Tolerability of BRAF/MEK inhibitor combinations: adverse event evaluation and management

Abstract

The inhibition of the mitogen-activated protein kinases signalling pathway through combined use of BRAF and MEK inhibitors (BRAFi+MEKi) represents an established therapeutic option in patients with BRAF-mutated, advanced melanoma. These efficient therapies are well tolerated with mostly moderate and reversible side effects and a discontinuation rate due to adverse events of 11.5%–15.7%. Median duration of therapy ranges between 8.8 and 11.7 months. Based on data from confirmatory trials, safety profiles of three BRAFi+MEKi combinations were reviewed, that is, dabrafenib plus trametinib, vemurafenib plus cobimetinib and encorafenib plus binimetinib. Many adverse events are class effects, such as cutaneous, gastrointestinal, ocular, cardiac and musculoskeletal events; some adverse events are substance associated. Fever (dabrafenib) and photosensitivity (vemurafenib) are the most common and clinically prominent examples. Other adverse events are less frequent and the association to one substance is less strong such as anaemia, facial paresis (encorafenib), neutropenia (dabrafenib), skin rash, QTc prolongation and increased liver function tests (vemurafenib). This narrative review provides recommendations for monitoring, adverse event evaluation and management focusing on the clinically relevant side effects of the three regimens.

Hypertensive Cardiotoxicity in Cancer Treatment—Systematic Analysis of Adjunct, Conventional Chemotherapy, and Novel Therapies—Epidemiology, Incidence, and Pathophysiology

“…They also inhibit other growth factors and kinases including c-kit protein, platelet-derived growth factor receptor (PDGFR), and FMS-like tyrosine kinase-3 [ 107 , 108 ]. The B-rapid accelerating fibrosarcoma (BRAF) (dabrafenib, vemurafenib, encorafenib) and mitogen extracellular signal-regulated kinase (MEK) inhibitors (trametinib, cobimetinib, binimetinib) are serine-threonine kinase inhibitors that are active against V600 mutations in melanoma and colorectal carcinomas [ 39 ]. Hypertension of all grades remains a significant treatment adverse effect with these drugs, with evidence of a class effect.…”

“…Ibrutinib and lenvatinib were associated with the highest rate of all grade hypertension 49–68% and high grade CTCAE 3 or 4 hypertension in 16–42%, respectively. The BRAF and MEK inhibitors, typically used in combination therapy for melanoma with V600 mutations, evoked a hypertensive response of any grade in 20.6% and CTCAE grade 3 or 4 in 10.1% [ 39 ].…”

Fertility Outcomes and Sperm-DNA Parameters in Metastatic Melanoma Survivors Receiving Vemurafenib or Dabrafenib Therapy: Case Report

“…In fact, in most of the cell lines with BRAF mutations, IC 50 of vemurafenib is nearly one order of magnitude greater than that observed for of dabrafenib (<1,000 nmol/L vs. <100 nmol/L, respectively) (28). In addition, according to the biopharmaceutics classification system, vemurafenib is classified with low solubility-low permeability properties, differing from the low solubility-high permeability classification of dabrafenib (29)(30)(31). On these bases, it is reasonable to expect that the anti-proliferative effects of these two drugs may reverberate differentially on the reproductive function and in particular on spermatogenesis which is highly sensitive to environmental noxae (32).…”

The miRNAs Role in Melanoma and in Its Resistance to Therapy

“…A combination of immunotherapy drugs for people who have less advanced melanoma was evaluated by Heinzerling et al They showed the efficiency of BRAF and MEK inhibitors (BRAFi + MEKi), combined, as an established therapeutic option in patients with BRAF-mutated advanced melanoma. In particular, the dabrafenib + trametinib (D + T) combination has been demonstrated to prolong overall survival in the adjuvant setting [67].…”