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

Purpose: Patients with BRAF V600 wild-type melanoma whose tumors progress on checkpoint inhibition currently have limited therapeutic options, and additional rational treatment targets are needed. ERBB2 alterations may be amenable to targeted inhibition, but the rate of ERBB2 alterations across melanoma subtypes is not well described. Experimental Design: 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 ERBB2 and the other known canonical driver genes BRAF, NRAS, KIT, NF1, GNAQ , and GNA11 Results: A patient with acral melanoma resistant to checkpoint inhibition was found to have ERBB2 amplification and achieved a durable complete response to trastuzumab emtansine. Tumor sequencing results from 732 melanoma cases were analyzed for ERBB2 and canonical driver gene alterations. ERBB2 amplifications were detected in acral (3%) and mucosal (3%) melanomas. ERBB2 mutations were found in cutaneous (1%), acral (2%), and mucosal (2%) subtypes and frequently cooccurred with NF1 alterations. Among the 140 patients whose tumors lacked canonical driver alterations, ERBB2 amplifications were detected in acral (7%) and mucosal (6%) melanomas. Conclusions: ERBB2 amplification is present in a minority of acral lentiginous and mucosal melanomas. Activating mutations in ERBB2 were identified in nonuveal melanoma subtypes and are frequently comutated with canonical drivers. HER2 could represent a therapeutically relevant target across melanoma subtypes. Significance: This article describes a case of durable complete response to HER2-directed therapy, trastuzumab emtansine, in ERBB2 -amplified acral melanoma resistant to checkpoint inhibition. Acral and mucosal melanomas that lack canonical driver alterations may harbor ERBB2 amplifications, and ERBB2 assessment should be considered for these rare tumors. Clin Cancer Res; 1-5. ©2018 AACR.