Severe pyrexia from nivolumab‐resistant advanced melanoma after successful combined therapy with encorafenib plus binimetinib

Abstract

Various serious adverse events (AE) have been reported to occur at a high rate in patients treated with BRAF plus mitogen-activated protein kinase kinase (MEK) inhibitor combination therapy, but their subtypes differ among the BRAF/MEK inhibitors. Pyrexia or a spike of fever are well-known AE of BRAF inhibitors, with or without MEK inhibitors, and have been reported to have a high incidence after dabrafenib/trametinib, but not after encorafenib/binimetinib. In this report, we describe three cases of severe pyrexia in nivolumab-resistant advanced melanoma after successful combined therapy with encorafenib plus binimetinib. Interestingly, in all cases, the serum levels of soluble CD163 C-X-C motif chemokine (CXCL)9, CXCL10 and CXCL11, which are known biomarkers for adult-onset Still's disease (AOSD), increased in parallel with the development of pyrexia. Our present cases suggest that pyrexia caused by BRAF/MEK inhibitors may possess a similar pathophysiology as that of AOSD.

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

“…Moreover, CXCL9, CXCL10, and CXCL11, which are ligands of CXCR3 expressed on activated T cells (Th1 cells, Th17 cells, CD8 T cells, etc. ), 14 were increased in a patient with severe pyrexia caused by E + B combination therapy 5 . In addition to these soluble factors, another previous report suggested that baseline levels of CXCL5 might correlate with severe rhabdomyolysis caused by D + T combination therapy 15 .…”

Treatment of Advanced Melanoma: Past, Present and Future

“…To date, little is known about the mechanisms of AEs developing from melanoma patients treated with BRAF/MEK inhibitors [40,42,43]. Among them, recently, Amagai et al reported a case series with pyrexia developing from advanced melanoma treated with E + B therapy, and suggested that serum levels of soluble CD163 as well as IFN-γ induced chemokines [C-X-C motif chemokine (CXCL9, CXCL10, CXCL11)] were increased in the pyrexia group compared with the non-pyrexia group [42].…”

“…To date, little is known about the mechanisms of AEs developing from melanoma patients treated with BRAF/MEK inhibitors [40,42,43]. Among them, recently, Amagai et al reported a case series with pyrexia developing from advanced melanoma treated with E + B therapy, and suggested that serum levels of soluble CD163 as well as IFN-γ induced chemokines [C-X-C motif chemokine (CXCL9, CXCL10, CXCL11)] were increased in the pyrexia group compared with the non-pyrexia group [42]. Notably, all of these soluble factors had previously been reported as biomarkers for adult-onset Still's disease (AOSD) [44,45], and the manifestations of AOSD (including pyrexia, transient skin rash, fatigue and arthritis [44,45]) are well-known AEs developing from BRAF/MEK inhibitors [40].…”

Erythema nodosum developed in a patient with advanced cutaneous melanoma treated with dabrafenib plus trametinib combination therapy

“…Chemokines could be a biomarker for adverse events not only in immunotherapy 5 but also in targeted therapy such as BRAF inhibitors plus MEK inhibitors combination therapy. 6 Indeed, Amagai et al 6 reported that increased serum levels of CXCL9, CXCL10, and CXCL11 could be biomarkers for pyrexia in advanced melanoma patients treated with encorafenib plus bimimetinib combination therapy. Since CXCL9, CXCL10, and CXCL11 recruit CXCR3-expressing Th1, Th17, and activated CD8+ T cells, 2 and since Th1 and Th17 are induced in patients with EN, 7,8 we hypothesized that these interferon-gamma-induced F I G U R E 1 A, Multiple painful erythematous nodules on the upper and lower extremities.…”

“…Chemokines could be a biomarker for adverse events not only in immunotherapy 5 but also in targeted therapy such as BRAF inhibitors plus MEK inhibitors combination therapy 6 . Indeed, Amagai et al 6 reported that increased serum levels of CXCL9, CXCL10, and CXCL11 could be biomarkers for pyrexia in advanced melanoma patients treated with encorafenib plus bimimetinib combination therapy.…”