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.
Issue link: https://skincancer.epubxp.com/i/319518
melanomas. This mutation has been shown to switch on melanomas. The FDA also approved one im- munotherapy, ipilimumab (Yervoy ® ), and at least two more immunothera- pies are likely to be approved in the relatively near future. ( See Figure 1.) Researchers are trying to determine exactly when and how to use each therapy individually or in combina- tion with other therapies to achieve optimum results. IMMUNE-CHECKPOINT BLOCKADE THERAPY T his type of immunotherapy allows the immune system to release more disease-f ghting T-cells to f ght the melanoma. Ipilimumab, for example, is an antibody that blocks a molecule called cytotoxic T-lymphocyte-associ- ated antigen 4 (CTLA-4), which holds back the T-cells. FDA-approved in 2011, ipilimumab was the f rst drug ever to demonstrate improved survival of ad- vanced melanoma patients in a large human trial. 1 Some patients have sur- vived 5-10 years and counting. Two additional immune-checkpoint blockading drugs, nivolumab and MK- 3475 (pembrolizumab), are likely to be FDA-approved in 2014 or 2015. Both inhibit another molecule (programmed death-1, or PD-1) that suppresses T- cells. PD-1 can directly interact with tumor cells by binding to a molecule called programmed death ligand-1 (PD-L1), and cancer cells may use PD- L1 to hide from attack by T-cells. A third drug, MPDL3280A, is designed to inhibit PD-L1, and appears to hold promise in early clinical studies. TARGETED THERAPIES V emurafenib (Zelboraf ® ), a drug that inhibits the mutated form of the BRAF gene, has also been shown to improve patient survival. Like ipilim- umab, vemurafenib was FDA-approved in 2011. When mutated, BRAF can promote malignancy in melanocytes (pigment cells), where melanoma arises. In 2013, two other treatments directed toward BRAF and a related molecule called MEK were also approved: the BRAF inhibitor dabrafenib (Taf inar ® ) and the MEK inhibitor trametinib (Mekinist ® ). 2 Recently, the FDA also approved the use of these two drugs in combination. The hope is that these dif erent drugs and drug combinations will increase shrinkage of tumors and extend the length of time before the melanoma starts growing again. BRAF and MEK Inhibitors vs. Immune-Checkpoint Blockade A lthough the likelihood of a mela- noma shrinking when treated with BRAF and MEK inhibitors is high, the response to treatment often lasts for only a certain period. Ipilimumab is less likely to shrink melanoma metasta- ses, and a few weeks to several months are usually required before improve- ments are seen. However, in patients who respond, ipilimumab of ers greater potential for long-term control of the melanoma and more prolonged sur- vival. The new immune-checkpoint blockade therapies – nivolumab and MK-3475 – appear to of er long-lasting ef ects comparable to ipilimumab, and may bring about a more rapid response, shrinking the melanoma. THE CASE FOR COMBINING TARGETED THERAPY AND IMMUNE - CHECKPOINT INHIBITION B oth targeted drugs and immuno- therapy are now important treatment options. However, the best ways to use them are not yet clear. For several years, we have known that the benef ts of ipilimumab could be improved by adding other treatments. Because of the substantial melanoma-killing ac- tivity of BRAF and MEK inhibitors, of patients who received ipilimumab are alive after 10 years. 20% Timeline of FDA approval for Melanoma drugs Immunotherapy Interferon-alpha 1995 Interleukin-2 1998 Ipilimumab 2011 Vemurafenib 2011 Dabrafenib,Trametinib 2013 Dabrafenib + Trametinib (combo ) 2014 Chemotherapy Dacarbazine 1975 2014 /2015 (projected) Nivolumab, MK3475 Targeted Therapy Figure 1 69