Isotretinoin for the treatment of severe acneiform eruptions associated with the MEK inhibitor trametinib

Trametinib is a selective inhibitor of mitogen-activated protein kinase (also known as MEK) blocking the phosphorylation of mitogen-activated protein kinase. Trametinib has been approved as a treatment for metastatic non–small cell lung cancer and unresectable or metastatic melanoma with specific BRAF mutations. Other off-label uses in the pediatric population include treatment of glioma with mitogen-activated protein kinase activation, low-grade glioma with BRAF fusion and neurofibromatosis type 1 (NF1) with plexiform neurofibroma, or low-grade glioma. Trametinib is administered at a dose of 0.025 mg/kg/d (maximum, 2 mg). The dose can be reduced if there is a severe adverse effect; however, this may diminish efficacy; currently serologic levels are not measured routinely. Acneiform eruptions have been reported to be the most common adverse effect associated with trametinib occurring in up to 77% of users.1Anforth R. Liu M. Nguyen B. et al.Acneiform eruptions: a common cutaneous toxicity of the MEK inhibitor trametinib.Australas J Dermatol. 2014; 55: 250-254Crossref PubMed Scopus (46) Google Scholar Effective treatment of this eruption is important to allow for continued use of MEK inhibitors. However, some patients do not respond to traditional therapy.2Boull C. Hook K. Moertel C. Maguiness S. Cutaneous reactions in children treated with the mitogen-activated protein kinase extracellular signal-regulated kinase inhibitor trametinib for neural tumors.Pediatr Dermatol. 2017; 34: 90-94Crossref PubMed Scopus (14) Google Scholar We report our experience with isotretinoin as a treatment of severe acneiform eruptions to MEK inhibitor trametinib. A 16-year-old girl with NF1 and a voluminous plexiform neurofibroma of the right thigh, began trametinib and, 2 weeks later, presented with a dramatic monomorphic papulopustular eruption on her forehead, nose, and chin. The patient was started on doxycycline, 100 mg twice daily. At 6-week follow-up, there was marked improvement of the eruption, but a subsequent visit 4 weeks later found recurrence and worsening of skin lesions in spite of persistent therapy (Fig 1, A). She was started on isotretinoin, 10 mg/d (0.2 mg/kg/d) for 1 month, followed by 20 mg/d (0.35 mg/kg/d). Three months later, there was significant clearing with only erythematous macules remaining (Fig 1, B). Isotretinoin was well tolerated and she continues with the same treatment for 1 year. A 16-year-old boy with NF1 and an unresectable painful right paravertebral plexiform neurofibroma was treated with trametinib and subsequently had a monomorphic papulopustular eruption on his nose and back 4 weeks later. The patient was started on isotretinoin, 10 mg/d (0.15 mg/kg/d), and topical dapsone gel twice daily. At 1-month follow-up, the patient had dramatic clearing of inflammatory lesions, and he continues with the same treatment for 6 months. A 13-year-old boy with NF1 presented with worsening of baseline comedonal and mild inflammatory acne 4 weeks after starting trametinib for multiple facial neurofibromas despite application of topical 0.025% tretinoin cream. He had multiple comedones and an extensive monomorphic papulopustular eruption on his face, chest, and back (Figs 2, A and 3, A). The patient was started on isotretinoin, 10 mg/d (0.2 mg/kg/d). At 3 months follow-up (Fig 2, B), the patient showed significant improvement of the face with clearing of the back and he continues with the same treatment for 1 year (Fig 3, B).Fig 3A, Monomorphic papulopustular eruption of the back 4 weeks after starting trametinib for facial neurofibromas. B, Dramatic improvement of back acneiform eruption after 12 months on isotretinoin.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Time to onset of acneiform eruptions after initiation of trametinib was fast, varying from 2 to 4 weeks, which is consistent with previously reported data.1Anforth R. Liu M. Nguyen B. et al.Acneiform eruptions: a common cutaneous toxicity of the MEK inhibitor trametinib.Australas J Dermatol. 2014; 55: 250-254Crossref PubMed Scopus (46) Google Scholar, 2Boull C. Hook K. Moertel C. Maguiness S. Cutaneous reactions in children treated with the mitogen-activated protein kinase extracellular signal-regulated kinase inhibitor trametinib for neural tumors.Pediatr Dermatol. 2017; 34: 90-94Crossref PubMed Scopus (14) Google Scholar, 3Manousaridis I. Mavridou S. Goerdt S. Leverkus M. Utikal J. Cutaneous side effects of inhibitors of the RAS/RAF/MEK/ERK signalling pathway and their management.J Eur Acad Dermatol Venereol. 