Serum soluble CD163 and proinflammatory chemokines may be biomarkers of the onset of adverse events in dabrafenib plus trametinib combination therapy for advanced melanoma.

Various adverse events (AEs) have been reported to occur at a high rate in patients treated with dabrafenib plus trametinib (D + T) combination therapy. Among such AEs, the incidence of pyrexia was highest among the series of AEs in patients treated with D + T combination therapy. Although little is known about the mechanisms of pyrexia caused by D + T combination therapy, a recent report suggested that sCD163, as well as interferon-inducible chemokines (CXCL9, CXCL10, CXCL11), might correlate with pyrexia caused by encorafenib plus binimetinib combination therapy. In addition to these soluble factors, CXCL5 is a biomarker for predicting immune-related AEs in melanoma patients treated with nivolumab. From the above findings, we hypothesized that these soluble factors might also correlate with the onset of AEs in D + T combination therapy. The serum levels of sCD163 were increased in patients with pyrexia in parallel with their severity, whereas the serum levels of CXCL5 were increased in patients without pyrexia. Moreover, increased levels of CXCL9, CXCL10, and CXCL11 were prominent in patients with AEs over G2 levels. As these chemokines recruit Th1, Th17, and activated CD8+ T cells, increased serum levels of these chemokines might correlate with the positive feedback of inflammatory reactions related to AEs.

Successful treatment of BRAF/MEK inhibitor-resistant advanced cutaneous melanoma with nivolumab plus ipilimumab combination therapy followed by intensity-modulated radiotherapy.

BRAF kinase inhibitors in combination with MEK kinase inhibitors are among the most promising chemotherapeutic regimens for the treatment of advanced BRAF-mutant melanoma. Although the NCCN guideline for cutaneous melanoma recommended BRAF/MEK inhibitors as first-line therapies for unresectable BRAF-mutated melanoma, resistance to these drugs should be taken into account in real-world practice. Therefore, development of a protocol for BRAF/MEK inhibitor-resistant advanced melanoma is needed. In this report, a case of BRAF/MEK inhibitor-resistant advanced cutaneous melanoma that was successfully treated with nivolumab plus ipilimumab combination therapy followed by intensity-modulated radiotherapy (IMRT) is reported. In the present case, not only the locally irradiated lesion, but remote metastases including inguinal lymph nodes decreased after ipilimumab plus nivolumab followed by IMRT treatment leading to complete remission, suggesting that IMRT triggered an abscopal response. Moreover, immunohistochemical analysis showed increased CD3+ , CD4+ , and CD8+ T cells after radio-immunotherapy (RIT). This case suggests that RIT might break the tolerance in the tumor microenvironment and induce a systemic anti-melanoma immune response.