Adverse Cutaneous Reactions Associated with MEK Inhibitor Therapy in a Pediatric Population.

To the Editor: MEK inhibitors (MEKis) are approved in adult populations to target the mitogen-activated protein kinase signaling pathway implicated in approximately one-third of all malignancies. Although these therapies are generally well tolerated, cutaneous toxicities are common. Until April 2020, when selumetinib was approved for children, MEKi therapy was limited to investigational and compassionate use and data regarding cutaneous adverse effects (AEs) were limited compared with adults. A recent report, including 43 children on MEKi therapy, demonstrated a mean of 3.7 cutaneous reactions per patient, similar to findings in smaller studies.1Boull C.L. Gardeen S. Abdali T. et al.Cutaneous reactions in children treated with MEK inhibitors, BRAF inhibitors, or combination therapy: a multicenter study.J Am Acad Dermatol. 2021; 84: 1554-1561Abstract Full Text Full Text PDF PubMed Scopus (9) 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 (17) Google Scholar, 3Song H. Zhong C.S. Kieran M.W. Chi S.N. Wright K.D. Huang J.T. Cutaneous reactions to targeted therapies in children with CNS tumors: a cross-sectional study.Pediatr Blood Cancer. 2019; 66e27682Crossref Scopus (15) Google Scholar, 4Balagula Y. Lacouture M.E. Cotliar J.A. Dermatologic toxicities of targeted anticancer therapies.J Support Oncol. 2010; 8: 149-161PubMed Google Scholar However, only patients seen by a dermatologist were included, potentially skewing the true prevalence of cutaneous reactions. Our primary objective was to characterize cutaneous AEs of MEKi therapy in children who were seen by oncology but not necessarily seen by dermatology. This study was deemed exempt by our institution’s institutional review board. Patients aged 0 to 21 years who initiated MEKi therapy at our center from January 2010 to December 2021 with at least 3 months of follow-up were included. Patients were identified from internal patient registries from the sections of neuro-oncology and comprehensive vascular anomalies, 2 groups that most commonly prescribe MEKi therapy. Data were collected via retrospective chart review. We included 98 patients (52% male) with a median age of 10 years (IQR, 6-15 years) at therapy initiation (Table I). The first cutaneous AE was reported with a median of 15 days (IQR, 9-38.5 days) after treatment initiation, and 25.5% of cases required a dermatology visit as determined by the prescribing oncologist. In all, 85.7% of patients experienced a cutaneous AE, and the most common reactions were acneiform eruption (45.9%), unspecified rash (30.6%), paronychia (25.5%), and dry skin (20.4%). Although rare (<3%), other cutaneous AEs included alopecia, hair lightening, panniculitis, photosensitivity, and urticaria. Most skin toxicities were considered Common Terminology Criteria for Adverse Events grade 1, but 14 patients experienced effects requiring a drug hold with 1 patient permanently discontinuing MEKi therapy. Cutaneous reactions were associated with 16 dose reductions (Table II). Total number of skin reactions, acneiform eruptions, eczematous reactions, paronychia, and xerosis differ significantly by specific drug; however, statistical power among drug-drug comparisons is limited (Table II). Postpubertal children had a higher risk of acneiform eruptions. Prepubertal children had a higher risk of unspecified rashes (Table II).Table ICharacteristics of study population and overall cutaneous adverse effectsStudy population characteristicN = 98Male sex, N (%)51 (52.0%)Age (y) therapy initiated, median (IQR)10 (6-15)Primary MEKi indication, N (%) Glioma41 (41.8%) Plexiform neurofibroma38 (38.8%) Lymphatic/vascular anomaly13 (13.3%) Other6 (6.1%)Mutation, N (%) BRAF V600E16 (16.3%) BRAF other12 (12.2%) NF145 (45.9%) Other/unknown25 (25.5%)MEKi prescribed, N (%) Trametinib43 (43.9%) Selumetinib∗Nineteen patients with plexiform neurofibroma were included in the SPRINT Selumetinib trial. Three patients with plexiform neurofibroma were included in the NF108/PNOC010 Binimetinib trial.38 (38.8%) Dabrafenib†Dabrafenib is a RAF inhibitor./trametinib14 (14.3%) Binimetinib∗Nineteen patients with plexiform neurofibroma were included in the SPRINT Selumetinib trial. Three patients with plexiform neurofibroma were included in the NF108/PNOC010 Binimetinib trial.3 (3.1%)MEKi drug associated with dose reduction, N (%)16/98 (16.3%) Trametinib11/43 (25.6%) Selumetinib3/38 (7.9%) Dabrafenib†Dabrafenib is a RAF inhibitor./trametinib1/14 (7.1%) Binimetinib1/3 (33.3%)Cutaneous AE caused drug hold, N (%)14/98 (14.3%) Trametinib10/43 (23.3%) Selumetinib2/38 (5.3%) Dabrafenib†Dabrafenib is a RAF inhibitor./trametinib1/14 (7.1%) Binimetinib1/3 (33.3%)CTCAE reaction associated with drug hold, N (%) Grade 2, acneiform eruption3/14 (21.4%) Grade 3, acneiform eruption1/14 (7.1%) Grade 2, eczematous rash3/14 (21.4%) Grade 2, paronychia2/14 (14.3%) Grade 2, skin infection2/14 (14.3%) Grade 3, skin infection1/14 (7.1%) Grade 2, pruritus1/14 (7.1%) Grade 2, photosensitivity1/14 (7.1%)Flare after restart following drug hold, N (%)8/14 (57.1%)Inpatient/outpatient dermatology visit for cutaneous AE, N (%)25/98 (25.5%)Medical treatments cited for improving AE, N (%), some patients received ≥1 treatment Self-improved‡Self-improved indicates that patient did not require any prescribed therapy for their cutaneous AE; these include acneiform eruption (n = 3), eczematous rash (n = 2), paronychia (n = 1), rash unspecified (n = 4), xerosis (n = 3), and pruritus (n = 1).14/84 (16.7%) Emollient18/84 (21.4%) Topical antibiotic41/84 (48.8%) Oral antibiotic21/84 (25.0%) Topical or oral steroids21/84 (25.0%) Other§Includes antifungals, retinoids, and antihistamines.5/84 (6.0%)AE, Adverse event; CTCAE, Common Terminology Criteria for Adverse Events; IQR, interquartile range.∗ Nineteen patients with plexiform neurofibroma were included in the SPRINT Selumetinib trial. Three patients with plexiform neurofibroma were included in the NF108/PNOC010 Binimetinib trial.† Dabrafenib is a RAF inhibitor.‡ Self-improved indicates that patient did not require any prescribed therapy for their cutaneous AE; these include acneiform eruption (n = 3), eczematous rash (n = 2), paronychia (n = 1), rash unspecified (n = 4), xerosis (n = 3), and pruritus (n = 1).§ Includes antifungals, retinoids, and antihistamines. Open table in a new tab Table IICutaneous adverse effects by drug regimen and pubertal statusOverall (n = 98)Trametinib (n = 43)Selumetinib (n = 38)Binimetinib (n = 3)Trametinib/dabrafenib (n = 14)Drug regimen P valuePrepubertal (n = 50)Postpubertal (n = 48)Pubertal P valueMedian number of reactions2 (1-3)2 (1-2)1 (1-2)4 (3-4)1.5 (1-2).0492 (1-2)2 (1-3).24Acneiform eruption45(45.9%)14 (32.5%)24 (63.2%)3 (100%)4 (28.6%).0047 (14.0%)38 (79.2%)<.001Eczematous rash17 (17.4%)7 (16.3%)3 (7.9%)2 (66.7%)5 (35.7%).028 (16.0%)9 (18.8%).72Paronychia25 (25.5%)14 (32.6%)8 (21.1%)2 (66.7%)1 (7.1%).0811 (22.0%)14 (29.2%).42Skin infection8 (8.2%)3 (7.0%)4 (10.5%)0 (0%)1 (7.1%).914 (8.0%)4 (8.3%)1.00Seborrheic dermatitis8 (8.2%)3 (7.0%)4 (10.5%)0 (0%)1 (7.1%).913 (6.0%)5 (10.4%).48Rash unspecified30 (30.6%)18 (41.9%)8 (21.1%)0 (0%)4 (28.6%).1523 (46.0%)7 (14.6%).001Xerosis20 (20.4%)13 (30.2%)1 (2.6%)1 (33.3%)5 (35.7%).00112 (24.0%)8 (16.7%).37Pruritus unspecified14 (14.3%)7 (16.3%)7 (18.4%)0 (0%)0 (0%).3410 (20.0%)4 (8.3%).15Data presented as median (IQR) or N (%). Continuous variable analyzed using Kruskal-Wallis test (drug regimen) or Wilcoxon rank-sum test (pubertal status). Categorical variables analyzed using χ2 or Fisher exact test, as appropriate. Postpubertal status defined by Tanner stage 2 or greater pubic hair, testes, or breast development at visit nearest to time of medication initiation. Open table in a new tab AE, Adverse event; CTCAE, Common Terminology Criteria for Adverse Events; IQR, interquartile range. Data presented as median (IQR) or N (%). Continuous variable analyzed using Kruskal-Wallis test (drug regimen) or Wilcoxon rank-sum test (pubertal status). Categorical variables analyzed using χ2 or Fisher exact test, as appropriate. Postpubertal status defined by Tanner stage 2 or greater pubic hair, testes, or breast development at visit nearest to time of medication initiation. Our study contributes to the understanding of MEKi skin toxicity and includes a large number of children as well as data on the recently approved selumetinib. Our data demonstrate that cutaneous AEs are commonly associated with MEKi use and may appear several weeks into treatment. Thus, MEKi prescribers and dermatologists should be aware of these common reactions to closely follow and treat accordingly. As a retrospective cross-sectional study, our data do not demonstrate causation. Additionally, because not all patients were evaluated by dermatology, some AEs were described nonspecifically (eg, Rash Unspecified and Other) and may have been missed without a complete skin examination. Future research should include preventative strategies and the best treatment practices to address skin toxicities in patients prescribed MEKi. Dr Fisher receives research funding from AstraZeneca and Array BioPharma for other clinical trials. Dr Perman is a consultant for Abeona. The other authors have no potential conflict of interest to disclose.