Evaluation of cutaneous adverse events of encorafenib and binimetinb: COMMENT on article by Graf et al.

Abstract

Since the approval of the BRAF inhibitor encorafenib and the MEK inhibitor binimetinib, three different combination regimens for BRAF-mutated advanced melanoma are now available in Europe and we are somewhat spoilt for choice. None of the three combination treatments (encorafenib plus binimetinib, dabrafenib plus trametinb and vemurafenib plus cobimetinib) have ever been tested head-to-head within a clinical trial. 1-3 Cross-trial comparisons have to be made with caution as clinical trial set-up, demographics as well as time of trial recruitment and available treatment options differ. Yet, when advising patients on treatment, one must know differences in response rate, duration of response but also adverse events. BRAF as well as MEK inhibitors are notorious for cutaneous adverse events. Both inhibitors block a kinase within the MAPK pathway, but while BRAF inhibitors primarily bind to mutated BRAF, MEK inhibitors bind to wild-type MEK. Cutaneous adverse event profiles of BRAF and MEK inhibitors are very distinct, and unlike many other combinations some specific cutaneous adverse events occur less frequently when BRAF and MEK inhibitors are used concomitantly. A paradoxical activation of the MAPK pathway induced by BRAF inhibitors in BRAF wild-type cells 4 is thought to be counteracted by MEK inhibitors that block a kinase downstream of RAF and vice versa.While cutaneous adverse events are well described for first-generation BRAF and MEK inhibitors, Graf et al. 5 aimed to describe the cutaneous toxicity profiles of encorafenib, binimetinib and their combination. To this end, they retrospectively reviewed charts of patients treated with BRAF and/or MEK inhibitors in clinical trials at the University Hospital Zurich. Results for encorafenb, binimetinib and their combination were then compared to dabrafenib, vemurafenib, cobimetinib and trametinib. A total of 111 patients receiving 123 treatments were identified. Unfortunately, some groups (e.g. vemurafenib monotherapy) were very small with <10 patients making comparisons difficult. According to their data, cutaneous adverse events were lower in patients treated with encorafenib plus binimetinib (32.7%) than any other mono-or combination therapy (45.4-100%). Encorafenib induced less keratinocytic disorders than vemurafenib; encorafenib's most frequent cutaneous adverse events were palmoplantar erythrodysesthesia (58.3%) and palmoplantar hyperkeratosis (54.2%) followed by alopecia (45.8%). Cutaneous adverse event profiles of binimetinib were similar to trametinib, drug-induced papulopustular eruptions ranked first for both MEK inhibitors (64% and 75%, respectively). When combining encorafenib and binimetinib, all cutaneous adverse events of the single agents decreased to less or around 10%. Graf et al. 5 argue that the lower toxicity rate of encorafenib is a consequence of a lower paradoxical activation of the MAPK pathway 6 and encorafenib's longer dissociation time. 7,8 Even though conclusions from this investigation must be drawn with caution due to the low patien...