COPENHAGEN – Five years on, patients with high-risk stage III melanoma treated with the checkpoint inhibitor ipilimumab, following complete resection, continue to have significantly better overall, recurrence-free, and distant metastasis–free survival, compared with patients treated with placebo, reported investigators in a phase III trial.
Five-year overall survival among patients who received a 10-mg/kg dose of ipilimumab (Yervoy) in the EORTC 18071 trial was 65.4%, compared with 54.4% for patients who received placebo. This difference translated into a hazard ratio for death with ipilimumab of 0.72 (P = .001), reported Alexander M.M. Eggermont, MD, from the Gustave Roussy Cancer Center in Villejuif, France.
Dr. Alexander Eggermont
The survival benefit with ipilimumab “was consistent across all survival endpoints,” he said at a briefing prior to his presentation of the data in a symposium at the European Society for Medical Oncology Congress.
He noted, however, that the 10-mg/kg dose of ipilimumab selected in phase II trials is associated with significant toxicities.
“Ipilimumab is not an easy drug to handle. My recommendation is to keep it in [cancer] centers,” he said.
In the trial, 951 patients with high-risk, stage III, completely resected melanoma were randomly assigned to receive induction therapy with ipilimumab 10 mg/kg every 3 weeks for four cycles or placebo, followed by maintenance with the assigned therapy every 12 weeks for up to 3 years.
The investigators previously reported that, at a median follow-up of 2.7 years, ipilimumab was associated with significantly prolonged overall survival (the primary endpoint), with a hazard ratio vs. placebo of 0.75 (P = .001).
At ESMO 2016, Dr. Eggermont reported final survival results from the trial, at a median follow-up of 5.3 years.
The rate of 5-year overall survival for the 475 patients assigned to ipilimumab was 65.4%, compared with 54.4% among the 476 patients assigned to placebo (HR, 0.72, P = .001).
At 5 years, 41% of patients assigned to ipilimumab were free of recurrences, compared with 30% of patients on placebo, The median recurrence-free survival was 27.6 months vs. 17.1 months, respectively (HR, 0.76, P = .0008).
Similarly, the rate of distant metastasis-free survival at 5 years was 48.3% for patients assigned to ipilimumab, vs. 38.9% in the placebo group (HR for death or distant metastasis, 0.76; P = .002).
The safety analysis showed that twice as many patients assigned to ipilimumab had grade 3 or 4 adverse events (54.1% vs. 26.2%). Grade 3 or 4 adverse immune events occurred in 41.6% vs. 2.7%, respectively.
Five patients assigned to ipilimumab died from immune-related causes: three from colitis (two of whom had intestinal perforations), one from myocarditis, and one from multiorgan failure associated with Guillain-Barré syndrome.
Dr. Olivier Michielin
“The final analysis shows, for the first time, that checkpoint blockade is effective in the adjuvant setting,” he said.
The data suggest, however, that the benefit appears to be concentrated in patients with higher-risk features, such as involvement of four or more lymph nodes, microscopic nodal disease, or ulceration, he said.
The discussant also agreed with Dr. Eggermont’s assertions that the decision to treat patients with ipilimumab should factor in toxicity, and that treatment should be administered only in centers experienced in using the drug.
The trial was sponsored by Bristol-Myers Squibb. Dr. Eggermont disclosed serving on an advisory board for Bristol-Myers Squibb and Merck. Dr. Michielin disclosed consulting and/or honoraria from Amgen, Bristol-Myers Squibb, Roche, Merck Sharp & Dohme, Novartis, and GlaxoSmithKline.