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Emerging drugs offer promise for advanced melanoma patients

Targeted Therapy
“If you had stage IV melanoma before 2011, the median survival was about a year or less. Modern-day immunotherapy using checkpoint inhibitors is offering positive responses for many patients.” – Alan Tan, MD, Clinical Research Medical Director at our hospital near Phoenix. Read more.

Less than a decade ago, a diagnosis of metastatic (advanced) melanoma offered little hope for the chance of a positive outcome. That’s because few treatments existed for the aggressive disease and fewer than 10 percent of patients responded to those that did exist. The toxicity of the standard immunotherapy (high-dose interleukin-2) regimen earned it the nickname “sepsis in a bottle” because its side effects mimicked infection-induced sepsis—fever, shaking and severe swelling, with patients retaining up to 20 pounds of water weight.

“If you had stage IV melanoma before 2011, the median survival was about a year or less. Modern-day immunotherapy using checkpoint inhibitors is offering positive responses for many patients.” – Alan Tan, MD, Clinical Research Medical Director at our hospital near Phoenix 

This is heartening news for the more than 90,000 people the National Cancer Institute estimates will be diagnosed with melanoma in 2018, making it the fifth most common cancer in the United States.

In 2011, the U.S. Food and Drug Administration (FDA) approved the monoclonal antibody ipilimumab for patients with advanced melanoma. Known as a checkpoint inhibitor, ipilimumab is one drug in an emerging treatment category called immunotherapy, which stimulates the body’s immune system to target and kill cancer cells. A few years after ipilimumab, the FDA approved two more checkpoint inhibitors, pembrolizumab and nivolumab.

“These drugs were certainly game changers for melanoma first and then subsequently for many other cancers,” Dr. Tan says. “We went three decades without anything new for melanoma. Finally, something new came out that was practice-changing and is helping people live much longer, some with no further evidence of disease.”

In October 2017, The New England Journal of Medicine published data from a study of advanced melanoma patients treated with nivolumab, ipilimumab or a combination of the two. At the three-year mark, 52 percent of patients treated with nivolumab alone were still alive, compared with 34 percent of those given only ipilimumab and 58 percent of those who received the combination.

“Combination checkpoint inhibitors have shown better responses,” says Ankur Parikh, DO, Medical Director of Precision Medicine at Cancer Treatment Centers of America® (CTCA). “Patients are living longer, living better, and some responses to immunotherapy have been incredible.”

Another breakthrough is targeted therapy, which uses drugs, in the form of a pill, to target and block the specific molecules fueling the cancer’s growth. These drugs are designed to either stop cancer cells from dividing or by destroying them altogether. Traditional chemotherapy is systemic, meaning the drugs travel throughout the body, but by contrast, targeted therapy finds the cancerous cells while avoiding most of the healthy ones.

>Drs. Tan and Parikh caution that not every therapy works for every patient. It’s important for patients with stage III or IV melanoma to have their tumors tested for a mutation (abnormal change) in the BRAF gene, a key protein involved in cell division and cell death. Knowing whether a patient has a BRAF mutation helps the oncologist better predict which treatments may offer a better chance for a positive outcome. A BRAF mutation is present in about half of all melanomas, according to the American Cancer Society, and patients with this mutation have been shown to respond better to targeted therapy than those who don’t have the mutation.

“As we start to learn more about which patients respond to which treatments, precision medicine plays a key role, and we will do genomic profiles of tumors to identify other mutations that we might target down the road,” Dr. Parikh says.

The BRAF inhibitor vemurafenib, which in 2011 received FDA approval for advanced melanoma, was the first targeted therapy drug on the market, followed by another, dabrafenib, two years later. The FDA has also green-lighted targeted therapy drugs (trametinib and cobimetinib, for example) that are designed to work on MEK proteins, which, like the BRAF gene, help normal cells mutate to cancerous ones. Recently, encorafenib and binimetinib became the latest FDA-approved combination for BRAF V600-type mutations. 

“We’re just at the tip of the iceberg, with more immune checkpoints and targeted combinations in the pipeline,” says Dr. Tan. These newer drugs are helping some though not all stage IV melanoma patients, but Dr. Tan says other strategies are being explored to help overcome primary resistance to immunotherapy. Examples include combining immune checkpoint inhibitors with intratumoral injections to help the melanoma become more recognizable to the immune system.  

Since every individual’s cancer and personal circumstances are unique, Dr. Parikh says it’s imperative for patients and their oncologists to discuss the pros, cons and potential outcomes before choosing a treatment approach. It is not lost on many of today’s oncologists, though, that these conversations could not have happened just a decade ago, when patients had fewer, and less promising, options.

“This is increasingly becoming a disease that can be managed like a chronic illness,” Dr. Parikh says.