Rates of <i>ERBB2</i> Alterations across Melanoma Subtypes and a Complete Response to Trastuzumab Emtansine in an <i>ERBB2</i>-Amplified Acral Melanoma.

Abstract

Patients with <i>BRAF</i> V600 wild-type melanoma whose tumors progress on checkpoint inhibition currently have limited therapeutic options, and additional rational treatment targets are needed. <i>ERBB2</i> alterations may be amenable to targeted inhibition, but the rate of <i>ERBB2</i> alterations across melanoma subtypes is not well described. All patients with nonuveal melanoma (cutaneous, acral, mucosal, and unknown primary) whose tumors underwent multigene sequencing with MSK-IMPACT at Memorial Sloan Kettering Cancer Center (New York, NY) from 2014 to 2018 were reviewed for known or likely oncogenic somatic alterations in <i>ERBB2</i> and the other known canonical driver genes <i>BRAF, NRAS, KIT, NF1, GNAQ</i>, and <i>GNA11</i>. A patient with acral melanoma resistant to checkpoint inhibition was found to have <i>ERBB2</i> amplification and achieved a durable complete response to trastuzumab emtansine. Tumor sequencing results from 732 melanoma cases were analyzed for <i>ERBB2</i> and canonical driver gene alterations. ERBB2 amplifications were detected in acral (3%) and mucosal (3%) melanomas. <i>ERBB2</i> mutations were found in cutaneous (1%), acral (2%), and mucosal (2%) subtypes and frequently cooccurred with <i>NF1</i> alterations. Among the 140 patients whose tumors lacked canonical driver alterations, <i>ERBB2</i> amplifications were detected in acral (7%) and mucosal (6%) melanomas. <i>ERBB2</i> amplification is present in a minority of acral lentiginous and mucosal melanomas. Activating mutations in <i>ERBB2</i> were identified in nonuveal melanoma subtypes and are frequently comutated with canonical drivers. HER2 could represent a therapeutically relevant target across melanoma subtypes.