- •Adjuvant therapy with ipilimumab significantly improved the outcomes.
- •Compared with placebo, it prolonged RFS (hazard ratio [HR], 0.75), DMFS (HR, 0.76) and (OS; HR, 0.73).
- •The estimated absolute increase in the 7-year OS rate was 8.7%.
- •The benefit was sustained long term and consistent across subgroups.
Since 2015, adjuvant therapy with ipilimumab is an approved treatment for stage III melanoma based on a significantly prolonged recurrence-free survival (RFS). At a median follow-up of 5.3 years, RFS, distant metastasis-free survival (DMFS) and overall survival (OS) were each significantly prolonged in the ipilimumab group compared with the placebo group, despite a 53.3% (ipilimumab) versus 4.6% (placebo) treatment discontinuation rate due to adverse events. We present now long-term follow-up results of this European Organisation for Research and Treatment of Cancer 18071 trial.
Patients, methods and results
A total of 99 sites randomised 951 patients with stage III cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis) with adequate resection of lymph nodes to receive intravenous infusions of ipilimumab 10 mg/kg or placebo, every 3 weeks for 4 doses, then every 3 months for up to 3 years. The RFS, DMFS and OS, as reported by the local investigators, were assessed by the intention-to-treat analysis. Among 431 patients randomised at 63 sites and who were still alive at the analysis reported in 2016, recent follow-up information could be obtained for 264 patients. The median OS follow-up was 6.9 years. The RFS (hazard ratio [HR] 0.75, 95% confidence interval 0.63–0.88; P < 0.001), DMFS (HR 0.76, 0.64–0.90; P = 0.002) and OS (HR 0.73, 0.60–0.89; P = 0.002) benefit observed in the ipilimumab group was durable with an 8.7% absolute difference at 7 years for OS. The benefit was consistent across subgroups.
Adjuvant therapy with ipilimumab prolongs RFS, DMFS and OS significantly. The benefit is sustained long term and consistent across subgroups.
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- Cutaneous melanoma.Lancet. 2014; 383: 816-827
- Survival of patients with advanced metastatic melanoma: the impact of novel therapies-update 2017.Eur J Canc. 2017; 83: 247-257
- Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomized, double-blind, phase 3 trial.Lancet Oncol. 2015; 16: 522-530
- Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma.N Engl J Med. 2017; 377: 1824-1835
- Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma.N Engl J Med. 2017; 377: 1813-1823
- Adjuvant pembrolizumab versus placebo in resected stage III melanoma.N Engl J Med. 2018; 378: 1789-1801
- Prolonged survival with Ipilimumab as adjuvant in stage III melanoma.N Engl J Med. 2016; 375: 1845-1855
- Health-related quality of life with adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): secondary outcomes of a multinational, randomized, double-blind, phase 3 trial.Lancet Oncol. 2017; 18: 393-403
- Final version of 2009 AJCC melanoma staging and classification.J Clin Oncol. 2009; 27: 6199-6206
- Sentinel node tumor burden according to the Rotterdam criteria is the most important prognostic factor for survival in melanoma patients: a multicenter study in 388 patients with positive sentinel nodes.Ann Surg. 2008; 248: 49-55
- The prognostic significance of sentinel node tumour burden in melanoma patients: an international, multicenter study of 1539 sentinel node-positive melanoma patients.Eur J Canc. 2014; 50: 111-120
- Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomized phase III trial.Lancet. 2008; 372: 117-126
- Long term results of the randomized phase III trial EORTC 18991 of adjuvant therapy with pegylated interferon alfa-2b versus observation in resected stage III melanoma.J Clin Oncol. 2012; 30: 3810-3818
- Post-surgery adjuvant therapy with intermediate doses of interferon alfa 2b versus observation in patients with stage IIb/III melanoma (EORTC 18952): randomized controlled trial.Lancet. 2005; 366: 1189-1196
- Ulceration and stage are predictive of interferon efficacy in melanoma: results of the phase III adjuvant trials EORTC 18952 and EORTC 18991.Eur J Canc. 2012; 48: 218-225
- Long term follow up of the EORTC 18952 trial of adjuvant therapy in resected stage IIB-III cutaneous melanoma patients comparing intermediate doses of interferon-alpha-2b (IFN) with observation: ulceration of primary is key determinant for IFN-sensitivity.Eur J Canc. 2016; 55: 111-121
- On behalf of the International Melanoma Meta-Analysis Collaborative Group (IMMCG). Adjuvant interferon-α for the treatment of high-risk melanoma: an individual patient data meta-analysis.Eur J Canc. 2017; 82: 171-183
- United States Intergroup E1609: a phase III randomized study of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon-α2b for resected high-risk melanoma.J Clin Oncol. 2019; : 9504
- Relapse-free survival as a surrogate for overall survival in the evaluation of stage II-III melanoma adjuvant therapy.J Natl Cancer Inst. 2018; 110: 87-96
- Outcomes by line of therapy and programmed death ligand 1 expression in patients with advanced melanoma treated with pembrolizumab or ipilimumab in KEYNOTE-006: a randomized clinical trial.Eur J Canc. 2018; 101: 236-243
- Melanoma staging: evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual.CA Cancer J Clin. 2017; 67: 472-492
- Prognostic and predictive value of AJCC-8 staging in the phase 3 EORTC1325/KEYNOTE-054 trial of pembrolizumab vs placebo in resected high-risk stage III melanoma.Eur J Canc. 2019; 116: 148-157
- Complete lymph node dissection versus no dissection in patients with sentinel lymph node biopsy positive melanoma (DeCOG-SLT): a multicentre, randomized, phase 3 trial.Lancet Oncol. 2016; 17: 757-767
- Completion dissection or observation for sentinel-node metastasis in melanoma.N Engl J Med. 2017; 376: 2211-2222
- Risk stratification of sentinel node-positive melanoma patients defines surgical management and adjuvant therapy treatment considerations.Eur J Canc. 2018; 96: 25-33
- The 2017 complete overhaul of adjuvant therapies for high-risk melanoma and its consequences for staging and management of melanoma patients.Eur J Canc. 2017; 86: 101-105
- The new era of adjuvant therapies for melanoma.Nat Rev Clin Oncol. 2018; 15: 535-536
- Neoadjuvant therapy in melanoma: the next step?.Lancet Oncol. 2018; 19: 151-153
- Neoadjuvant plus adjuvant dabrafenib and trametinib versus standard of care in patients with high-risk, surgically resectable melanoma: a single-centre, open-label, randomized, phase 2 trial.Lancet Oncol. 2018; 19: 181-193
- Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma.Nat Med. 2018; 24: 1655-1661
Published online: August 07, 2019
Accepted: July 5, 2019
Received: July 4, 2019
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