Managing Advanced Melanoma: Targeting the PD-1 Pathway with Pembrolizumab

Melanoma is a malignancy that arises from melanocytes found mostly in the skin and represents the most dangerous form of skin cancer owing to its metastatic potential and historically poor responsiveness to therapeutic intervention. Recently, key pathways and mechanisms involved in subverting anti-tumor immune based activity have been discovered. Integral to these advances are “immune checkpoints,” discovered to control immune reactivity to cancer cells and the tumor microenvironment. The mechanisms to which cancer hijacks the immune regulatory response signals serve as vital targets for therapeutic interventions. Pembrolizumab – Keytruda® was granted accelerated approval on October 28, 2014 under the FDA’s priority review program and represents the first approved humanized, monoclonal antibody directed against PD-1. Targeting PD-1, pembrolizumab re-activates suppressed T-cell mediated immune reactivity benefiting patients with unresectable or metastatic melanoma and disease progression following ipilimumab or BRAF inhibitor therapy. This paper will review the PD-1 signaling pathway and the role of pembrolizumab in advanced melanoma management.