Clinical characterization of ERBB2 exon 20 insertions and heterogeneity of outcomes responding to afatinib in Chinese lung cancer patients

PURPOSE: ERBB2 exon 20 insertions (20ins) have been identified as oncogenic drivers in lung cancers. Lung cancer patients with 20ins benefit from afatinib. However, response heterogeneity was observed in patients harboring different 20ins subtypes. In this study, we interrogated clinical characteristics in ERBB2-mutated Chinese lung cancer and investigated the clinical outcomes of specific ERBB2 20ins in response to afatinib. EXPERIMENTAL DESIGN: In this study, we retrospectively collected genomic profiling data of 7,520 lung cancer patients sequenced using next-generation sequencing in a Clinical Laboratory Improvement Amendments-certified laboratory. We analyzed the clinical and molecular features of patients harboring ERBB2 20ins and evaluated clinical outcomes of 19 patients with clinical records after afatinib treatment. RESULTS: ERBB2 20ins were identified in 2.27% (171/7,520) of this lung cancer cohort. It occurred with a high proportion in females with adenocarcinoma histology. ERBB2 20ins was mutually exclusive with other well-established lung cancer oncogenic driver mutations. The most frequently appearing subtype was Y772_A775dup (69.6%) and several novel insertion subtypes were also identified. The correlations of specific 20ins subtypes and survival were investigated. The presence of a glycine at position 778 in ERBB2 was suggested to be a common feature of drug sensitivity mutations. Patients harboring G778_P780dup (G778) subtype achieved longer median progression-free survival and median overall survival than other 20ins (non-G778) subtypes (median progression-free survival, 10 vs 3.3 months, P=0.32; median overall survival, 19.7 vs 7 months, P=0.16). Moreover, we presented the first clinical case of a lung squamous cell carcinoma patient harboring ERBB2 20ins who achieved partial response to afatinib. CONCLUSION: This study interrogated the characteristics of ERBB2 20ins in a large cohort from single ethnicity and demonstrated the response heterogeneity to afatinib among different ERBB2 20ins subtypes. Further studies in a larger cohort are needed to investigate the underlying molecular mechanisms and clinical response of different ERBB2 20ins subtypes.