Elsevier

The Lancet Oncology

Volume 16, Issue 5, May 2015, Pages 522-530
The Lancet Oncology

Articles
Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial

https://doi.org/10.1016/S1470-2045(15)70122-1Get rights and content

Summary

Background

Ipilimumab is an approved treatment for patients with advanced melanoma. We aimed to assess ipilimumab as adjuvant therapy for patients with completely resected stage III melanoma at high risk of recurrence.

Methods

We did a double-blind, phase 3 trial in patients with stage III cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis) with adequate resection of lymph nodes (ie, the primary cutaneous melanoma must have been completely excised with adequate surgical margins) who had not received previous systemic therapy for melanoma from 91 hospitals located in 19 countries. Patients were randomly assigned (1:1), centrally by an interactive voice response system, to receive intravenous infusions of 10 mg/kg ipilimumab or placebo every 3 weeks for four doses, then every 3 months for up to 3 years. Using a minimisation technique, randomisation was stratified by disease stage and geographical region. The primary endpoint was recurrence-free survival, assessed by an independent review committee, and analysed by intention to treat. Enrollment is complete but the study is ongoing for follow-up for analysis of secondary endpoints. This trial is registered with EudraCT, number 2007-001974-10, and ClinicalTrials.gov, number NCT00636168.

Findings

Between July 10, 2008, and Aug 1, 2011, 951 patients were randomly assigned to ipilimumab (n=475) or placebo (n=476), all of whom were included in the intention-to-treat analyses. At a median follow-up of 2·74 years (IQR 2·28–3·22), there were 528 recurrence-free survival events (234 in the ipilimumab group vs 294 in the placebo group). Median recurrence-free survival was 26·1 months (95% CI 19·3–39·3) in the ipilimumab group versus 17·1 months (95% CI 13·4–21·6) in the placebo group (hazard ratio 0·75; 95% CI 0·64–0·90; p=0·0013); 3-year recurrence-free survival was 46·5% (95% CI 41·5–51·3) in the ipilimumab group versus 34·8% (30·1–39·5) in the placebo group. The most common grade 3–4 immune-related adverse events in the ipilimumab group were gastrointestinal (75 [16%] vs four [<1%] in the placebo group), hepatic (50 [11%] vs one [<1%]), and endocrine (40 [8%] vs none). Adverse events led to discontinuation of treatment in 245 (52%) of 471 patients who started ipilimumab (182 [39%] during the initial treatment period of four doses). Five patients (1%) died due to drug-related adverse events. Five (1%) participants died because of drug-related adverse events in the ipilimumab group; three patients died because of colitis (two with gastrointestinal perforation), one patient because of myocarditis, and one patient because of multiorgan failure with Guillain-Barré syndrome.

Interpretation

Adjuvant ipilimumab significantly improved recurrence-free survival for patients with completely resected high-risk stage III melanoma. The adverse event profile was consistent with that observed in advanced melanoma, but at higher incidences in particular for endocrinopathies. 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.

Funding

Bristol-Myers Squibb.

Introduction

The rapidly rising incidence of cutaneous melanoma has also led to an increased number of patients with regional positive lymph nodes (stage III disease) being diagnosed each year.1 Breslow thickness, mitotic index, and ulceration of primary melanoma are the strongest prognostic factors for the presence of micrometastasis in regional lymph nodes.2 The likelihood of systemic metastatic disease in patients with regional lymph node metastasis is closely associated with microscopic versus palpable nodal disease and with number of positive nodes.3 In an analysis of 3307 patients by the American Joint Committee on Cancer (AJCC),2 5-year melanoma-specific survival was 78% for stage IIIA, 59% for stage IIIB, and 40% for stage IIIC melanoma. Recurrence at 5 years has been reported to be 37% in patients with stage IIIA disease, 68% for IIIB disease, and 89% for patients with stage IIIC disease.4 Even within the sentinel node-positive patient population, heterogeneity is remarkable and is closely associated with tumour load in the sentinel node, as defined by the Rotterdam criteria.5, 6, 7 Patients with a metastasis bigger than 1 mm have a highly significant increased risk of recurrence and death than do patients with a metastasis 1 mm or smaller.5, 6, 7

Research in context

Systematic review

The final protocol for this trial was submitted in January, 2008. In the preceding 2 years we assessed the scientific literature, restricted to English language publications, on PubMed (1980–2007), on adjuvant therapy in melanoma in patients with high risk for recurrence. A simple literature search using the search terms “melanoma”, “adjuvant therapy”, and “randomised trial” provided all relevant studies.

