Combination therapy: toxicity

BRAF targets in melanoma. Biological mechanisms, resistance, and drug discovery. Cancer drug discovery and development. Volume 82. Ed. Ryan J. Sullivan. Springer (2015)

The toxicity profile was significantly altered by combining BRAF and MEK inhibition compared with monotherapy. The incidence of cutaneous squamous cell carcinoma was decreased (19 vs. 7%) as was the classic BRAF inhibitor-associated dermatitis (36 vs. 27%). The addition of a MEK inhibitor appears to attenuate the risk of secondary malignancies by preventing paradoxical MAPK activation. The acneiform dermatitis induced by MEK inhibitors also appeared to occur less frequently than in the METRIC trial [35]. Other class toxicities characteristic of trametinib were observed in the combination group including decreased ejection fraction (9%) and ocular events (one patient with retinopathy). Also significantly, 25% of patients on the combination 150/2 mg arm developed severe pyrexia (defined as associated with severe chills, hypotension, or requiring hospitalization). Anti-pyretics and temporary interruption of therapy are generally sufficient in mild cases although severe cases may necessitate intravenous fluid repletion and oral steroids. The onset of pyrexia is not predictable and may occur even after prolonged therapy. Neutropenia (11%), fatigue, nausea, and diarrhea also occurred more commonly in the combination arms.

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