The use of combination of BRAF and MEK inhibitors have achieved an increase in the rates of progression free survival and overall survival of melanoma patients in Phase 3 clinical trials compared to conventional chemotherapy1. However, these agents administered chronically to patients are associated with drug-related toxicities and some patients have to discontinued from therapy. Although grade 3-4 adverse events were uncommon in dabrafenib treated patients, fever was identified as a new potentially serious toxicity2, 3. About 30% of patients developed fever at some stage during dabrafenib monotherapy whereas over 50% of patients who received combination therapy developed fever at some stage. The increased incidence of pyrexia with dabrafenib monotherapy, and the lack of pyrexia with trametinib monotherapy suggests that trametinib influences the dabrafenib driven-pyrexia process but the exact nature of this is still unknown and requires further research.
Drug hypersensitivity is an immune-mediated reaction to a drug. It can be immediate, which is associated with IgE or delayed, which is T-cell mediated. Drug allergy is an important public health problem because of their potential to cause life-threatening adverse reactions. If this “allergic reaction” is predictable or preventable, we can either avoid giving patients the medications or modify the combinations for a more favourable outcome. We hypothesise that 1) dabrafenib induces drug hypersensitivity in a group of patients, 2) drug hypersensitivity is inhibited by Tregs, and 3) Treg function is inhibited by trametinib.
To test our hypotheses, we performed lymphocyte proliferation assay for drug hypersensitivity testing and cytometric bead assay to measure cytokines released in in vitro cell culture supernatants. Suppression assays were done to test Treg functions in the absence or presence of inhibitor.
Our finding shows that, dabrafenib induces T cell proliferation in PBMCs of a group of patients and predominantly stimulates production of IL-1β and IL-6 in PBMCs. This was also demonstrated in a group of healthy donors. In addition, trametinib inhibits suppressive function of Tregs, which may be the caused for exacerbating drug hypersensitivity. Based on our observations, the toxicity of the combination of dabrafenib and trametinib should be carefully evaluated before putting the patients on treatment.