Added value of the study

This trial is, to the best of our knowledge, the first to assess an approved drug with an effect on survival in advanced melanoma in the adjuvant setting, and the first to study an immune checkpoint inhibitor in this setting. Our findings show that adjuvant use of ipilimumab has a significant effect on recurrence-free survival in the intention-to-treat population. We noted efficacy of the treatment across subgroups including those with palpable lymph nodes. Nevertheless, our results show important side-effects, in particular grade 3–4 colitis and hypophysitis. Our data neither support nor refute the need for maintenance treatment with ipilimumab. However, the effect on recurrence-free survival is potentially better than that of adjuvant interferon.

Interpretation

Ipilimumab is an active drug in the adjuvant setting in patients with high-risk disease, although side-effects are significant. In view of its activity across subgroups including those with high tumour burden, it represents an option in the current adjuvant landscape for those who have experience with administering the drug. Overall survival data are not yet mature and will be reported in the future.

Ipilimumab, a fully human monoclonal antibody that blocks CTLA-4 to augment anti-tumour immune responses, is an approved treatment for advanced melanoma because of its effect on overall survival.8, 9, 10 The unmet need for an improved adjuvant treatment for melanoma is shown by the hazard ratio (HR) for recurrence or death of 0·83–0·85 with high-dose or low-dose interferon compared with observation only.11 Interferon is approved in both the USA and the EU as an adjuvant therapy for resected melanoma; however, the treatment is not widely regarded as the standard of care. In the current context of only marginally effective adjuvant therapies with interferons, without a demonstrable dose–response or duration–response effect in meta-analyses,11, 12, 13 the study of ipilimumab in the adjuvant setting is appropriate.

Here, we report results from the European Organisation for Research and Treatment of Cancer (EORTC) 18071 trial of adjuvant ipilimumab in high-risk patients with stage III cutaneous melanoma after having undergone a complete regional lymph node dissection.

Section snippets

Study design and patients

In this multinational, randomised, double-blind, phase 3 trial done in 91 hospitals located in 19 countries, eligible patients were at least 18 years of age and had histologically confirmed melanoma metastatic to lymph nodes only. According to the AJCC 2009 (for stage III identical to AJCC 2002) classification, patients had to have either stage IIIA melanoma (if N1a, at least 1 metastasis >1 mm), stage IIIB or stage IIIC, with no in-transit metastasis.2 The primary cutaneous melanoma must have

Results

Between July 10, 2008, and Aug 1, 2011, 951 patients were randomly assigned (475 in the ipilimumab group and 476 in the placebo group). Table 1 shows patient and disease characteristics. Overall, 186 (20%) patients had stage IIIA, 420 (44%) had stage IIIB, and 345 (36%) had stage IIIC disease; 400 (42%) patients had an ulcerated primary, and 548 (58%) had macroscopic lymph node involvement.

Six patients did not start the allocated treatment by randomisation (figure 1). Of the remaining patients,

Discussion

Our data show that 10 mg/kg ipilimumab for up to 3 years as adjuvant treatment in patients with adequate resection of lymph nodes and high-risk stage III melanoma significantly improved recurrence-free survival, the primary endpoint of the trial, compared with use of adjuvant placebo. Patients remain in follow-up for the secondary endpoints of distant metastasis-free survival and overall survival.

The dose of 10 mg/kg was chosen based on data from a randomised phase 2 trial15 that compared

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