Characterization of ERBB2 alterations in non-small cell lung cancer.

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e21553 Background: ERBB2 alteration (mutation and/or amplification) is associated with poor survival in non-small cell lung cancer (NSCLC) and is commonly reported as a resistance mechanism to EGFR tyrosine kinase inhibitors. Several clinical trials are ongoing for the management of ERBB2-altered NSCLC. Here we report the prevalence of different ERBB2 alterations in NSCLC. Methods: We retrospectively analyzed ERBB2 alterations in NSCLC tumors that underwent next-generation sequencing (NGS) with Caris Life Sciences. De-identified pathological and molecular information was collected. ERBB2 copy number of greater than 6 was defined as amplification; mutations were classified among 7 groups based on their mechanism of action. Results: A total of 12946 NSCLC tumors with ERBB2 NGS results were available. Among them, 12492 had ERBB2 copy number alteration (CNA) data available. 321 tumors (2.5%) had ERBB2 alteration (mutation or amplification). Among them, ERBB2 was mutated in 197 tumors (1.5%) and amplified in 134 (1.1%) tumors. Type of ERBB2 mutation, respective median age and distribution among sex is in the table. 10 tumors with ERBB2 mutation (7.46%) also showed ERBB2 amplification. Six percent of tumors (8/135) with ERBB2 exon 20 insertion mutations had co-occurring ERBB2 amplification. One tumor for each extracellular domain (ECD) and transmembrane group had co-occurring ERBB2 amplification. Eight tumors with ERBB2 mutation had an overlapping EGFR L858R or exon19del mutation. Seven of these 8 tumors were from the ECD group (7/21) and all had mutations in the S310 locus. One tumor was from the transmembrane group. Conclusions: Exon 20 insertion mutation is the most commonly found ERBB2 mutation among NSCLC, a few of them had co-occurring ERBB2 amplification. One third of tumors with extracellular domain ERBB2 mutation had EGFR mutation. Tarloxitinib (NCT03805841), trastuzumab deruxtucan (NCT03505719), pyrotinib (NCT02500199), poziotinib (NCT03318939) are just a few of the novel ERBB2 inhibitors available in clinical trials. It will be critical to utilize next generation sequencing to effectively capture uncommon mutations and amplifications in ERBB2 so that patients may be offered therapy directly targeted to their genomic alterations. [Table: see text]