Development of Cutaneous Toxicities During Selective Anti-BRAF Therapies: Preventive Role of Combination with MEK Inhibitors

Abstract

This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta Acta Derm Venereol 2017; 97: 258-260 258 Activated BRAF mutations affecting the mitogen-activated protein kinases (MAPK) pathway are present in 50% of metastatic melanomas. Targeted therapies have been developed to block such mutations (1, 2). There is a risk of other components of the MAPK signalling pathway, such as MEK, being reactivated after the use of BRAF inhibitors (3-5). Given the evidence of drug resistance and side-effects of BRAF inhibitors, combined treatments with BRAF and MEK inhibitors are being tested in clinical trials for metastatic melanoma. Trametinib is one of these MEK inhibitors. Skin toxicities from BRAF inhibitors, such as photosensitivity, palmoplantar keratoderma (PPK) and keratosis pilaris (KP), have been reported (4, 6-11). Also, non-melanoma skin cancers (NMSC) are considered one of the most significant sideeffects (3, 11). We report here the profile of skin toxicities from vemurafenib, dabrafenib alone, or dabrafenib and trametinib combined treatment. MATERIALS AND METHODSA total of 59 patients (47 treated with only vemurafenib (71%) or dabrafenib (9%) and 12 with dabrafenib and trametinib in combination (20%)) were seen in the Hospital Clinic, Barcelona, Spain. All patients underwent dermatological evaluation at baseline and monthly during treatment, or whenever patients presented with a complaint. All skin toxicities, including squamous-proliferative, keratinizing, inflammatory, follicular/adnexal disorders, were evaluated clinically and/or histopatho logically. Any patients presenting new melanocytic tumours or changes in their preexisting naevi were excluded from the current study. The study was approved by the ethics committee and patients gave their written informed consent.Statistical analysis with significant value (p ≤ 0.05) was performed with paired-sample Student t-test for differences between the duration of toxicities and Pearson χ 2 with 95% confidence interval (95% CI) for analysing the significance of the existence of each side-effect.

Cutaneous Side Effects of Single Versus Combined BRAF Inhibitors: A Comment to Erfan et al.

“…With 58% occurring on chronic sundamaged skin and 33.3% occurring on low chronic sun-damaged areas (sun-protected). This correlates with Erfan et al's statement that only two patients had signs of sun damage (actinic keratoses) prior to treatment (1,2).…”

“…We read with interest the paper by Erfan et al (1) on the cutaneous toxicities of anti-BRAF inhibitor therapy in 59 patients with metastatic melanoma. We note that their patient population was mainly treated with vemurafenib (71%) with only 9% receiving dabrafenib.…”

Genomic analysis and clinical management of adolescent cutaneous melanoma

“…In July 2014, she was commenced on systemic therapy with the BRAF kinase inhibitor, vemurafenib. Ten days into therapy, she experienced arthralgia, blepharitis, meibomian gland inflammation (presenting with suppuration from the sebaceous gland at the rim of the eyelids and treated with topical and oral antibiotics), as well as a widespread cutaneous rash necessitating interruption of treatment (Erfan et al., ; Figure ). Treatment was reintroduced 2 weeks later at a 25% dose reduction.…”

Decreased photosensitivity to UVA on vemurafenib combined with cobimetinib

“…4 However, studies have shown a protective effect of cobimetinib on the frequency and time to onset of some secondary cutaneous adverse events (carcinomas and dyskeratoses). 5,6 Note that four patients had a difference in MED of more than six joules between both treatment periods, which corresponded Letters to the Editor e87 to a clinically visible difference in photosensitivity (present during the period on vemurafenib alone). Among these four patients, three did not experience any photosensitivity on vemurafenib and cobimetinib, whereas they experienced photosensitivity during the week on vemurafenib alone.…”