The Immune Revolution

Perry Robins, MD, and Maritza Perez, MD

How the latest “checkpoint blockade” drugs are helping to transform advanced melanoma from a deadly to a treatable disease.

The words “revolution” and “revolutionary” are often overused today. “It’s a revolution in dinnerware!” “The revolutionary new brine that makes sour pickles even sourer!” You see our point?

However, in the field of melanoma treatment, there are no better terms to describe the new generation of immunotherapies, drugs that boost the immune system’s ability to fight disease. Led by a series of recently FDA-approved “checkpoint blockade” drugs, they are for the first time allowing patients with advanced, metastatic melanoma, who once had very little hope, a legitimate chance of long-term survival.

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 percent 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 percent when the disease reaches the nearby lymph nodes (Stage III), and 16 percent when it metastasizes to distant organs (Stage IV).

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. [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 appreciably 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 increasing 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. [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 percent lived three years or longer, and 84 percent of those survivors were alive after 5 years and 10 years. One recent report, in fact, suggested that 20 percent of patients who received ipilimumab are alive after 10 years. In contrast, only about 4-6 percent of patients were ever found to achieve long-term survival with Interleukin-2, and no overall survival advantage was ever demonstrated with chemotherapy.

Pembrolizumab and nivolumab inhibit a different 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. [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 surgery; *and have had disease progression after treatment with ipilimumab; *and, 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 approved in 2013).

Not to Be Contained

Soon, nivolumab and pembrolizumab may become front-line, first-resort therapies, because their results have been simply too good to keep them in reserve. The National Comprehensive Cancer Network recently noted that both anti-PD-1 agents have “higher response rates and less toxicity compared to ipilimumab. . . and should be included as options for first-line treatment.”

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 unprecedented 80 percent of patients were alive at two years – patients who would have survived only 9-12 months just a few years ago.

In a new development that could be a huge boon to patients, the checkpoint blockade therapies could soon start to be used earlier 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 metastasis beyond the lymph nodes. Acceptance of the application was based on results from a phase III trial showing a 25 percent 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 Alexander 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.”

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 melanoma 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 possibilities exist than ever before, and more are just around the bend.

Perry Robins, MD, is the Founder and President of The Skin Cancer Foundation. He is Professor Emeritus of Dermatology and former Chief of the Mohs Micrographic Surgery Unit at New York University Medical Center. Dr. Robins has been honored for distinguished service by the four leading dermatologic societies and is chairman of skin cancer conferences in the US and around the world. He is the founder-president of the International Society for Dermatologic Surgery, founder/former president of the American College of Mohs Micrographic Surgery, and former president of the American Society of Dermatologic Surgery. He has published extensively in major medical journals, authored 5 books, and is the Founder of the Journal of Dermatologic Surgery and the Journal of Drugs in Dermatology. Dr. Robins has been named an honorary member of 11 international dermatology societies.

Maritza I. Perez, MD, Founder and Director of Advanced Dermaesthetics in New Canaan, CT, is Director of Cosmetic Dermatology at Mt. Sinai Roosevelt Medical Center, Associate Director of Procedural Dermatology at Beth Israel Medical Center, and Associate Clinical Professor of Clinical Dermatology at Mount Sinai Icahn School of Medicine in New York City. She is a recipient of the Dermatology Foundation Award and Fellowship and The Skin Cancer Foundation’s Joseph G. Gaumont Fellowship in Dermatologic Surgery with Dr. Perry Robins at New York University Medical Center, New York City. Dr. Perez is also a Senior Vice President of The Skin Cancer Foundation.

Published on June 16, 2015