Successful Rechallenge Therapy for BRAF/MEK Inhibitor‐resistant Multiple Brain Metastases of Melanoma

Combination therapy with BRAF and MEK inhibitors (BRAFi/MEKi) have dramatically improved prognosis among patients with BRAF-mutant metastatic melanoma compared with traditional treatment, such as chemotherapy. However, resistance to these targeted agents occurs invariably, thereby limiting their clinical efficacy. Recently, it has been reported that the ligand-independent phosphorylation of erythropoietin-producing hepatocellular receptor A2 (EphA2) at Ser-897 signaling is a driver of BRAF inhibitor resistance in melanoma. A melanoma patient with multiple metastases was treated with dabrafenib plus trametinib therapy and maintained complete remission for more than 2 years. As brain metastasis occurred, we had switched to nivolumab plus ipilimumab therapy. However, new lesions were observed after four cycles of nivolumab plus ipilimumab therapy, she was rechallenged with encorafenib plus binimetinib therapy, and she maintained progression-free status for more than 7 months. We performed immunohistochemical staining of EphA2, phospho-EphA2 (p-EphA2; Ser-897), and epidermal growth factor receptor (EGFR) of melanoma cells before and/or after dabrafenib and trametinib therapy. Immunohistochemical examination showed higher expression of EphA2, p-EphA2, and EGFR in the melanoma cells after dabrafenib plus trametinib therapy as compared with that before therapy. Our results may indicate that EphA2, p-EphA2, and EGFR can be critical factors for resistance and reversible response of BRAFi/MEKi in metastases of melanoma. Our case presents a possible treatment that can help overcome BRAFi/MEKi resistance and improve prognosis of melanoma.