CORRESPONDENCE
1267 ActaDV ActaDV
Advances in dermatology and venereology Acta Dermato-Venereologica
Cutaneous Side Effects of Single Versus Combined BRAF Inhibitors: A Comment to Erfan et al.
Rachael ANFORTH and Pablo FERNANDEZ-PENAS Department of Dermatology, Westmead Hospital, 2145 Sydney, Australia
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. This is of significance as the toxicities are slightly different between the two agents. The authors concluded that cutaneous squamous cell carcinomas( cuSCC) appeared in 23.7 % of their patients. This figure is consistant with their population with the reported rate of vemurafenib induced cuSCC being higher than that of dabrafenib( 19 – 26 % versus 10 – 12 %)( 2). Similarly they found that cuSCC were common in older patients and presented in both sun-exposed and non-sun-exposed sites.
In 2015, we published on a cohort of 134 patients who were treated with dabrafenib( n = 106; 79 %) and vemurafenib( n = 28; 21 %)( 2). In this study we found that the only significant risk for development of cuSCC during treatment was age(> 60 years old). The patient’ s sex or mutation status did not affect time to development of cuSCC. Interestingly patients on vemurafenib appeared to develop their cuSCCs earlier in the treatment course compared with dabrafenib.
As with Erfan et al., we also found that location of cuSCC varied. 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
Reply to the comments by Anforth and Fernandez-Penas
signs of sun damage( actinic keratoses) prior to treatment( 1, 2).
The authors findings that photosensitivity is present in both treatment groups was interesting. Photosensitivity is a vemurafenib-specific toxicity and in our experience very rarely encountered in dabrafenib or dabrafenib and trametinib combination therapy( 3). Perhaps, given the small population of dabrafenib in their cohort, it may be worth reviewing.
The addition of the MEK inhibitor trametinib to treatment has been shown to negate the majority of the single agents toxicities, in particular cuSCC and other hyperkeratotic conditions. It does this by preventing the activation of ERK, which in single agent treatment has been shown to be unregulated. It is therefore interesting that the authors found palmoplantar keratoderma persisted in their cohort treated with combination therapy. We reported on 30 patients treated with the combination of dabrafenib and trametinib and found a significant reduction in the number of PPK cases( 47 % in dabrafenib alone versus 5 % in the combination group)( 4). We too found that folliculitis was higher in the combination group, likely the result of the MEK inhibitor.
The consistency of cutaneous toxicities is reassuring as it will improve the clinical management of patients treated with BRAF inhibitors, with clinicians aware to pay closer attention to older patients and examine sunprotected areas.
Gamze ERFAN 1, Cristina CARRERA 2 – 4, Josep MALVEHY 2 – 4 and Susana PUIG 2 – 4
1
Dermatology Department, Namık Kemal University Faculty of Medicine, Tekirdag, Turkey, 2 Dermatology Department, Melanoma Unit, Hospital Clinic & IDIBAPS( Institut d’ Investigacions Biomèdiques August Pi i Sunyer, 3 CIBER de Enfermedades raras, Instituto de salud Carlos III, and 4 Universitat de Barcelona, Barcelona, Spain. E-mail: spuig @ clinic. ub. es
First of all we really appreciate the comments by Anforth & Fernandez-Penas and their interest in our paper on the cutaneous toxicities of anti-BRAF inhibitor therapy in patients with metastatic melanoma( 1). As they noted, our population was mainly treated with vemurafenib and only 9 % received dabrafenib, which is the main limitation of the study. Besides pointing out this limitation and, similar to previous reports, we found that the development of new non-melanoma skin cancer and keratoacanthoma was significantly higher in patients with single anti-BRAF treatment( OR-combined: 0.5, p = 0.02, OR: 0.74, p = 0.05 and OR-combined: 0.75, p = 0.05) also when comparing combined and single dabrafenib( OR: 0.6, p = 0.02 and OR: 0.6, p = 0.02) with no differences between single treatment of vemurafenib and dabrafenib. All patients with SCC were under single anti-BRAF treatment( OR: 0.9, p = 0.29). Unlike the study of Anforth et al.( 2) in our study we observed that the patients on dabrafenib appeared to develop their cuSCCs earlier in the treatment course compared with vemurafenib( mean days to cuSCC diagnosis with single dabrafenib was 48 days compared to 80.5 days in single vemurafenib).
As Anforth & Fernandez-Penas mention, in our study, photosensitivity was diagnosed in 26( 44.1 %) patients
This is an open access article under the CC BY-NC license. www. medicaljournals. se / acta Journal Compilation © 2017 Acta Dermato-Venereologica. doi: 10.2340 / 00015555-2763 Acta Derm Venereol 2017; 97: 1267 – 1268