Case Report: Delayed Onset Multi-Organ Toxicities in a Melanoma Patient Achieving Complete Response to BRAF/MEK Inhibition.

Autoimmune toxicities, while common following treatment with cancer immunotherapies, are not well-characterized in patients treated with BRAF/MEK inhibitors. Emerging data suggest that autoimmune effects may be linked with superior responses to both treatment modalities; however, there is little evidence describing mechanisms of immune-related toxicity for patients on BRAF/MEK inhibitors. Here we describe the experience of a 59-year-old HLA-A2, A29, B27-positive male with recurrent/metastatic melanoma. After progression on checkpoint inhibitor therapy, he was treated with dabrafenib/trametinib followed by encorafenib/binimetinib, which were well-tolerated and resulted in a complete response. Eighteen months into BRAF/MEK inhibitor therapy, and three months after initially finding a complete response, he developed a series of sudden-onset, severe toxicities: namely, bilateral panuveitis, cytopenias, joint pain, skin rash, hypercalcemia, and interstitial nephritis, which led to BRAF/MEKi cessation. Immunological analyses revealed induction of a peripheral type-17 cytokine signature characterized by high IL-23, IL-6, IL-10, IL-17A/F, IL-1β, and IL-21 among other cytokines in plasma corresponding with the height of symptoms. These findings highlight a novel instance of delayed autoimmune-like reaction to BRAF/MEK inhibition and identify a possible role for Th/Tc17 activation in their pathogenesis thus warranting future clinical and immunological characterization.