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Adjuvant ipilimumab in stage III melanoma: New landscape, new questions

  • Alexander M.M. Eggermont
    Correspondence
    Corresponding author: Gustave Roussy Cancer Campus Grand Paris, 114 Rue Edouard Vaillant, 94805 Villejuif, France. Fax: +33 1 42 11 52 52.
    Affiliations
    Gustave Roussy Cancer Campus Grand Paris, Villejuif, France

    Universite Paris-Sud, Kremlin-Bicêtre, France
    Search for articles by this author
Published:November 03, 2016DOI:https://doi.org/10.1016/j.ejca.2016.10.009

      Abstract

      The recently reported significant prolongation of overall survival with ipilimumab as adjuvant in high-risk stage III melanoma patients represents an important event in the adjuvant treatment landscape. The European Organisation for Research and Treatment of Cancer 18071 trial demonstrated a 28% reduction in risk of death in patients treated with ipilimumab at 10 mg/kg (hazard ratio for death, 0.72; 95.1% CI, 0.58−0.88; P = 0.001) compared with placebo. All end-points—recurrence-free survival (RFS), distant-metastasis-free survival (DMFS) and overall survival (OS)—showed similar benefits. Survival rates at 5 years in ipilimumab-treated patients were OS 11%, DMFS 9% and RFS 11% higher than in placebo-treated patients. Global Health quality-of-life scores were not significantly different between treatment arms, in spite of significant adverse event rates that resulted in only 42% of patients receiving more than four doses of ipilimumab and only 28.9% of patients going beyond 1 year of treatment. Grades 3–4 immune-related adverse events occurred in 41.6% of ipilimumab-treated patients and in 2.7% of placebo-treated patients. One can speculate on dose and duration of treatment, as well as on the requirement for complete lymph-node dissection in sentinel-node-positive patients. The remaining role of interferons will be discussed regarding differences in sensitivity profiles—such as in ulcerated melanoma versus non-ulcerated melanoma—and access to new drugs. Ongoing trials with targeted agents and with anti programmed cell death protein 1 (anti-PD-1) agents may bring significant additional results in the next few years that will redefine how we treat stage III patients. Overall, pricing of new treatments will determine access and whether patients will actually benefit from new treatment options.

