Patients with high risk melanoma who undergo surgery to remove their tumors may markedly benefit from Yervoy (ipilimumab) following surgery, according to the results of a Phase 3 trial.

The study, which was recently presented at the European Society for Medical Oncology (ESMO) 2016 Congress, Oct. 7-11 in Copenhagen, Denmark, shows that Yervoy significantly reduces patients’ risk of death and improves their survival rates.

Despite surgical intervention, most patients with stage 3 melanoma still experience disease recurrence and eventually progress to matestatic melanoma, revealing the urgent need for adjuvant therapies (given after surgery) that prevent the disease from recurring.

“Ipilimumab is an immune checkpoint inhibitor that blocks cytotoxic T-lymphocyte antigen-4 (CTLA-4),” lead author Prof. Alexander Eggermont, director general of the Institut Gustave Roussy in Villejuif, France, said in a press release. “It was approved in 2011 for first-line treatment of advanced melanoma in the U.S. and Europe. The next question was its utility in the adjuvant setting.”

The EORTC 10871 trial (NCT00636168), a randomized, double-blind Phase 3 study, was designed to address that question. The study enrolled 951 patients with high risk stage 3 melanoma who were randomized to receive either Yervoy or a placebo following surgery.

Treatment was administrated through intravenous injection, four times every 21 days, and then starting from week 24 every 12 weeks until week 156 (three years) or until disease recurrence or unacceptable toxicity.

In 2015, the study had already reached its primary endpoint after a median follow-up of 2.3 years, with Yervoy significantly improving recurrence-free survival (RFS). This analysis was the basis of Yervoy’s approval by the U.S. Food and Drug Administration (FDA) for adjuvant treatment of melanoma patients.

Now, updated five-year results show that Yervoy’s superior recurrence-free survival compared to a placebo was maintained, with a median RFS of 27.6 months in the Yervoy group versus 17.1 months in the placebo group.

Yervoy also improved patients’ overall survival (OS), inducing a 28 percent reduction in the risk of death versus placebo and a five-year OS rate 11 percent higher than in the placebo group (65.4 percent vs. 54.4 percent). The risk of developing distant metastasis was also reduced by 24 percent in patients taking Yervoy compared to those taking a placebo. Consistently, median distant metastasis-free survival was 48.3 months for Yervoy and 27.5 months for a placebo.

“This was the first attempt to use checkpoint blockade in the adjuvant setting of melanoma,” said Dr. Olivier Michielin, head of Personalized Analytical Oncology at CHUV in Lausanne, Switzerland. “Ipilimumab works by stimulating the immune system against tumor antigens. In the adjuvant setting there is microscopic residual disease and, until now, it was not clear if there was a sufficient amount of antigens to trigger a response.”

Importantly, no new deaths or additional toxicities were observed since the initial report at two years. Immune-related adverse events were more frequent with Yervoy than with a placebo, with the most important grade 3 to 4 adverse events being gastrointestinal, hepatic, and endocrine.

Although most of these adverse events were resolved in a median of four to eight weeks, only about half of patients with endocrine adverse events had their symptoms resolved, and they took on average 54.3 weeks.

“The risks and benefits of this option should now be discussed with our patients,” Michielin said. “The toxicity is not negligible and patients need to be aware of the adverse event profile. The 10 mg/kg regimen used in the trial is associated with potentially severe toxicities and should be reserved for experienced centers.”

“This trial represents an important milestone in the treatment of melanoma,” he added. “These results open the door for other studies based on checkpoint blockade to try and improve cure rates in the adjuvant setting of melanoma as well as other disease types. We are currently waiting for the results of several trials, including EORTC 1325, which is investigating pembrolizumab, a PD-1 checkpoint blocking antibody, compared to placebo in the adjuvant setting.”

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