The Skin Cancer Foundation Journal

MAY 2015

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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Page 78 of 115

MELANOMA: A FORCE TO RECKON WITH Melanoma is genuinely a frightening disease. When caught early – at the noninvasive, in situ stage or at Stage I, before it has spread beyond the original tumor – it is curable about 98% of the time. 1 However, a single millimeter in growth can greatly increase the chances that the disease will spread, and once it spreads, the odds of long-term survival plummet. Average 5-year survival falls to 63% when the disease reaches the nearby lymph nodes (Stage III), and 16% when it metastasizes to distant organs (Stage IV). 1 For decades, researchers worldwide strove with minimal success to improve the survival odds for these advanced melanoma patients. The FDA approved one chemotherapy, dacarbazine (DTIC), before 1984, and two different immunotherapies (interferon-Alfa-2b for Stage III and interleukin-2 for Stage IV) in 1995 and 1998, respectively. [See Figure 1.] After that, not a single new drug was approved for more than a decade. Except in fairly rare instances, none of these existing drugs apprecia- bly increased lifespan; most patients were dead within months. Then the revolution began. Based on studies showing significantly improved survival, in 2011 two new drugs were approved for Stage IV patients: first the checkpoint blockade immunotherapy ipilimumab (Yervoy ® ), then the "targeted" therapy vemurafenib (Zelboraf ® ), which inhibits the mutated, cancer-producing BRAF gene. (About half of melanoma patients have that faulty gene.) Since those two approvals, a wave of other targeted therapies and checkpoint blockade immunotherapies have been approved in rapid succession, changing the landscape of treatment for advanced melanoma forever. THE GOLD STANDARD To date, the checkpoint blockade immunotherapies have led the charge. Following on the heels of ipilimumab, two new therapies, pembrolizumab (Keytruda ® ) and nivolumab (Opdivo ® ), received FDA approval just last year. Together, these drugs are offering an increas- ing number of Stage IV patients substantially longer lifespans. Some metastatic melanoma patients treated with these techniques have now survived for several years, and researchers believe that in the near future, this will be the rule rather than the exception. Ipilimumab, pembrolizumab, and nivolumab are called "checkpoint blockade" therapies because they block certain checkpoints in the immune system that keep our healing T cells from fighting melanoma. [See Figure 2.] Ipilimumab, the first successful example of these drugs, is a monoclonal antibody (a purified class of antibodies cloned and mass-produced in the lab from one specific type of cell or cell line) that blocks CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), a kind of natural "brake" in the immune system that can inhibit activation of T cells to keep them from overproducing. Ipilimumab is thus considered an "anti-CTLA-4 therapy": It inhibits CTLA-4 so that more T cells can be produced to fight the melanoma. Ipilimumab has yielded dramatic, sustained responses akin to cures in certain patients. In a study of 1,861 patients treated with ipilimumab, about 22% lived three years or longer, and 84% of those survivors were alive after 5 years and 10 years. One recent report, in fact, suggested that 20% of patients who received ipilimumab are alive after 10 years. 2 In contrast, only about 4-6% of patients were ever found to achieve long-term survival with interleukin-2, and no overall survival advantage was ever demonstrated with chemotherapy. FIGURE I. 77 DRUGS APPROVED FOR ADVANCED MELANOMA Before 1984 dacarbazine chemotherapy 1995 interferon-Alfa-2b immunotherapy 1998 interleukin-2 (Proleukin®) immunotherapy 2011 ipilimumab (Yervoy®) anti-CTLA-4 checkpoint blockade immunotherapy vemurafenib (Zelboraf®) targeted BRAF inhibitor pegylated interferon-Alfa-2b immunotherapy 2013 dabrafenib (Taflinar®) targeted BRAF inhibitor trametinib (Mekinist®) targeted MEK inhibitor 2014 pembrolizumab (Keytruda®) anti-PD-1 checkpoint blockade immunotherapy nivolumab (Opdivo®) anti-PD-1 checkpoint blockade immunotherapy combination dabrafenib + trametinib targeted BRAF inhibitor and MEK inhibitor 2015* MPDL3280A anti-PD-L1 checkpoint blockade immunotherapy combination cobimetinib + vemurafenib targeted BRAF inhibitor and MEK inhibitor *expected approvals 1999 - 2010 12 LONG YEARS WITH NO NEW APPROVED THERAPIES

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