The final analysis on the impact of ipilimumab on relapse-free survival from a randomised phase III study, EORTC 18071, indicates that adjuvant (post-surgery) therapy with ipilimumab for patients with high-risk stage III melanoma decreases the relative risk of cancer recurrence by roughly 25 percent compared to placebo.

This is the third effective adjuvant treatment for lymph node-positive (stage III) patients who are at a very high risk of recurrence after surgery (interferon alfa-2a and peginterferon alfa-2b), though side effects were substantial.

Longer follow-up on this study is needed to assess the overall survival benefit of this treatment approach. “This is a promising treatment ─ we saw substantially fewer recurrences among patients who are at high risk of relapse,” said lead study author Professor Alexander Eggermont, MD, PhD, director general of the Gustave Roussy Cancer Campus Grand Paris in France.

“We’ve seen many impressive new treatments for advanced melanoma in recent years. This trial with ipilimumab is the first to show we may be able to give these new drugs earlier in the course of disease, where they can do more good and potentially cure more patients.”

The immunotherapy drug ipilimumab is FDA-approved for the treatment of inoperable stage IV (metastatic) melanoma, albeit at a lower dose than in the current study.

This is the first study to show that ipilimumab is also effective in an adjuvant setting for earlier-stage disease.

The impact on relapse-free survival was observed both in patients with microscopic metastases, and in patients with macroscopic metastases in lymph nodes, who are at the highest risk of relapse (microscopic metastases are tiny areas of cancer cells found during a lymph node biopsy or surgical removal of lymph nodes. Macroscopic metastases are larger areas of cancer in the lymph nodes).

High-dose interferon alpha2b and pegylated interferon-alpha2b are approved by the FDA as a post- surgery treatment for patients with stage III melanoma who are at a high risk of relapse.

The EORTC 18991 trial that resulted in the approval of pegylated interferon-alpha2b did not show an appreciable effect in patients with macroscopic metastases in lymph nodes.

In the present study, 951 patients with surgically treated stage III cutaneous melanoma were randomly assigned to receive ipilimumab or placebo.

A sizeable proportion of patients had a high likelihood of recurrence because the cancer had spread to the lymph nodes.

Ipilimumab (10 mg/kg) was given every three weeks for four doses, and the treatment continued at three-month intervals for up to three years.

At a median follow-up period of 2.7 years, ipilimumab substantially reduced the risk of melanoma recurrence.

There were 294 recurrences in the placebo group compared to 234 in the ipilimumab group.

The three-year recurrence-free survival rates were 34.8 and 46.5 percent in the placebo and ipilimumab groups, respectively.

Overall, ipilimumab reduced the relative risk of recurrence by 25 percent compared to placebo.

Subgroup analysis showed a 33 percent risk reduction among patients with microscopic disease in lymph nodes and a 17 percent reduction among patients with macroscopic disease.

Side effects were considerable, however.

There have been five treatment-related deaths on the study, and 52 percent of patients discontinued treatment due to side effects, most within the first 12-16 weeks.

The side effects were consistent with those observed in treatment of stage IV melanoma ─ inflammation of the colon (colitis), thyroid, and pituitary gland, and skin rash.

Researchers will continue following patients on this study to evaluate overall survival.

Dr. Eggermont remarked that adjuvant therapy with ipilimumab clearly emerges as a new option for patients with high- risk stage III disease and that more research is needed to fully assess the balance of benefits and risks associated with this treatment.

A separate, ongoing phase III study (ECOG1609) is comparing two different doses (3 mg/kg and 10 mg/kg) of adjuvant ipilimumab with high-dose interferon.

“The results of this study are promising. Ipilimumab is an effective treatment in stage IV melanoma. This is the first study to demonstrate its clinical benefit in stage III melanoma,” said Steven O’Day, MD, ASCO Expert.

“The magnitude of the clinical benefit, the side effects, and the dosing schedule warrant further follow up and additional comparative studies with interferon, which are ongoing.”

Source: ASCO