Risk of selected gastrointestinal toxicities in cancer patients treated with MEK inhibitors: a comparative systematic review and meta-analysis

Abstract

We performed a systematic review and meta-analysis of the risk of gastrointestinal (GI) toxicities associated with MEK inhibitors. Eligible studies included randomized Phase II and III trials of cancer patients on the three MEK inhibitors (trametinib, selumetinib and cobimetinib), describing events of stomatitis, diarrhea and vomiting. Our search strategy yielded 250 potentially relevant citations from Pubmed/Medline, Google scholar and CENTRAL Cochrane registry. After exclusion of ineligible studies, a total of 16 clinical trials were considered eligible for the meta-analysis. The relative risks of all-grade stomatitis, diarrhea and vomiting were 2.03 (95% CI 1.41–2.96; p = 0.002), 1.92 (95% CI 1.48–2.50; p < 0.00001) and 1.35 (95% CI 1.06–1.71; p = 0.01). Subgroup analyses according to agent used (trametinib vs Selumetinib), the regimen used (monotherapy vs combination) and the cancer treated (melanoma vs nonmelanoma) did not reveal any significant difference between the subgroups. Our meta-analysis has demonstrated that MEK inhibitor-based treatment is associated with an increased risk of stomatitis, diarrhea and vomiting compared to control. Clinicians should be aware of this risk and perform regular assessment.

Keywords:

• cobimetinib
• diarrhea
• selumetinib
• stomatitis
• trametinib

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• We performed a systematic review and meta-analysis of the risk of gastrointestinal (GI) toxicities associated with MEK inhibitors.

• Eligible studies included randomized Phase II and III trials of patients with cancer on the three MEK inhibitors (trametinib, selumetinib and cobimetinib); describing events of stomatitis, diarrhea and vomiting.

• After exclusion of ineligible studies, a total of 16 clinical trials were considered eligible for the meta-analysis.

• The RRs of all-grade stomatitis, diarrhea and vomiting were 2.03 (95% CI 1.41–2.96; p = 0.002), 1.92 (95% CI 1.48–2.50; p < 0.00001) and 1.35 (95% CI 1.06–1.71; p = 0.01), respectively.

• Subgroup analyses according to the agent used (trametinib vs Selumetinib), the regimen used (monotherapy vs combination) and the cancer treated (melanoma vs nonmelanoma) did not reveal any significant difference between the subgroups.