Nivolumab-based combination therapy using immunomodulatory drugs is of great interest among dermato-oncologists. Since IFN-b increases the number of cytotoxic T cells in the tumor sites, the administration of IFNb enhances the anti-tumor immune response of anti-PD-1 Abs against B16F10 melanoma in vivo. To apply this combination therapy for the treatment of metastatic melanoma patients, we performed an open label, non-randomized, phase 1 trial, using a traditional rule-based 3+3 design. In addition, we evaluated the serum levels of autoimmune-related chemokines, CXCL5 and sCD163, for the prediction of immune-related adverse events (irAE) at day 0 and day 42. Patients were eligible if they had unresectable stage III or stage IV melanoma. The administration of nivolumab was fixed at 2 mg/kg every 3 weeks. IFN-b was administered at a dose of 1 million units, 2 million units and 3 million units in each group at day 0. The dose-limiting toxicities (DLTs) were defined as any grade 3 or 4 AE at least possibly related to nivolumab and IFN- occurring between day 0 and day 42. A data and safety monitoring committee was established to provide oversight of the safety and efficacy considerations. Of the 9 patients who received this combined therapy, none experienced DLT and all completed the treatment phase of this study. The patients were followed up on every 6 months after the last treatment. 5 out of 9 patients developed progressive disease and changed treatment during the follow up. No patient in the study or follow up phase developed grade 3~5 AE. One patient who developed grade 2 isolated ACTH defficiency showed increased serum levels of CXCL5 and sCD163. Our present study revealed the safe dose of IFN-b is 3 million units.

Safety dose and prediction of immune-related adverse event of nivolumab combined with IFN-beta in patients with advanced melanoma