Clinical management of lung adenocarcinoma patients with HER2 V659E mutation.

e21521 Background: ERBB2 mutations, mostly affecting the kinase domain (KD), were later found in the transmembrane domain (TMD), most frequently seen in residues V659, G660, but with a much lower prevalence. Comparing to other solid tumors, ERBB2-mutant NSCLC shows a lower response rate to HER2 inhibitors (HER2i). ERBB2 V659E has been reported to respond to lapatinib in combination with carpecitabine, afatinib, or ado-trastuzumab emtansine (TDM-1). However, since the prevalence of ERBB2 V659E is low, no study has reported the subsequent clinical management after developing resistance to HER2i. Methods: We retrospectively screened genomic profiles of 7,812 lung adenocarcinoma (LADC) patients. Molecular docking of lapatinib, afatinib and pyrotinib with the HER2 KD was simulated with AutoDock 4.2 and the binding affinity was predicted by MMPBSA.py program in AmberTools18. Results: We analyzed NGS data of 7812 LADC patients and identified 14 patients (0.18%) with HER2 TMD mutation, mostly V659E mutation (11/7812, 0.14%); other mutations included V664F, T652M, V664F; each occurred in 1 patient. In this cohort, all adenocarcinomas harbor a dinucleotide missense mutation, including 10 TT→AA and 6 TT→AG (c.1976_1977). T P53 was the most frequently co-mutated gene (n = 4) followed by HER2 (n = 2), NSD1 (n = 2) and RARA (n = 2). Treatment history of 9 advanced LADC patients were collected and analyzed. 3 of them had chemotherapy as first-line therapy. 5 patients were treated with HERi as first-line therapy, achieving a median PFS of 192 days (ranged from 60-515days), comparing to patients treated with chemotherapy (71.7±53.3days). 1 patient who was treated with different HERi sequentially in the order of lapatinib, afatinib, TDM-1, achieving an overall PFS of 515 days. Subsequently, she was treated with pyrotinib and had a PFS of 92 days. Molecular docking simulation showed the covalent inhibitors Afatinib and Pyrotinib are more favorable for blocking HER2 KD than non-covalent inhibitor Lapatinib. Between the two covalent inhibitors, Pyrotinib (∆GPyrotinib = -65.92kcal/mol) shows stronger non-covalent binding ability than Afatinib (∆GAfatinib = -59.71 kcal/mol) (p < 0.001). Conclusions: To the best of our knowledge, this is the largest-reported HER2 V659E mutation cohort. We revealed the prevalence of ERBB2 V659E in Chinese LUAD patients and elucidated the genomic profile of ERBB2 V659E mutant. This study paves avenue for the utilization of the novel HER2 inhibitors pyrotinib in ERBB2 V659E mutant LUAD patients.