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      References

        • Eggermont A.M.M.
        • Spatz A.
        • Robert C.
        Cutaneous melanoma.
        Lancet. 2014; 383: 816-827
        • Balch C.M.
        • Gershenwald J.E.
        • Soong S.J.
        • Thompson J.F.
        • Atkins M.B.
        • Byrd D.R.
        • et al.
        Final version of 2009 AJCC melanoma staging and classification.
        J Clin Oncol. 2009; 27: 6199-6206
        • Balch C.M.
        • Gershenwald J.E.
        • Soong S.J.
        • Thompson J.F.
        • Ding S.
        • Byrd D.R.
        • et al.
        Multivariate analysis of prognostic factors among 2,313 patients with stage III melanoma: comparison of nodal micrometastases versus macrometastases.
        J Clin Oncol. 2010; 28: 2452-2459
        • van der Ploeg A.P.
        • van Akkooi A.C.
        • Schmitz P.I.
        • Koljenovic S.
        • Verhoef C.
        • Eggermont A.M.
        EORTC Melanoma Group sentinel node protocol identifies high rate of submicrometastases according to Rotterdam criteria.
        Eur J Cancer. 2010; 46: 2414-2421
        • van Akkooi A.C.
        • Nowecki Z.I.
        • Voit C.
        • Schäfer-Hesterberg G.
        • Michej W.
        • de Wilt J.H.
        • et al.
        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: 949-955
        • van der Ploeg A.P.
        • van Akkooi A.C.
        • Rutkowski P.
        • Nowecki Z.I.
        • Michej W.
        • Mitra A.
        • et al.
        Prognosis in patients with sentinel node-positive melanoma is accurately defined by the combined Rotterdam tumor load and Dewar topography criteria.
        J Clin Oncol. 2011; 29: 2206-2214
        • van der Ploeg A.P.
        • van Akkooi A.C.
        • Haydu L.E.
        • Scolyer R.A.
        • Murali R.
        • Verhoef C.
        • et al.
        The prognostic significance of sentinel node tumour burden in melanoma patients: an international, multicenter study of 1539 sentinel node-positive melanoma patients.
        Eur J Cancer. 2014; 50: 111-120
        • Kirkwood J.M.
        • Strawderman M.H.
        • Ernstoff M.S.
        • Smith T.J.
        • Borden E.C.
        • Blum R.H.
        Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684.
        J Clin Oncol. 1996 Jan; 14: 7-17
        • Eggermont A.M.
        • Suciu S.
        • Santinami M.
        • Testori A.
        • Kruit W.H.
        • Marsden J.
        • et al.
        Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial.
        Lancet. 2008; 372: 117-126
        • Wheatley K.
        • Ives N.
        • Hancock B.
        • Gore M.
        • Eggermont A.
        • Suciu S.
        Does adjuvant interferon-alpha for high-risk melanoma provide a worthwhile benefit? A meta-analysis of the randomised trials.
        Cancer Treat Rev. 2003; 29: 241-252
        • Mocellin S.
        • Pasquali S.
        • Rossi C.R.
        • Nitti D.
        Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis.
        J Natl Cancer Inst. 2010; 102: 493-501
        • Suciu S.
        • Ives N.
        • Eggermont A.M.
        • Kirwood J.M.
        • Lorigan P.
        • Markovic S.
        • et al.
        Predictive importance of ulceration on the efficacy of adjuvant interferon-a (IFN): an individual patient data (IPD) meta-analysis of 15 randomized trials in more than 7,500 melanoma patients (pts).
        J Clin Oncol. 2014; 32 (abstract 9067)
        • Garbe C.
        • Peris K.
        • Hauschild A.
        • Saiag P.
        • Middleton M.
        • Bastholt L.
        • et al.
        Diagnosis and treatment of melanoma. European consensus-based interdisciplinary guideline – update 2016.
        Eur J Cancer. 2016; 63: 201-217
        • Hodi F.S.
        • O'Day S.J.
        • McDermott D.F.
        • Weber R.W.
        • Sosman J.A.
        • Haanen J.B.
        • et al.
        Improved survival with ipilimumab in patients with metastatic melanoma.
        N Engl J Med. 2010; 363: 711-723
        • Robert C.
        • Thomas L.
        • Bondarenko I.
        • O'Day S.
        • Weber J.
        • Garbe C.
        • et al.
        Ipilimumab plus dacarbazine for previously untreated metastatic melanoma.
        N Engl J Med. 2011; 364: 2517-2526
        • Wolchok J.D.
        • Neyns B.
        • Linette G.
        • Negrier S.
        • Lutzky J.
        • Thomas L.
        • et al.
        Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study.
        Lancet Oncol. 2010; 11: 155-164
        • Ascierto P.A.
        • Del Vecchio M.
        • Robert C.
        • Mackiewicz A.
        • Chiarion-Sileni V.
        • Arance Fernandez M.
        • et al.
        Overall survival and safety results from a phase 3 trial of ipilimumab at 3 mg/kg vs. 10 mg/kg in patients with metastatic melanoma.
        Ann Oncol. 2016; 27 (abstract1106O)
        • Eggermont A.M.
        • Chiarion-Sileni V.
        • Grob J.J.
        • Dummer R.
        • Wolchok J.D.
        • Schmidt H.
        • 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 May; 16: 522-530
        • Eggermont A.M.
        • Chiarion-Sileni V.
        • Grob J.J.
        • Dummer R.
        • Wolchok J.D.
        • Schmidt H.
        • et al.
        Prolonged survival with Ipilimumab as adjuvant in stage III melanoma.
        N Engl J Med. 2016;Oct 7;
        • Coens S.
        • Suciu S.
        • Chiarion-Sileni V.
        • Grob J.J.
        • Dummer R.
        • Wolchok J.D.
        • et al.
        Phase III trial (EORTC 18071/CA184–029) of post-operative adjuvant ipilimumab compared to placebo in patients with resected stage III cutaneous melanoma: Health Related Quality of Life (HRQoL) results.
        Lancet Oncol. 2016; ([in press])
        • Leiter U.
        • Stadler R.
        • Mauch C.
        • Hohenberger W.
        • Brockmeyer N.
        • Berking C.
        • et al.
        Complete lymph node dissection versus no dissection in patients with sentinel lymph node biopsy positive melanoma (DeCOG-SLT): a multicentre, randomised, phase 3 trial.
        Lancet Oncol. 2016 Jun; 17: 757-767
        • Eggermont A.M.
        • Suciu S.
        • MacKie R.
        • Ruka W.
        • Testori A.
        • Kruit W.
        • et al.
        Post-surgery adjuvant therapy with intermediate doses of interferon alfa 2b versus observation in patients with stage IIb/III melanoma (EORTC 18952): randomised controlled trial.
        Lancet. 2005; 366: 1189-1196
        • Eggermont A.M.
        • Suciu S.
        • Rutkowski P.
        • Kruit W.H.
        • Punt C.J.
        • Dummer R.
        • et al.
        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 Cancer. 2016 Mar; 55: 111-121
        • Eggermont A.M.
        • Suciu S.
        • Testori A.
        • Santinami M.
        • Kruit W.H.
        • Marsden J.
        • et al.
        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
        • Eggermont A.M.
        • Suciu S.
        • Testori A.
        • Kruit W.H.
        • Marsden J.
        • Punt C.J.
        • et al.
        Ulceration and stage are predictive of interferon efficacy in melanoma: results of the phase III adjuvant trials EORTC 18952 and EORTC 18991.
        Eur J Cancer. 2012; 48: 218-225