A drug is a medicine or substance that exerts a physiologic effect on an organism. In dermatology, medications and substances are utilized on a daily basis from topical treatments to anesthetics in micrographic surgery. Dermatology is a field of diverse diseases with a wide range of therapeutic options both available and in development. In the recent decade, melanoma immunotherapy has been transformed from disrupting extracellular signal cascades to include newer agents, which directly target T-cell receptors. This article will focus on the mechanism of action, usage, and alternatives of the medication pembrolizumab, a humanized monoclonal antibody that directly blocks the effects of programmed cell death-1 (PD-1; Improta et al., 2015).
USES AND MECHANISM OF ACTION
As the most common malignancy of humans, nonmelanoma skin cancer is diagnosed in over a million patients each year (Geller & Annas, 2003). Although the incidence of basal cell carcinomas and squamous cell carcinomas greatly outnumbers that of melanomas, cutaneous malignant melanomas cause the vast majority of all skin-cancer-related deaths (Saito Rde, Tortelli, Jacomassi, Otake, & Chammas, 2015). In fact, melanoma was the cause of nearly 12,000 deaths in the United States in 2011 (Siegel, Ward, Brawley, & Jemal, 2011). Although, historically, melanoma has been difficult to treat at advanced stages, new emerging therapies are providing promising therapeutic options.
Cutaneous melanoma arises from the unregulated proliferation of epidermal melanocytes. Its high metastatic potential and chemoresistance make it a challenging disease to treat (Saito Rde et al., 2015). Patients with advanced-stage melanoma often have high morbidity rates because of frequent metastases. Pembrolizumab, a humanized monoclonal antibody that inhibits PD-1, is the most recent drug indicated by the Food and Drug Administration for advanced melanoma treatment which falls under the category of cancer immunotherapy (Callahan & Wolchok, 2013). Recently, it has become increasingly recognized that recruitment of the immune system may be a powerful strategy in treating oncologic processes. Essential to this theory is the role of cytotoxic T-lymphocytes, which distinguish "self" from "nonself" antigens to avoid immune overactivation (Ribas, 2012). Cancer cells proliferate by using these immune checkpoints to their advantage to avoid detection by the immune system.
One example of an immune checkpoint is the PD-1 receptor, an inhibitory T-lymphocyte receptor that prevents the activation and proliferation of T-lymphocytes. Whereas PD-1 is found on T-cells, its ligands, PD-L1 and PD-L2, are found on tumor cells. The binding of PD-1 with PD-L1 and PD-L2 downregulates T-cell activation and proliferation and decreases the expression of antiapoptotic molecules, cytokine, and the mammalian target of rapamycin pathway (Keir, Butte, Freeman, & Sharpe, 2008). Cancer cells take advantage of this PD-1/PD-L1 interaction as a mechanism for the tumor cells to avoid immune detection. To counter this effect, pembrolizumab binds PD-1, effectively blocking the binding between PD-1 and PD-L1 and PD-L2 and preventing the inhibition of T-cell immune surveillance of tumors (Improta et al., 2015; Figure 1). This blockade also increases the expression of interferon gamma (IFN-[gamma]), interleukin-2 (IL-2), and interleukin-7 (IL-7) and an enhanced memory response to the tumor antigen, increasing responsiveness against the tumor cells (Faghfuri, Faramarzi, Nikfar, & Abdollahi, 2015). Pembrolizumab has been shown in Phase III trials to significantly increase 6- and 12-month progression-free survival rates in patients with unresectable stage III or IV melanoma to 47.3% and 74.1%, respectively, when administered every 2 weeks (Robert et al., 2015). Currently, it is indicated for most patients with advanced melanoma who are either treatment naive or have failed ipilimumab.
ADVERSE EFFECTS
The most common treatment-related adverse events seen in patients who received pembrolizumab in a Phase III randomized clinical trial were fatigue, diarrhea, rash, and pruritus (Robert et al., 2015). Because of its action on the immune system, the more rare side effects of pembrolizumab include autoimmune or immune-related diseases, including both hypothyroidism and hyperthyroidism. Colitis, nephritis, liver failure, pneumonitis, and hepatitis were rarely reported (Faghfuri et al., 2015). Adverse effects also include infusion reactions, which include chills, shortness of breath, fever, and dizziness.
ALTERNATIVE OPTIONS
Before the advent of cancer immunotherapy, patients with advanced melanoma experienced poor treatment options with minimal effectiveness. As a resource to the reader and to maintain the column scope, a brief review of the frontrunner therapeutic agents is provided (Table 1). Initially, patients often failed treatment with the alkylating agent dacarbazine and cytokines including interferon and interleukin. The first signs of clinical improvement in patients with advanced melanoma were seen in 2011 with vemurafenib, a B-rapidly accelerating fibrosarcoma (BRAF) V600 kinase inhibitor that was developed after the identification of BRAFV600 somatic mutations in melanoma (McArthur et al., 2014). Dabrafenib, another BRAF inhibitor (Hauschild et al., 2012), and the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib (Flaherty et al., 2012) were approved 2 years later as single-agent treatments for BRAF-mutated unresectable or metastatic melanoma. Combination therapy with BRAF and MEK inhibitors has been studied and has shown increased apoptosis of tumor cells and delayed onset of resistance to therapy (Paraiso et al., 2010).
Therapies for melanoma continued to advance to include ipilimumab, a fully humanized monoclonal antibody blocking the cytotoxic T-lymphocyte antigen 4. Similar to the PD-1 receptor, the cytotoxic T-lymphocyte antigen 4 engages the antigen-presenting cell and inhibits T-cell co-stimulation (Leach, Krummel, & Allison, 1996). Thus, ipilimumab acts in a similar manner to pembrolizumab, blocking the inhibition of cellular immune activation and encouraging a T-cell response against tumor cells. However, in a recent Phase III trial comparing ipilimumab against pembrolizumab in patients with advanced melanoma, ipilimumab was found to have inferior efficacy and increased toxicity (response rate of 11.9% vs. 33.7% with pembrolizumab every 2 weeks; Robert et al., 2015).
Nivolumab is another monoclonal antibody to PD-1 that received official indication for advanced melanoma shortly before pembrolizumab with similar high efficacy. The combination of nivolumab with ipilimumab has been studied and showed increased efficacy as well as a tolerable side effect profile (Wolchok et al., 2013). In addition, several patients treated with both nivolumab and ipilimumab showed an increased depth of response with a tumor regression of 80% or more (Wolchok et al., 2013). This strong response was more common in combination therapy than in patients receiving either therapy alone.
CONCLUSION
With the ever changing landscape and advancing research developments in dermatology, therapeutic options for patients continue to improve in effectiveness and safety. Once a highly resistant disease with almost no clinically effective treatment, advanced melanoma now has options in immunotherapy that have undergone extensive clinical trials. Pembrolizumab is the newest immunotherapy option that has shown promising results. Future studies combining pembrolizumab with ipilimumab for the treatment of advanced melanoma may reveal an increased potential for the effectiveness and complete resolution of the disease.
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