Severe gastrointestinal toxicity of MEK inhibitors

Gastrointestinal toxicities of MEK inhibitors in melanoma patients are frequent. In clinical trials, the most common digestive adverse events were nausea, vomiting, and diarrhoea. However, severe toxicities such as colitis and gastrointestinal perforation, some with fatal outcomes, have been reported. These rare but severe adverse events are not well described. We performed a retrospective analysis of all patients with stage IV and unresectable stage III melanoma treated with a MEK inhibitors at Saint-Louis Hospital, Paris, between 1 August 2013 and 15 October 2018. Among 119 patients exposed to MEK inhibitors, 78 were treated with trametinib, 19 with cobimetinib, four with binimetinib, and 18 patients with two different MEK inhibitors at separate times. All grade digestive adverse events were observed in 39 (32.7%) patients. Grade 3 and 4 adverse events occurred in 6 (5%) patients: 2 (1.7%) developed perforations, 3 (2.5%) had colitis and 1 (0.8%) had grade 4 diarrhoea. These adverse events were all reversible following a permanent discontinuation of the MEK inhibitors, or a temporary interruption followed by resumption at a dose lower than conventional posology. There were no fatal outcomes; however one patient had a permanent ileostomy. The mechanism underlying these toxicities is not well known. Clinicians should be aware of such toxicities.