Breaking barriers: Pembrolizumab's role in overcoming targeted therapy resistance in BRAF-mutant melanoma

Abstract

Melanoma, a malignancy of melanocytes, has increased globally, posing significant treatment challenges. BRAF mutations, particularly V600E and V600K variants, occur in approximately 40–60 ​% of cutaneous melanomas and activate the MAPK/ERK signaling pathway. Although BRAF and MEK inhibitors have improved response rates and survival, acquired resistance—due to genetic alterations, activation of alternative pathways, and phenotypic changes—remains a major hurdle.

Pembrolizumab, an anti-PD-1 immune checkpoint inhibitor, has emerged as a promising option to overcome resistance to targeted therapies. This review explores the rationale for using pembrolizumab post-resistance, emphasizing its ability to enhance immune recognition through the immunogenic effects of prior targeted therapies and its synergistic potential when combined with BRAF and MEK inhibitors. Clinical evidence from KEYNOTE trials and real-world studies demonstrates pembrolizumab's efficacy as monotherapy and in combination regimens, leading to improved progression-free and overall survival in patients with advanced melanoma. Mechanistic insights from preclinical studies suggest that targeted therapies modulate the tumor microenvironment and enhance antigen presentation, augmenting the effectiveness of pembrolizumab. Novel biomarkers such as tumor mutational burden (TMB), PD-L1 expression, and circulating tumor DNA (ctDNA) are examined for their potential to predict treatment response and guide personalized therapy. Challenges related to increased toxicity in combination therapies, economic impact, and patient heterogeneity are discussed, highlighting the need for careful patient selection and management strategies. Future directions include optimizing treatment sequencing, exploring novel therapeutic combinations, and advancing personalized medicine through integrative genomic and immunologic data. This review underscores the pivotal role of pembrolizumab in managing BRAF-mutant melanoma and emphasizes the importance of integrated therapeutic strategies to improve patient outcomes.