Advanced melanoma: Groundbreaking trials could transform treatment

Results from two international clinical trials could transform the treatment of advanced melanoma, the deadliest skin cancer type. But at present, melanoma patients whose cancer has spread face an uncertain and often bleak future.

But now, experts reporting the trial results say that the newly tested therapies should reduce the chances of the disease recurring and improve survival for many patients.

The researchers recently presented the findings of the trials at the European Society for Medical Oncology 2017 Congress, held in Madrid, Spain. They are also published in the New England Journal of Medicine.

Studies have already shown that immunotherapies and targeted therapies can successfully treat melanoma patients whose cancer has reached an advanced stage (stage IV) but cannot be surgically removed.

Immunotherapies are treatments that boost the immune system, and targeted therapies target specific disease genes or proteins associated with them.

However, the two new trials are the first in the world to offer melanoma patients the option of treatment at an earlier stage of the disease with the goal of preventing spread and relapse.

"Results from these clinical trials suggest we can stop the disease in its tracks - effectively preventing it from spreading and saving lives," says study author Prof. Georgina Long, chair of melanoma medical oncology and translational research at the University of Sydney in Australia, who worked on both trials.

Metastatic melanoma much harder to treat

Melanoma is predominantly a cancer of the skin, but it can also arise elsewhere in the body, such as the eyes. It begins in cells called melanocytes, which produce melanin - the pigment that gives skin, hair, and eyes their color. Exposure to ultraviolet light, such as from the sun or tanning beds, is a major risk factor for melanoma.

Although it is less common than many other skin cancer types, melanoma is "more likely to grow and spread." Most cancer deaths result from metastasis, which is a disease stage wherein cancer cells from the original tumor escape and give rise to harder-to-treat secondary tumors in other parts of the body.

In the United States, the rate of new cases of melanoma doubled between 1982 and 2011, a year in which more than 65,000 people discovered that they had the disease and more than 9,000 died of it.

In Australia, where Prof. Long is also conjoint medical director of Melanoma Institute Australia, the rate of melanoma is one of the highest in the world. In 2017, nearly 14,000 people in the country are expected to be diagnosed with the disease and more than 1,800 are expected to die of it.

If detected early, there is a very good chance of curing melanoma through the surgical removal of the primary tumor. However, in around 10 percent of cases, the cancer is detected too late and has already produced secondary tumors (metastases).

Melanoma patients at high risk of relapse are often given drugs to try to prevent metastases after initial cancer treatment, such as after surgery. The two trials tested two different kinds of adjuvant therapy for advanced melanoma.

COMBI-AD trial

In the COMBI-AD trial, researchers tested a combination of two drugs - dabrafenib and trametinib - against a placebo as a post-surgery treatment for patients with advanced melanoma (stage III), mutations in the BRAF gene, and thought be at high risk of recurrence.

The results showed that compared with a placebo, the combination led to "significantly lower risk of recurrence" and improved survival. They also showed no new toxic effects from the drugs used in combination.

The double-blind, placebo-controlled trial randomly assigned the 870 patients to receive 12 months of either a combination of dabrafenib (at an oral dose of 150 milligrams twice daily) and trametinib (at an oral dose of 2 milligrams once daily), or two matched placebo tablets.

The results showed that 58 percent of patients survived a median of 2.8 years with no relapse, compared with 39 percent in the placebo group - a reduction in risk of 53 percent.

The combination therapy group also showed an improved overall 3-year survival rate (that is, a risk reduction of 43 percent), "improved distant metastasis-free survival, and freedom from relapse."

CheckMate 238 trial

In the CheckMate 238 trial, the team found that the drug nivolumab was safer and more effective in treating patients who have had surgery for advanced melanoma (stage III and stage IV) than the current standard of care drug ipilimumab. It also found that nivolumab resulted in "significantly longer recurrence-free survival."

Both drugs are immune checkpoint inhibitors approved for the treatment of advanced melanoma. They target a switch on immune cells to boost their attack on cancer cells.

For the double-blind trial, researchers recruited 906 patients who were undergoing surgery to completely remove stage III or stage IV melanoma and were considered to be at high risk of relapse.

They were randomly assigned to receive intravenous infusions of either 3 milligrams of nivolumab per kilogram of body weight every 2 weeks, or 10 milligrams of ipilimumab per kilogram every 3 weeks for four doses and then every 12 weeks, for up to 1 year.

The committee monitoring the trial stopped it because the interim results showed clear evidence of the benefit of nivolumab compared with ipilimumab. At 18 months, the rate of relapse-free survival with nivolumab was 66.4 percent, whereas with ipilimumab it was only 52.7 percent.

Principal investigator Jeffrey S. Weber, deputy director of the Perlmutter Cancer Center at the New York University School of Medicine, says that these results show that "nivolumab is more effective in treating patients with stage III and IV melanoma, cutting the risk of relapse by a third."

As Prof. Long concludes, "Our ultimate goal of making melanoma a chronic rather than a terminal illness is now so much closer to being achieved."

"Results like this will change how we practice medicine."

Jeffrey S. Weber