The Skin Cancer Foundation Journal

MAY 2014

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.

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S K I N C A N C E R F O U N D A T I O N J O U R N A L 70 it may be particularly attractive to com- bine them with ipilimumab or other checkpoint-blockade immunotherapies. It is hypothesized that by killing mela- noma cells, BRAF and MEK inhibitors release antigens that in- crease activation of im- mune cells to attack any remaining melanoma cells. When BRAF is inhibited, it may also make mela- noma cells more visible to the immune system, thereby facilitating attack by immune cells. Finally, blocking BRAF appears to draw more specif c anti- melanoma immune cells into the tumor, which can then kill the cancer cells. THE CASE AGAINST COM- BINING TARGETED THERAPY AND IMMUNE- CHECKPOINT INHIBITION W hile BRAF and MEK inhibitors cause melanoma tumors to shrink relatively quickly, there are potential drawbacks to combining them with immune treatment. These drugs induce rapid shrinkage of cancer, but resistance to treatment sometimes develops within months, which may make it more dif- f cult for the immune system to attack the cancer. Additionally, while BRAF inhibitors may strengthen the immune response, in the laboratory it appears that MEK inhibitors (such as trametinib) may dampen the immune response. Therefore, while combining BRAF and MEK inhibitors allows for maxi- mum cancer-killing ef ects initially, the combination could also suppress the immune response, limiting the ability to control the melanoma long -term. Finally, it must be noted that the initial attempt to combine a BRAF inhibitor (vemurafenib) with immune- checkpoint blockade therapy (ipi- limumab) was deemed unsafe, so this combination should not currently be used in standard clinical practice. 3 Sev- eral clinical trials are now evaluating combinations of these drugs used in dif erent ways; for example, using them in sequence rather than concurrently. NEXT STEPS: IMPROVING LONG-TERM SURVIVAL T he advances in understand- ing melanoma and the im- mune system have set the stage for continual improvements in the treatment of advanced dis- ease. Some patients have already derived signif cant long-term benef ts. One recent report sug- gested that 20 percent of pa- tients who received ipilimumab are alive after 10 years. 4 (In con- trast, only about 4-6 percent of patients were ever found to achieve long-term survival with Interleukin-2, and no overall surviv- al advantage was ever demonstrated with chemotherapy.) Similarly, ear- ly clinical trials have described an improved likelihood of significant tumor shrinkage using combinations of these new drugs, specifically dab- rafenib combined with trametinib or ipilimumab with nivolumab. 5,6 The next goal will be to determine which combinations are most suitable to shrink melanoma most ef ectively, maintain the best possible quality of life for patients, and extend patients' lives as long as possible. This will be accomplished by working to identify whether administering several drugs simultaneously or in sequence is more ef ective. Given the dif erent properties of targeted therapy and immuno- therapy, it seems likely that the two approaches are complementary. Many other novel approaches are also on the horizon, currently either in active laboratory study or clinical trials; the hope is to turn metastatic melanoma from a deadly disease into a manage- able chronic condition. Health The hope is to turn metastatic melanoma from a deadly disease into a manageable chronic condition. References available on p.97

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