Adjuvant Ipilimumab Increases RFS for Stage III Melanoma Patients

Adjuvant ipilimumab results demonstrate improved recurrence-free survival but substantial side effects for patients with stage III melanoma

medwireNews: Phase III clinical trial findings for ipilimumab versus placebo demonstrate a significant improvement in recurrence-free survival (RFS), but substantial side effects, for patients with completely resected high-risk stage III melanoma.

After a median of 2.74 years, median RFS was 26.1 months for the 475 patients given the CTLA-4 antibody treatment at a dose of 10 mg/kg, initially for four doses at 3-week intervals followed by repeat dosing every 3 months for up to 3 years.

This was significantly higher than the median RFS of 17.1 months for the 476 patients given placebo, giving a hazard ratio of 0.75. Three-year RFS was achieved by 46.5% and 34.8% of the ipilimumab and placebo groups, respectively.

Post-hoc analysis indicated that ipilimumab was more effective in patients with stage IIIC disease, 41% of whom had ulcerated melanoma, than those with stage IIIA disease, none of whom had ulcerated disease.

Ipilimumab also appeared to be more effective in patients with macroscopic, palpable lymph node disease than in those with positive sentinel nodes and microscopic disease, and this was especially noted among patients with ulcerated primary melanoma.

“These observations suggest that ulcerated melanoma is a separate biological entity, for which a number of additional observations have been reported in terms of stromal components, gene profiling, and immune-suppressed status of associated sentinel nodes”, write Alexander Eggermont, from Gustave Roussy Cancer Campus Grand Paris in Villejuif, France, and co-authors in The Lancet Oncology.

However, the researchers report that the adverse event profile for ipilimumab was “substantial”, so that 49% of patients discontinued due to drug-related adverse events, and 39% discontinued before entering the maintenance phase, a higher rate than previously reported for the same dose in advanced melanoma patients.

Discontinuation due to disease recurrence occurred in 28% and 58% of ipilimumab-treated patients and controls, respectively, but just 7% of ipilimumab patients completed 3 years of treatment compared with 16% of controls.

In all, 25% of ipilimumab-treated patients experienced a grade 3 or 4 adverse event, most commonly affecting the gastrointestinal, hepatic or endocrine systems. Immune-related endocrine adverse events – hypophysitis and hypothyroidism – took longer to resolve than other immune-related events (median 31.1 versus 4.0–8.0 weeks) and were less likely to resolve to grade 1 or baseline (56 vs 82–95%).

Five (1%) patients died from ipilimumab-related events including three cases of colitis, one case of myocarditis and one death from multiorgan failure associated with Guillain-Barré syndrome.

“The risk–benefit ratio of adjuvant ipilimumab at this dose and schedule requires additional assessment based on distant metastasis-free survival and overall survival endpoints to define its definitive value”, the team therefore concludes.

Vernon Sondak, from Moffitt Cancer Center in Tampa, Florida, USA, and Grant McArthur, from the University of Melbourne in Victoria, Australia, agree in an accompanying comment that the toxicity profile in the trial “raises concern” and emphasise the need for mature overall survival data before adjuvant ipilimumab can be recommended for stage III patients.

“If overall survival for the two groups does not differ significantly, it would suggest that reserving ipilimumab for salvage treatment is preferable to exposing all patients to the toxicity (and cost) of adjuvant use”, they explain.

“Conversely, if overall survival is improved despite the potential for crossover on relapse, then the toxicity and cost of adjuvant therapy would be more clearly justified.”

Regardless, they conclude: “Now that the study by Eggermont and colleagues has shown unequivocally that one immune checkpoint inhibitor can improve recurrence-free survival in the adjuvant setting, randomised adjuvant trials of PD-1-blocking antibodies are eagerly anticipated in view of their more favourable safety profile and substantial activity not only against advanced melanoma but other cancers as well.”


Eggermont AMM, Chiarion-Sileni V, Grob J-J, et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol 2015; Advance online publication 31 March. Doi:

Sondak VK, McArthur GA. Adjuvant immunotherapy for cancer: the next step. Lancet Oncol 2015; Advance online publication 31 March. Doi:

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