Severe gastrointestinal toxicity of MEK inhibitors

Abstract

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.

Gastrointestinal perforation following dabrafenib and trametinib administration in non-small cell lung carcinoma with BRAF V600E mutation: a case report and literature review

“…We searched PubMed for related articles published before September 2020. The clinical features of the patients in previously reported clinical trials and case reports are summarized in Table 1 [8][9][10][11]. Among these cases, four were of melanoma, one oral cavity squamous cell carcinoma, and our case NSCLC.…”

“…In a phase study of patients with neuroblastoma RAS viral oncogene homolog (NRAS)-mutated advanced melanoma treated with binimetinib (MEK162, a potent, selective inhibitor of MEK1 and MEK2), one (3%) of 30 patients in the NRAS-mutated group had a small intestinal perforation [10]. In another retrospective analysis of patients with melanoma treated with MEK inhibitors (cobimetinib, trametinib, or binimetinib), two (1.7%) of 117 patients developed colonic perforations [8].…”

“…However, severe gastrointestinal toxicities of MEK inhibitors, such as gastrointestinal perforation, have been reported in melanoma and oral cavity squamous cell carcinoma patients [8][9][10][11]. Herein, we report a case with NSCLC who developed gastrointestinal perforation secondary to MEK inhibitor treatment.…”

Efficacy and Adverse Events in Metastatic Melanoma Patients Treated with Combination BRAF Plus MEK Inhibitors Versus BRAF Inhibitors: A Systematic Review

“…In terms of gastrointestinal (GI)-related events, MEK inhibitors have been previously associated with multiple GI-related adverse events, which can be easily reversed by temporary discontinuation and restarting at a lower dose [23]. Constipation was significantly more common in the encorafenib plus binimetinib and dabrafenib plus trametinib combination groups compared to vemurafenib monotherapy.…”

Safety of BRAF+MEK Inhibitor Combinations: Severe Adverse Event Evaluation

“…However, despite numerous studies comparing different agents, there are no head-to-head clinical trials comparing the different combinations, and most safety data originate from the confirmatory phase III trials [ 19 ]. Moreover, there are no studies directly comparing the safety profile of all the combinations, and instead, are either comparing only between two products (e.g., vemurafenib versus dabrafenib) [ 26 , 27 , 28 , 29 , 30 , 31 ], focusing on specific adverse events [ 26 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ], or based on confirmatory studies alone [ 19 ]. Defining and characterizing BRAFi+MEKi combination-specific events is a crucial issue for patient safety, especially given that a large proportion of patients are expected to develop severe toxicities.…”