Management of skin adverse events associated with immune checkpoint inhibitors in patients with melanoma: A nursing perspective

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The immune system plays a pivotal role in preventing, controlling, and eliminating cancer cells. However, multiple mechanisms of immune suppression and evasion occur within the tumor microenvironment that allow cancers to grow and spread (Postow, Callahan, & Wolchok, 2015a; Spranger, 2016). Cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4) is an inhibitory receptor expressed on the surface of effector T cells of the adaptive immune system, which play a critical role in the antitumor immune response (Melero, Hervas‐Stubbs, Glennie, Pardoll, & Chen, 2007). CTLA‐4 has an established role in regulating the immune system by downregulating effector T‐cell function. Thus, blocking the activity of CTLA‐4 was proposed as a means to promote the endogenous host immune response to tumor cells (Hoos et al., 2010). Programed death‐1 (PD‐1) is another inhibitory receptor expressed on the surface of T cells (Melero et al., 2007). While CTLA‐4 and PD‐1 have distinct roles in regulating the immune system, both limit T‐cell activity and thus the antitumor immune response (Topalian, Drake, & Pardoll, 2012).
The advent of agents that target negative immune regulators (immune checkpoint inhibitors) has transformed the treatment of advanced melanoma (Hodi et al., 2010; Larkin et al., 2015; Postow et al., 2015b; Robert et al., 2015a; Robert et al., 2015b; Weber et al., 2015b). Ipilimumab, which blocks CTLA‐4, was the first systemic therapy to improve overall survival in a randomized, controlled, phase 3 trial in these patients (Hodi et al., 2010). Ipilimumab is approved for the treatment of unresectable or metastatic melanoma in several countries worldwide (Bristol‐Myers Squibb, 2015c). Nivolumab and pembrolizumab, two agents that target PD‐1, have shown greater efficacy and less toxicity than ipilimumab (Larkin et al., 2015; Robert et al., 2015a), and recently have been incorporated into the standard of care for advanced melanoma (Garbe et al., 2016; National Comprehensive Cancer Network (NCCN), 2016). A phase 3 study beginning in 2012 first demonstrated that nivolumab is effective in patients without a BRAF mutation (Robert et al., 2015a). A mutation in the BRAF gene is one of the most frequent driver oncogenic mutations in melanoma (Tímár, Vizkeleti, Doma, Barbai, & Rásó, 2016). Overactivity of BRAF kinase may contribute to the growth of cancers through the uncontrollable proliferation of abnormal cells. At that time of this phase 3 study, standard of care was a BRAF and/or MEK inhibitor for the approximately 40% of patients with advanced melanoma that also had a mutation in BRAF. At the time, dacarbazine was standard treatment for the remaining patients in most regions outside of the United States, leaving these patients with an unmet need for treatment. Later, phase 2 and phase 3 trials demonstrated that combination therapy with nivolumab and ipilimumab improves tumor response and progression‐free survival compared with ipilimumab alone in treatment‐naive patients with advanced melanoma (Larkin et al., 2015; Postow et al., 2015a). The results of these trials supported the United States and EU approvals of the combination as a first‐line treatment for patients with unresectable or metastatic melanoma, regardless of BRAF mutation status (Bristol‐Myers Squibb, 2015a).
As a novel treatment modality that targets immune cell populations, immune checkpoint inhibitors are associated with a unique immune‐related side effect profile that requires prompt recognition and management (Berman et al., 2015). Skin toxicities are the most common, and often earliest to occur, among drug‐related adverse events (AEs) of any grade. A recent systematic literature review investigated the burden of dermatological AEs with the use of PD‐1 receptor inhibitors in various cancers and found the most commonly reported AEs were rash, pruritus, and vitiligo, reminiscent of those seen with ipilimumab (Belum et al., 2016).

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