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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Pembrolizumab and nivolumab inhibit a dif ferent checkpoint called programmed death-1, or PD-1, which, like CTLA-4, prevents T cells from attacking melanoma. PD-1 can directly interact with tumor cells by binding to a molecule called programmed death ligand-1 (PD-L1), and these cancer cells may use PD-L1 to hide from attack by T cells. Nivolumab and pembrolizumab prevent the binding between PD-1 and PD-L1, thereby releasing the T cells to fight the cancer. 3-5 [See Figure 2.] Currently, both pembrolizumab and nivolumab are approved for use as a second-line therapy in Stage IV patients: *whose melanoma has metastasized or cannot be removed by sur- gery; *and who have had disease progression after treatment with ipilimumab; *and who, if they have an abnormal BRAF gene, have had disease progression following treatment with a targeted BRAF inhibitor (vemurafenib or dabrafenib, a second BRAF inhibitor ap- proved in 2013). [See "Perfecting the Targeted Therapies".] NOT TO BE CONTAINED Soon, nivolumab and pembrolizumab may become front-line, first-resort therapies, be- cause their results have been simply too good to keep them in reserve. The National Com- prehensive Cancer Network recently noted that both anti-PD-1 agents have "higher response rates and less toxicity compared to ipilim- umab. . . and should be included as options for first-line treatment." 6 While the two anti-PD-1 drugs have not been followed for as long as ipilimumab, each has produced impressive, durable remissions. For example, follow-up data from a Phase I nivolumab study suggested that an unprec- edented 80% of patients were alive at two years – patients who would have survived only 9-12 months just a few years ago. 6 In a new development that could be a huge boon to patients, the checkpoint blockade therapies could soon start to be used ear- lier in the game, before Stage IV, when they may save even more lives. Recently the FDA accepted an application for ipilimumab to be used for Stage III patients at high risk of recurrence, after their tumor and local lymph nodes are removed. Here, it would be used as an "adjuvant" therapy – a supplementary treatment to prevent recurrences and metas- tasis beyond the lymph nodes. Acceptance of the application was based on results from a phase III trial showing a 25% improvement in recurrence-free survival in Stage III patients treated with ipilimumab versus placebo. "We saw substantially fewer recurrences among patients at high risk of relapse," said Alexan- der Eggermont, MD, PhD, Director General of the Gustave Roussy Cancer Campus Grand Paris in France, and one of the researchers on the ipilimumab study. "This trial . . . is the first to show we may be able to give these new drugs earlier in the course of disease, when they can do more good and potentially cure more patients." 7 The FDA is scheduled to make a decision on ipilimumab as a Stage III adjuvant therapy by October 28 of this year. Presumably, if it is approved, pembrolizumab and nivolumab might follow suit in the not-distant future. Other PD-1 inhibitors for advanced mela- noma are in clinical trials, and MPDL3280A, another drug in clinical trials, blocks PD-L1, the ligand that binds PD-1 to T cells and deactivates them. Several of these drugs, alone and in combination with others, could proceed to FDA approval in the next couple of years, as patients' lives are increasingly lengthened in the bargain. Remember, just a few years ago, ipilimumab, pembrolizumab and nivolumab were available only in clinical trial as well, and now they are all approved, widely available, and significantly extending lives. More effective immunotherapy possi- bilities exist than ever before, and more are just around the bend. FIGURE 2: How Checkpoint Blockade Therapies Work Antigen- Presenting Cell First Signal Second Signal T Cell TCR CD28 CTLA-4 INHIBITION ACTIVATION MHC B7 B7 Anti-CTLA-4 Antibodies Ipilimumab Tumor Cell MHC PD-L1 T Cell TCR PD-1 INHIBITION Anti-PD-1 Antibodies Nivolumab and Pembrolizumab Anti-PD-L1 Antibodies MPDL3280A CTLA-4 and PD-1 A. In lymphatic tissue, antigen-presenting cells (APC) activate naï ve T cells via the T cell receptor (TCR) and stimulatory receptor CD28. This leads to expression of CTLA-4 on the T cell surface, which binds to B7, leading to T cell inactivation. Ipilimumab binds to CTLA-4 and reverses this inactivation. B. In peripheral tissue, tumor cells upregulate PD-1 ligands, which bind to PD-1 on activated T cells, leading to T cell inhibition or death. Monoclonal antibodies that bind to either PD-1 or PD-L1 interfere with this, allowing antitumor T cells to survive and kill the tumor cells. A B *MHC= major histocompatibility complex, TCR=T cell receptor References on pages 105-107. 80

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