Challenging the standard of care in advanced melanoma: focus on pembrolizumab

Abstract

The last several years have seen a dramatic rise in the number of effective therapies that have been shown to improve survival outcomes for patients with advanced melanoma. Among these treatments are the immune checkpoint inhibitors, a new class of immunotherapy, that have demonstrated the ability to improve both response rates and survival outcomes. Pembrolizumab, an immune checkpoint inhibitor that blocks the negative regulatory PD-1 receptor on T-cell lymphocytes, has shown improved efficacy compared to standard therapies with an acceptable tolerability profile. Additionally, this agent is being evaluated in adjuvant and combination trial strategies that have great potential to further advance outcomes. This review focuses on the advances that pembrolizumab has made in melanoma and what studies are upcoming that could change the future of melanoma treatment yet again.

Keywords: MK-3475; PD-1 inhibitor; adjuvant therapy; combination therapies; immune checkpoint inhibitor; immunotherapy; keytruda.

Figure 1

Diagram of T-lymphocyte activation and regulation by immune checkpoints. Notes: 1. The T lymphocyte is activated by the binding of the TCR to antigen presented by the MCH complex on APCs. This activation requires a costimulatory signal as depicted by the CD28:B7 binding. 2. The T cell can be inhibited by the expression of negative stimulatory receptors such as CTLA-4 and PD-1, also known as immune checkpoints. The binding of these immune checkpoints to their respective ligands results in deactivation of the T lymphocyte. 3. The monoclonal antibodies, ipilimumab and pembrolizumab, can maintain the activated lymphocyte by binding and impairing function of the immune checkpoints, CTLA-4 and PD-1, respectively. The active T lymphocyte is then able to potentiate the immune response and result in cancer cell killing. Abbreviations: APCs, antigen-presenting cells; CTLA-4, cytotoxic lymphocyte antigen-4; MHC, major histocompatibility complex; PD-1, programmed death-1; PD-L1, programmed death-ligand 1 receptor; TCR, T-cell receptor.