Prolonged Survival With Adjuvant Ipilimumab in Stage 3 Melanoma

Zosia Chustecka

October 09, 2016

COPENHAGEN — Patients with completely resected stage 3 melanoma who received adjuvant treatment with ipilimumab (Yervoy, Bristol-Myers Squibb) lived longer than those who received placebo, show the latest results from the CA184-029 (EORTC 18071) study.

This is the first time such a clear survival benefit has been seen with adjuvant therapy in the patient population, commented lead researcher Alexander M.M. Eggermont, MD, PhD, director general, Cancer Institute Gustave Roussy in Villejuif, France, noting that previous trials with adjuvant interferon have suggested a survival benefit, but only in some subgroups of patients.

He reported the new 5-year analysis here today during a presidential session at the 2016 European Society for Medical Oncology (ESMO) Congress, which was simultaneously published in the New England Journal of Medicine.

The trial is a "historical landmark" commented Olivier Michielin, MD, head of Personalized Analytical Oncology, CHUV, Lausanne, Switzerland, who acted as discussant.

"This was the first attempt to use checkpoint blockade in the adjuvant setting of melanoma. The effect was a 28% reduction in the risk of death, which is statistically and clinically significant, and an 11% absolute gain in overall survival at 5 years," he said.

It was also "an important scientific discovery," Dr Michielin commented. "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."

In stage 3 melanoma, the disease has not yet spread to distant lymph nodes or other parts of the body, and standard management is surgical resection of the primary tumor as well as the involved lymph nodes. "Despite surgical intervention, most patients with stage 3 melanoma experience disease recurrence and progress to metastatic disease, reinforcing the unmet need for effective systemic therapies in the adjuvant setting," Dr Eggermont explained.

Dr Alexander Eggermont

Previous results from the CA184-029 (EORTC 18071) study that showed a reduction in recurrence have already been published and led to approval of adjuvant ipilimumab in stage 3 melanoma by the US Food and Drug Administration.

The new findings presented at the congress show a survival benefit.

The 5-year overall survival (OS) rates were 64% with ipilimumab vs 54.4% with placebo (hazard ratio [HR], 0.72; P = .001), and showed a 28% reduction in the relative risk of death.

OS was a secondary endpoint, as was distant metastasis-free survival (DMFS), which was also significantly improved vs placebo (HR, 0.76; P = .002). The 5-year DMFS rates were 48.3% for ipilimumab and 38.9% for placebo.

The primary endpoint was recurrence-free survival, which was previously reported, and the latest 5-year analysis showed the benefit was maintained (HR, 0.76; P < .001).

In this trial, ipilimumab was used at the higher dose of 10 mg/kg, administered as induction every 3 weeks for four doses, and then as maintenance every 12 weeks for up to 3 years.

At this higher dose, around 40% of patients developed grade 3/4 immune-related adverse events, including gastrointestinal (16.1%), hepatic (10.8%), and endocrine (7.9%) events. There were five patient deaths (1.1%) from adverse events attributed to ipilimumab: three patients died from colitis (two with intestinal perforation), one patient from myocarditis, and one patient from multiorgan failure associated with Guillain-Barré syndrome.

Dr Eggermont said the adverse events were managed by established algorithms and usually resolved within 4 to 8 weeks, but some of the endocrine adverse events took much longer to resolve, and some required permanent hormonal replacement therapies. He also said that, because of the adverse events, the use of ipilimumab at this dose should be restricted to centers that have experience with the therapy, and patients must be educated to report symptoms and clinicians primed to promptly respond.

"The risks and benefits of this option should now be discussed with our patients," said Dr Michielin. "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," he said, echoing Dr Eggermont's comments.

In his discussion, Dr Michielin pointed out that interferon and pegylated-interferon have also been approved as adjuvant therapy for the patient population. However, he suggested that the results seen with ipilimumab are better than those previously reported for interferon and noted that the pattern of responses is quite different.

With ipilimumab, the greatest benefit was seen in patients with the most advanced disease (stage 3C, > 4 positive lymph nodes), slightly less benefit was seen in stage 3C patients with 1 to 3 positive lymph nodes, and no benefit was seen in stage 3 patients with no affected lymph nodes, which "suggests a biology," he said.

In contrast, all the benefit with interferon was seen in stage 2b/3 patients with only one lymph node involved, whereas no benefit was seen in stage 3 patients.

Dr Michielin also calculated the number needed to treat as 9.1 for ipilimumab, compared with 35 for interferon.

Other Adjuvant Trials Underway

In view of the adverse events, there has been speculation that the lower 3 mg/kg dose of ipilimumab should be used instead to reduce toxicity. However, Dr Michielin warned that another presentation at this year's meeting showed that the lower dose is less effective than the higher dose of ipilimumab.

Another question is whether programmed cell death (PD) inhibitors could be used as adjuvant therapy instead, as they have shown greater efficacy and lower toxicity in other melanoma settings.

Dr Eggermont told Medscape Medical News that trials to answer these questions are currently underway and noted that this adjuvant trial began in 2008.

Dr Michielin concluded: "This trial represents an important milestone in the treatment of melanoma. 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."

The study was funded by Bristol-Myers Squibb. Dr Eggermont reports acting as a speaker for Bristol-Myers squibb and MSD. Disclosures for the coauthors are listed in the article.

European Society for Medical Oncology (ESMO) Congress. Abstract LBA2_PR. Presented October 9, 2016.

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