Abstract and Introduction
Abstract
Background and Aims: Dual blockade of BRAF and MEK kinases is a standard of care for metastatic V600E/K BRAF mutant melanoma. This study reports the first systematic description of colitis due to BRAF and MEK inhibitors.
Methods: We studied consecutive patients with melanoma, treated with BRAF and MEK inhibitors, who had colitis requiring hospitalisation. Electronic files were studied; endoscopic biopsies and colectomy specimens were read centrally.
Results: Between January 2021 and March 2022, nine women and one man, aged 50–90 years, were studied. Nine patients received encorafenib and binimetinib; one patient received dabrafenib and trametinib. The main symptoms were diarrhoea, haematochezia, abdominal pain and intestinal obstruction. Blood tests showed anaemia, increased CRP and low serum albumin levels in most patients. All patients had ulcerations of the right colon with (2/10) or without (8/10) stenosis of the ileocecal valve, and 4/10 patients also had ulcerations distal to the right colon. Histopathological findings were suggestive of ischaemia and mild inflammation. Nine of the 10 patients discontinued BRAF/MEK inhibitors. Drugs were reintroduced in four patients, three of whom had a severe relapse of diarrhoea. Two patients required surgery and underwent intestinal resection. One patient died of enterocolitis.
Conclusion: BRAF/MEK inhibitors can induce severe colitis characterised by ulcerations of the right colon.
Introduction
Many drugs can induce enterocolitis. The clinical spectrum is wide and encompasses microscopic colitis and severe colitis, among others.[1] Colitis may or may not resolve with discontinuation of medication.
The treatment of metastatic melanoma has improved significantly over the past 10 years. Immune checkpoint inhibitors (ICIs), such as anti-CTLA-4 (ipilimumab) and anti-PD1 (pembrolizumab, nivolumab) monoclonal antibodies, have prolonged survival of patients with metastatic melanoma.[2,3] ICIs enhance T-cell activity and lead to systemic loss of tolerance, resulting in anti-tumour efficacy but also in immune-related adverse effects, of which gastrointestinal adverse effects are the most frequent and severe.[4] The clinical picture, pathophysiology and treatment options for gastrointestinal immune-related adverse effects have been extensively studied.[4] Another therapeutic strategy consists in blocking the mitogen-activated protein kinase (MAPK) pathway, which is constitutively activated in about 40% of melanomas, due to somatic mutations of the BRAF oncogene (BRAF V600E/K).[5,6] Dual blockade of BRAF and MEK kinases has demonstrated clinical activity and has become standard of care for patients with metastatic V600E/K BRAF mutant melanoma. Three combinations of BRAF and MEK inhibitors (BRAF/MEKi) have shown superiority over BRAF inhibitor monotherapy, namely vemurafenib + cobimetinib,[7] dabrafenib + trametinib[8] and encorafenib + binimetinib.[9,10] The three combinations have similar efficacy in patients with metastatic BRAF-mutant melanoma. The objective response rate is approximately 70%, and the median progression-free survival is 12–15 months. The spectrum of adverse events with these regimens is overlapping but distinct. Photosensitivity is more frequent with vemurafenib and cobimetinib, whereas fever and chills are more frequent with dabrafenib and trametinib.[5–10] Although diarrhoea is commonly observed in patients treated with BRAF/MEKi, colitis has not been documented so far.
We report here a series of 10 patients with melanoma who had severe colitis while being treated with BRAF/MEKi.
Aliment Pharmacol Ther. 2023;57(7):792-799. © 2023 Blackwell Publishing
