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.

Keywords: BRAF; MEK; adverse events; melanoma; safety.

Figure 1

Structural and population pharmacokinetic properties (single drug) of BRAF indicator dabrafenib, vemurafenib and encorafenib and of MEK indicator trametinib, cobimetinib and binimetinib. AR, accumulation ratio; AUC 0–24, area under the curve for 0–24 h (AUC 0–8 : 0-8 h); BCS, biopharmaceuticsclassification system; C max, maximum concentration; C 24, concentration after 24 h; d, days; h, hours; MTD, maximum tolerated dose; od, once daily; RP2D, recommended phase 2 dose; t 1/2 eff, effective half-life, calculated as –0.693*tau/(ln[1–{1/AR}]); td, twice daily; t max, time taken to reach maximum concentration, reported as median. In brackets: (%CV b), between-subject coefficient of variation; (nc), not calculated; (nr), not reported; […], range. All reported values are means, if not indicated otherwise (i.e. median).

Figure 2

Differences in adverse event frequencies: combination therapies versus vemurafenib monotherapy. CPK, creatine phosphokinase; cSCC, cutaneous squamous cell carcinoma; PPH, palmoplantar hyperkeratosis.

Figure 3

Recommendations for the management of clinically relevant and/or very frequent AE of BRAFi+MEKi therapy. Disclaimer: Official recommendations for the management of the three combinations might differ (please consider first the detailed specifications and recommendations as outlined in the summary of product characteristics (European Union) or in the respective, official prescribing information documents (USA and other countries outside European Union)). CTC-AE, common terminology criteria for adverse events; Crea, creatinine; ld, low-dose; mhd, middle-to-high-dose; NSAID, nonsteroidal anti-inflammatory drugs; OCT, optical coherence tomography; RA, receptor antagonist; TEN, toxic epidermal necrolysis; UVA, ultraviolet A (radiation).