The 2012 edition of The Skin Cancer Foundation Journal features medically reviewed, reader-friendly articles such as tanning, the increasing incidence of skin cancer diagnoses among young women, & the prevalence of melanoma among white males over 50.
body directed against an immune cell called CTLA-4.2
Ipilimumab is an engineered anti- Antibodies are protein
molecules normally produced by the immune system against bacteria and other infections. Until recently, it was impossible to artificially create anti- bodies that would bind to a particular molecule. However, researchers suc- cessfully bound ipilimumab to CTLA-4, a naturally occurring immune cell
"brake," successfully blocking CTLA-4 from being engaged and thereby ac- tivating pre-existing immune cells capable of recognizing and attacking cancer cells [Figure 1, p.56]. These therapeutic antibodies can
safely be administered by intrave- nous infusion outside the hospital setting in a relatively short time. In numerous clinical trials spanning a decade, ipilimumab was given by short intravenous infusion (approximately one hour) once every three weeks for a total of four doses. The actual dose of the drug is calculated based on the patient's weight. The drug's efficacy has been
consistently documented in large clinical
trials.2,3 Approximately
10 percent of individuals treated demonstrate significant tumor shrinkage after three months, while an additional small proportion have some evidence of tumor growth at the three-month assessment, followed by significant tumor regression thereafter. Approximately 15 percent of patients have no significant change in tumor size at the three-month point, with a subset maintaining that stability over the long term. While it can be difficult to discern exactly which patients are deriving benefit early in the course of therapy, with long-term follow-up as much as 25 to 30 percent of patients can derive significant benefits, includ- ing months or years of progression-free and overall survival. Toxicities of ipilimumab are unique
compared with those of other cancer treatments. During and shortly after the infusions, side effects are uncom- mon. However, over the three-month treatment period, the risk increases that the immune system will attack certain normal tissues. Over all,
As much as 25 to 30 percent of patients taking ipilimumab can derive significant benefits, including months or years of progression-free and overall survival.
approximately 60 percent of individu- als treated experience some version of autoimmune toxicity. The most com- monly affected sites are the skin, large intestine, endocrine glands, and liver. One out of every four of these events (or 15 percent of all patients treated) is considered severe and is generally managed by withholding ipilimumab and administering corticosteroids. If not managed properly, these effects can sometimes be life-threatening; patients must maintain open com- munication with their physicians so that autoimmune toxicities can be detected as early as possible.
unregulated growth and escape from immune surveillance (detection and counterattack by the immune system). Vemurafenib is the first effective BRAF inhibitor [Figure 2, p.56]. It is taken in pill form, with a standard starting dose of four pills twice a day. The
benefits associated with
vemurafenib have been documented in several clinical trials and can best be summarized as a high likelihood of tumor regression early in the course of therapy, with the response lasting varying lengths of time.4,5 Approximately 90 percent of individu- als treated show some tumor shrinkage, ranging from slight
improvement
to complete resolution of all visible tumors. On average, vemurafenib will shrink and control tumors for six to seven months; however, 15 to 20 percent of patients maintain responses that last 18 months or longer. Generally, vemurafenib is given
until there is evidence of tumor growth. Therefore, length of treat- ment is determined by the ability of vemurafenib to maintain the tumor in a non-growing state. In most patients, tumors eventually grow in the face of continued vemurafenib treatment when they develop resistance, just as infections become resistant to antibiotics. Continuing vemurafenib even after evidence of tumor growth may benefit some patients, but generally once tumor growth starts again, doctors consider switching to another therapy. As the first BRAF inhibitor, vemu-
VEMURAFENIB (ZELBORAF™): SHUTTING DOWN A DEFECTIVE GENE Vemurafenib represents the first molecularly targeted
therapy for
melanoma. It began being designed about a decade ago, soon after the discovery of a mutation, or error, in a key enzyme (a protein that can prompt chemical changes) called BRAF. BRAF is present inside all cells, and mutated in approximately 50 percent of all melanoma cases. When mutated, it contributes to many of the malignant properties of melanoma, including
rafenib has unique side effects. The most common toxicities affect the skin, joints, and the patient's overall energy. Among the skin effects, rash (50 percent), increased sun sensitivity (50 percent), and the appearance of nonmelanoma skin lesions including squamous cell carcinomas (25 percent) are most frequently seen. Additionally, joint discomfort and/or swelling (60 percent) and fatigue (40 percent) are common. Approximately 40 percent of patients will require at least a tempo- rary dose reduction to manage severe or intolerable moderate toxicities. However, nearly all patients eventually achieve a tolerable dose level.
55