 33), were used for validation. Results: A total of 117 eligible patients were enrolled (median age: 59 [range: 24-82], males 57.3%, stage IV 68.4%, adenocarcinoma 93.2%), of whom 37 received subsequent ICI treatment. similar PD-L1 tumor proportion score (mean: 8.1% vs. 13.2%, p = 0.25) and significantly lower mutation number (mean: 3.0 vs. 6.2 muts/person, p < 0.01) were detected in patients with ERBB2 ex20ins, compared to patients with ERBB2 mutations other than ex20ins. Similarly, in the TCGA cohort, tumor mutation burden was significantly lower in ERBB2 ex20ins patients (mean: 2.2 vs. 10.3 muts/Mb, p = 0.02). Of 37 patients receiving ICIs, ERBB2 non-ex20ins patients displayed superior PFS (mPFS: 13.5 vs. 4.4 months, HR: 0.31, 95% CI: 0.14-0.71), relatively long OS (mOS: 27.5 vs. 8.1 months, HR: 0.47, 95% CI: 0.20-1.14), and a relatively high rate of durable clinical benefit (64.3% vs. 34.8%, p = 0.10) than ex20ins patients, consistent with what was observed in the META cohort (PFS, mPFS: 13.2 vs. 2.5 months, HR: 0.20, 95% CI: 0.06-0.68; OS, mOS: 23.3 vs. 8.0 months, HR: 0.32, 95% CI: 0.11-0.90). Moreover, the CD4+ T cell density appeared to be lower in the tumor stroma of ERBB2 ex20ins patients than that of non-ex20ins patients (300.5 vs. 1288.0 /mm2, p = 0.08), even though the general TIME features of ex20ins patients were similar to those of non-ex20ins patients. Conclusions: NSCLC patients carrying ERBB2 ex20ins demonstrated worse clinical outcome under ICI treatment, similar PD-L1 expression and lower mutation number when compared to those with non-ex20ins mutations. Genomic and TIME characteristics should be further investigated to elucidate the efficacy of ICIs in lung cancer patients carrying ERBB2 mutations.