This is a phase three clinical trial in which the authors of this paper are testing the outcomes of giving the antibody, ipilimumab, to patients who had stage III melanoma tumors successfully removed. The dose of ipilimumab in this trial is 10 mg per kg of body weight. The patients examined in this study were randomly assigned to receive either ipilimumab or placebo. The survival, recurrence rates, and distant metastasis rates of these two groups were measured about 5.3 years after the start of each patient’s treatment. The authors found that there was a greater rate of survival and less distant cancer spread among the treatment group, but more adverse immune effects.
Ipilimumab is an antibody that can strengthen immune responses against tumors. In 2011, the FDA allowed for 3 mg per kg of body weight of the antibody to be given to patients with advanced melanoma, a skin cancer. A clinical trial showed that at a dose of 10 mg per kg of body weight, the antibody was more effective in treating patients with advanced melanoma, but the antibody was also more toxic at this level. After receiving these results, the authors of this paper conducted another clinical trial. In this trial, they tested how effective ipilimumab was in treating melanoma patients who had their cancer surgically removed, but had a high chance of having it recur. They followed up with each of the patients after about 2.7 years after the start of their cancer remissions. They found that the patients who received the antibody had longer recurrence-free survival times. In this paper, the authors report the outcomes of these same patients after about 5.3 years after the start of their cancer remissions. This will provide a sense of how effective ipilimumab is in combating melanoma recurrence.
Patients that were examined in this study were all 18 and older and had melanoma that had spread to regional lymph nodes.
Trial Design and Regimen
Patients resided in a wide range of hospitals across 19 countries. They were separated into experimental groups based on their country and stage of melanoma. Patients were randomly assigned to receive either ipilimumab at 10 mg per kg of body weight or a placebo. Once a patient’s cancer went into remission, they would receive one dose every 3 weeks for 12 weeks, then one dose every three months until their cancer recurred.
All the patients in the study were tested for cancer recurrence and spread once every 3 months for three years, then once every 6 months after that. “Recurrence free survival” is the duration between the start of cancer remission and either recurrence or death.
This trial was approved by the EORTC protocol-review committee and several ethics committees. This trial was funded and sponsored by Bristol-Myers Squibb.
The authors discuss here the parameters they used in the statistical analyses they performed in this study.
Patients and Trial Regimen
A total of 951 melanoma patients were studied in this trial. Half received ipilimumab and the other half received placebo. Of the patients who received the antibody, 53.3% stopped treatment because of an adverse event, with most of these events being drug-related. Meanwhile, only 4.6% of the placebo group stopped because of an adverse event. 28.7% of patients in the treatment group stopped treatment because of cancer recurrence compared to 59.5% of patients in the placebo group. 13.4% of the treatment group were able to receive treatment for 3 years without stopping compared to 30.2% of the placebo group. The latest follow-up for each patient was about 5.3 years after their cancers initially went into remission.
Efficacy and Post Protocol Treatment
The average rate of recurrence-free survival at five years among the treatment group was 40.8%, compared to 30.3% in the placebo group. The average survival rate at five years among the treatment group was 65.4% in the treatment group compared to 54.4% in the placebo group. The average rate of survival without distant cancer spread at five years was 48.3% for the treatment group and 38.9% for the placebo group.
98.7% of the patients who received ipilimumab suffered an adverse event of some kind, with a little over half of these events being of higher severity. On the other hand, 91.1% of patients in the placebo group suffered an adverse event of some kind, with a little over a quarter of these events being of higher severity. Immune system-related adverse events were more frequent in the treatment group. 41.6% of patients in the treatment group suffered an immune-related adverse event of high severity compared to 2.7% in the placebo group. A total of 1.1% of patients in the treatment group died from complications that were caused by ipilimumab.
Treating melanoma patients after remission with ipilimumab is linked to longer overall survival and reduced chance of long-distance spread if the cancer recurs. This benefit was consistent even when factoring in different geographic regions and cancer stages. However, ipilimumab has a high risk of causing other adverse health effects. This clinical trial has extended and added to the trial on ipilimumab the authors had conducted previously.