2013; 27: 11-18Crossref PubMed Scopus (66) Google Scholar One review of 14 trials of cancer patients on 3 MEK inhibitors reported the relative risk of acneiform dermatitis at 8.44 (95% confidence interval, 2.39-29.81; P = .0009).4Abdel-Rahman O. El Halawani H. Ahmed H. Risk of selected dermatological toxicities in cancer patients treated with MEK inhibitors: a comparative systematic review and meta-analysis.Future Oncol. 2015; 11: 3307-3319Crossref PubMed Scopus (9) Google Scholar This eruption does not always respond to traditional acne therapy with topical treatment and oral antibiotics.2Boull C. Hook K. Moertel C. Maguiness S. Cutaneous reactions in children treated with the mitogen-activated protein kinase extracellular signal-regulated kinase inhibitor trametinib for neural tumors.Pediatr Dermatol. 2017; 34: 90-94Crossref PubMed Scopus (14) Google Scholar Skin toxicities are considered an important cause for treatment interruption of MEK inhibitors.4Abdel-Rahman O. El Halawani H. Ahmed H. Risk of selected dermatological toxicities in cancer patients treated with MEK inhibitors: a comparative systematic review and meta-analysis.Future Oncol. 2015; 11: 3307-3319Crossref PubMed Scopus (9) Google Scholar The cutaneous side-effect profile of MEK inhibitors closely resembles those of epidermal growth factor receptor (EGFR) inhibitors.1Anforth R. Liu M. Nguyen B. et al.Acneiform eruptions: a common cutaneous toxicity of the MEK inhibitor trametinib.Australas J Dermatol. 2014; 55: 250-254Crossref PubMed Scopus (46) Google Scholar,3Manousaridis I. Mavridou S. Goerdt S. Leverkus M. Utikal J. Cutaneous side effects of inhibitors of the RAS/RAF/MEK/ERK signalling pathway and their management.J Eur Acad Dermatol Venereol. 2013; 27: 11-18Crossref PubMed Scopus (66) Google Scholar,5Chiang H.C. Anadkat M.J. Isotretinoin for high-grade or refractory epidermal growth factor receptor inhibitor-related acneiform papulopustular eruptions.J Am Acad Dermatol. 2013; 69: 657-658Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar Although use of isotretinoin has been reported for treatment of EGFR inhibitor–induced acneiform eruptions, it has not been reported for those induced by MEK inhibitors.5Chiang H.C. Anadkat M.J. Isotretinoin for high-grade or refractory epidermal growth factor receptor inhibitor-related acneiform papulopustular eruptions.J Am Acad Dermatol. 2013; 69: 657-658Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar We expect to be able to eventually wean off isotretinoin, as is the experience with EGFR inhibitors. A report of EGFR inhibitor–related acneiform eruption notes that 8 of 11 patients showed at least moderate response to isotretinoin. Of these, 4 showed complete response and were able to stop isotretinoin. For the patients who stopped treatment because of significant xerosis, although prescribed dosing was not reported, we hypothesize these complications may have been in relation to higher dosing of isotretinoin (ie, ≥0.5 mg/kg/d).5Chiang H.C. Anadkat M.J. Isotretinoin for high-grade or refractory epidermal growth factor receptor inhibitor-related acneiform papulopustular eruptions.J Am Acad Dermatol. 2013; 69: 657-658Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar Our 3 cases support the use of low-dose isotretinoin (0.15 to 0.35 mg/kg/d) for satisfactorily improving MEK inhibitor–induced acneiform eruptions. Use of isotretinoin in this population is easily manageable, as it does not have a known clinically significant interaction with trametinib. Routine laboratory testing, including fasting lipid panel and liver function tests, should be performed periodically during treatment with isotretinoin.5Chiang H.C. Anadkat M.J. Isotretinoin for high-grade or refractory epidermal growth factor receptor inhibitor-related acneiform papulopustular eruptions.J Am Acad Dermatol. 2013; 69: 657-658Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar For our patients, in the context of the trametinib study, laboratory testing was done at baseline for most patients and repeated every 2 to 3 months. Isotretinoin was well tolerated in all 3 patients without significant increases in triglycerides or hepatotoxicity, and rapid improvement was noted within 1 to 3 months. All patients continued low-dose isotretinoin with consistent suppression of the acneiform eruption. We report 3 cases of severe acneiform eruptions occurring shortly after initiation of therapy with trametinib, which responded with very good efficacy and tolerance to low-dose oral isotretinoin. Successful treatment of these eruptions with oral isotretinoin is of important clinical significance, as it permits continuation of treatment with trametinib.

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