These reports suggested that this efficacy of nivolumab plus ipilimumab combination therapy in anti-PD1 Ab therapy-resistant patients is lower than that in anti-PD1 Ab therapy-na?ve patients. the recurrent tumor was limited to the nasal cavity, we employed intensity-modulated radiotherapy (IMRT) using CyberKnife with 45 Gy in 9 fractions. Two months after the radiotherapy, magnetic resonance imaging (MRI) revealed regression of the tumor (Fig. ?(Fig.1B).1B). However, 3 months after tumor regression, follow-up positron emission tomography (PET)-CT revealed multiple metastases in the lungs, scapula, and subcutaneous lesions (Fig. Hydroxyflutamide (Hydroxyniphtholide) ?(Fig.2A).2A). Since the melanoma was BRAFV600E mutation unfavorable, nivolumab (80 mg/kg/every 3 weeks) was given in combination with ipilimumab (3 mg/kg/every 3 weeks) for 4 cycles without any adverse events. In addition, since this patient showed metastatic melanoma of the bone, we administered denosumab 120 mg every month. Three months after the first administration of nivolumab plus ipilimumab combination therapy, the multiple metastases in the lungs, scapula, and subcutaneous WNT-4 lesions experienced regressed (Fig. ?(Fig.2B).2B). We continued to administer pembrolizumab (240 mg/kg/every 3 weeks), and there was no evidence of recurrence 6 months after achieving complete remission. Open in a separate windows Fig. 1. CT scan before radiotherapy: local recurrence of melanoma, 36.80 26.78 mm in size, in the nasal cavity (A). MRI at 2 months after IMRT treatment: regression of the tumor (B). Open in a separate windows Fig. 2. PET-CT image: metastasis at the scapula before (A) and after (B) combination therapy. Conversation The combination or sequential administration of nivolumab and ipilimumab with a planned switch is among the most effective chemotherapies against advanced melanoma [7, 8], but the efficacy of ipilimumab monotherapy in patients with nivolumab-resistant cutaneous and mucosal melanoma is usually low after objective tumor progression compared to its efficacy in patients with planned-switched treatment [5, 9]. These reports suggested that this efficacy of nivolumab plus ipilimumab combination therapy in anti-PD1 Ab therapy-resistant patients is lower than that in Hydroxyflutamide (Hydroxyniphtholide) anti-PD1 Ab therapy-na?ve patients. In addition, recently, Hamid et al. [4] has reported the results of a case series with mucosal melanoma treated with pembrolizumab monotherapy. The objective response rate to pembrolizumab for ipilimumab therapy-na?ve mucosal melanoma patients was 22%, suggesting a poor prognosis for mucosal melanoma compared to cutaneous melanoma patients [10]. Therefore, additional methods to enhance the anti-tumor effects of ICIs in patients with mucosal melanomas are needed. To enhance the anti-tumor effects of anti-PD1 Abdominal muscles, not only the induction of CD8+ T cells in the tumor lesion [11, 12], but also other targeting molecules that enhance the anti-tumor effects of ICIs should be taken into account [13]. Recently, Ahern et al. [14, 15] have highlighted the therapeutic effects of co-administration of anti-RANKL Abs with ICIs, such as anti-PD1 Abs and anti-CTLA4 Abs, against melanoma by the suppression of RANKL+ PD1highCD8 T cells in a B16F10 mouse melanoma model. They concluded that anti-RANKL Abs could enhance the anti-melanoma effects of ICIs. Indeed, in clinics, anti-RANKL Abs enhanced the therapeutic effects of ipilimumab in patients with terminal-stage metastatic melanoma [16, 17]. These reports suggested that denosumab might improve the Hydroxyflutamide (Hydroxyniphtholide) therapeutic effects of nivolumab plus ipilimumab combination therapy against advanced anti-PD1 Ab-resistant mucosal melanoma. In this report, we explained a case of anti-PD1 Ab-resistant advanced Hydroxyflutamide (Hydroxyniphtholide) mucosal melanoma treated with nivolumab, ipilimumab plus denosumab combination therapy. Our present case suggested that nivolumab, ipilimumab plus denosumab combination therapy is not only useful for standard cutaneous melanoma as we previously reported [17], but also useful for recurrent anti-PD1 Ab-resistant mucosal melanoma as a second-line therapy. Statement of Ethics The patient gave written informed consent. Disclosure Statement The authors have no conflicting interests to declare. Funding Sources This study was supported in part by the Japan Agency for Medical Research and Development (19cm0106434h0002). Author Contributions Taku Fujimura designed the research study. Taku Fujimura, Yumi Kambayashi, Ohuchi Kentaro, Ryo Amagai, Sato Yota, Tanita Kayo, and Akira Hashimoto treated the patient and acquired the clinical data. Taku Fujimura published the manuscript. Taku Fujimura and Setsuya Aiba supervised the study..