# Treatment-Related Adverse Events in Individuals with BRAF-Mutant Cutaneous Melanoma Treated with BRAF and MEK Inhibitors: A Systematic Review and Meta-Analysis

## TL;DR

This study reviews and analyzes the common side effects of BRAF and MEK inhibitors used to treat melanoma, highlighting key adverse events to improve treatment planning.

## Contribution

The paper provides a meta-analysis of treatment-related adverse events for BRAF and MEK inhibitors in melanoma patients, revealing distinct toxicity profiles.

## Key findings

- Arthralgia and rash are the most common adverse events with vemurafenib treatment.
- Fatigue and pyrexia are the most frequent adverse events with dabrafenib plus trametinib.
- Squamous cell carcinoma and keratoacanthoma are notable severe skin adverse events with vemurafenib.

## Abstract

Cutaneous melanoma (CM) is a major public health concern, with rising morbidity and mortality worldwide. Advances in pharmacological science have led to the development of small-molecule kinase inhibitors (SMIs), particularly those targeting the mitogen-activated protein kinase (MAPK) pathway—B-Rapidly Accelerated Fibrosarcoma (BRAF) inhibitors and MAPK/extracellular signal-regulated kinase (MEK) inhibitors—which can directly inhibit melanoma cell growth in tumors with specific oncogenic mutations. While these agents are designed to selectively target cancer cells and limit toxicity, clinical trials have reported a range of treatment-related adverse events (TRAEs). Understanding the prevalence of these TRAEs is essential for optimizing symptom management and developing personalized risk-stratified care pathways. In this study, we systematically reviewed the literature and conducted a meta-analysis to quantify the incidence of TRAEs associated with the currently approved BRAF and MEK inhibitors in individuals with CM. The most frequently observed TRAEs included joint pain (arthralgia), skin rash, fever (pyrexia), fatigue, and the development of certain skin lesions, such as squamous cell carcinoma and keratoacanthoma.

Objectives: We conducted a systematic review of clinical trials and case reports analyzing the safety of the currently approved BRAF and MEK inhibitors in adults with cutaneous melanoma (CM), and a meta-analysis to estimate the pooled prevalence of treatment-related adverse events (TRAEs). Methods: We systematically searched six databases for studies published since 2009. The TRAE absolute frequencies reported in primary studies were aggregated using the Metaprop command in Stata 17, which calculates 95% confidence intervals (CIs) incorporating the Freeman–Tukey double arcsine transformation of proportions to stabilize variances within random-effect models. Methodological quality was assessed using the RoB 2 tool for randomized controlled trials (RCTs) and the ROBINS-I tool for non-randomized studies. Results: Twelve RCTs, thirteen prospective cohort studies (PCSs), and ten case reports were included. Meta-analysis was feasible for two regimens: vemurafenib 960 mg monotherapy and dabrafenib 150 mg twice daily plus trametinib 1–2 mg daily. The most common TRAEs during vemurafenib treatment were musculoskeletal and connective-tissue disorders (24%, 95% CI: 6–41%, p = 0.01), with arthralgia as the most prevalent (44%, 95% CI: 29–59%, p < 0.001), followed by rash (39%, 95% CI: 22–56%, p < 0.001). The most common TRAEs during dabrafenib plus trametinib were constitutional toxicities (classified in CTCAE as ‘General disorders and administration site conditions’; 25%, 95% CI: 14–37%, p < 0.001), with fatigue as the most prevalent (47%, 95% CI: 38–56%, p < 0.001), followed by pyrexia (40%, 95% CI: 26–54%, p < 0.001). Squamous cell carcinoma and keratoacanthoma were among the most frequent grade ≥ 3 cutaneous adverse events observed with vemurafenib therapy. Conclusions: Although additional large-scale studies are needed to corroborate these findings, each treatment has a distinct toxicity profile that should be considered when developing personalized risk-stratified treatment plans and in guiding healthcare resource allocation in melanoma care.