Contents of The Skin Cancer Foundation Journal - MAY 2012

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.

Page 57 of 103

HEALTH
A T cell CTLA-4
B NRAS T cell CRAF CTLA-4 Ipilimumab APC APC ERK
Figure 1 (A) CTLA-4 binds to a stimulatory signal from antigen-presenting cells (antigens stimulate the production of antibodies) and inactivates T cells. (B) Ipilimumab blocks CTLA-4 so that it does not bind the stimulatory signal and T cells are activated.
Figure 1 (A) CTLA-4 binds to a stimulatory signal from antigen (antigens stimulate the production of antibodies) presenting cells & inactivates T cells. (B) Ipilimumab blocks CTLA-4 so that it does not bind stimulatory signal & T cells are activated.
Unregulated growth, resistance to cell death, escape from immune surveillance
Figure 2 The MAP kinase pathway, which includes BRAF. The pathway is activated by mutated BRAF, leading to uncontrolled growth, enhanced survival of the cancerous cells, and escape from immune system detection. Vemurafenib inhibits mutated BRAF, curtailing uncontrolled growth and causing tumors to regress.
CHOOSING AMONG AVAILABLE THERAPIES With two new therapies having just emerged as standard treatments, many metastatic melanoma patients and their doctors must decide which represents the better option. And for patients with newly diagnosed metastatic melanoma, other strate- gies exist as well, including surgical removal of new lesions on solitary sites of
recurrence, or high-dose
interleukin-2 for patients in excellent overall health with relatively small- volume, asymptomatic disease. Among this group, IL-2 offers a 5 to 7 percent chance of durable remission follow- ing two 5-day intravenous treatment courses in the hospital. Although the treatment can be very toxic, it does not appear to diminish the possibility of responding well to subsequent therapy and therefore remains an option as first-line treatment.5 Ipilimumab can be considered for
nearly all patients with metastatic melanoma,
though clinical trial
results indicate that patients with 56
very advanced, symptomatic meta- static disease are less likely to obtain durable response. Vemurafenib is
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.
initially low burden of disease (a single, concentrated area of disease limited to one body site). Thus, among patients whose tumors have a BRAF mutation, multiple options exist, and the choice between initial immunotherapy (such as interleukin-2 or ipilimumab) or vemurafenib is often based on how advanced the disease is. In addition, many combination therapies, includ- ing trials combining vemurafenib and ipilimumab or ipilimumab and radiation, are being launched as well. Further clinical trials are needed to address the optimal sequence of therapy and to help identify which patients are most likely to obtain long-term clinical benefits.
only relevant for those patients whose tumors harbor a BRAF mutation; therefore, testing tumor tissue for the presence of this mutation is essential before considering the treatment. Vemurafenib can benefit even those with very advanced, symptomatic metastatic disease, but it has been associated with durable, long-term responses only in those with an
KEITH T. FLAHERTY, MD is Director of Developmental Therapeutics, Massachusetts General Hospital Cancer Center, Boston, MA. He is internationally known for his expertise in clinical and translational research directed against signal transduction pathways in mela- noma, and he served as principal investigator for the first-in-human clinical trials of vemu- rafenib and other BRAF inhibitors.
References available on p.97. SK IN CANCER FOUNDAT ION JOURNA L
MEK BRAF vemurafenib