Adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): a randomised, double-blind, placebo-controlled, phase 2 trial

Nivolumab and ipilimumab, alone or in combination, are widely used immunotherapeutic treatment options for patients with advanced—ie, unresectable or metastatic—melanoma. This criterion, however, excludes patients with stage IV melanoma with no evidence of disease. We therefore aimed to evaluate the...

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Published in:The Lancet (British edition) 2020-05, Vol.395 (10236), p.1558-1568
Main Authors: Zimmer, Lisa, Livingstone, Elisabeth, Hassel, Jessica C, Fluck, Michael, Eigentler, Thomas, Loquai, Carmen, Haferkamp, Sebastian, Gutzmer, Ralf, Meier, Friedegund, Mohr, Peter, Hauschild, Axel, Schilling, Bastian, Menzer, Christian, Kieker, Felix, Dippel, Edgar, Rösch, Alexander, Simon, Jan-Christoph, Conrad, Beate, Körner, Silvia, Windemuth-Kieselbach, Christine, Schwarz, Leonora, Garbe, Claus, Becker, Jürgen C, Schadendorf, Dirk, Berking, Carola, Herbst, Rudolf A, Martens, Uwe M, Sell, Sabine, Stadler, Rudolf, Terheyden, Patrick, Utikal, Jochen
Format: Article
Language:English
Subjects:
Adjuvants
Adjuvants, Immunologic - administration & dosage
Adjuvants, Immunologic - adverse effects
Aged
Antineoplastic Agents, Immunological - administration & dosage
Antineoplastic Agents, Immunological - adverse effects
Antineoplastic Combined Chemotherapy Protocols - administration & dosage
Antineoplastic Combined Chemotherapy Protocols - adverse effects
Apoptosis
Clinical trials
Cytotoxicity
Double-Blind Method
Double-blind studies
Drug Administration Schedule
Health care facilities
Health services
Humans
Immune checkpoint
Immunosuppressive agents
Immunotherapy
Interactive systems
Intravenous administration
Ipilimumab - administration & dosage
Ipilimumab - adverse effects
Matching
Medical treatment
Melanoma
Melanoma - drug therapy
Metastases
Metastasis
Middle Aged
Monoclonal antibodies
Mucosa
Neoplasm Staging
Nivolumab - administration & dosage
Nivolumab - adverse effects
On-line systems
Patients
Progression-Free Survival
Radiation therapy
Randomization
Regulatory approval
Skin Neoplasms - drug therapy
Surgery
Survival
Targeted cancer therapy
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Summary:Nivolumab and ipilimumab, alone or in combination, are widely used immunotherapeutic treatment options for patients with advanced—ie, unresectable or metastatic—melanoma. This criterion, however, excludes patients with stage IV melanoma with no evidence of disease. We therefore aimed to evaluate the safety and efficacy of adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus a placebo in this patient population. We did a randomised, double-blind, placebo-controlled, phase 2 trial in 20 German academic medical centres. Eligible patients were aged 18–80 years with stage IV melanoma with no evidence of disease after surgery or radiotherapy. Key exclusion criteria included uveal or mucosal melanoma, previous therapy with checkpoint inhibitors, and any previous immunosuppressive therapy within the 30 days before study drug administration. Eligible patients were randomly assigned (1:1:1), using a central, interactive, online system, to the nivolumab plus ipilimumab group (1 mg/kg of intravenous nivolumab every 3 weeks plus 3 mg/kg of intravenous ipilimumab every 3 weeks for four doses, followed by 3 mg/kg of nivolumab every 2 weeks), nivolumab monotherapy group (3 mg/kg of intravenous nivolumab every 2 weeks plus ipilimumab-matching placebo during weeks 1–12), or double-matching placebo group. The primary endpoint was the recurrence-free survival in the intention-to-treat population. The results presented in this report reflect the prespecified interim analysis of recurrence-free survival after 90 events had been reported. This study is registered with ClinicalTrials.gov, NCT02523313, and is ongoing. Between Sept 2, 2015, and Nov 20, 2018, 167 patients were randomly assigned to receive nivolumab plus ipilimumab (n=56), nivolumab (n=59), or placebo (n=52). As of July 2, 2019, at a median follow-up of 28·4 months (IQR 17·7–36·8), median recurrence-free survival was not reached in the nivolumab plus ipilimumab group, whereas median recurrence-free survival was 12·4 months (95% CI 5·3–33·3) in the nivolumab group and 6·4 months (3·3–9·6) in the placebo group. The hazard ratio for recurrence for the nivolumab plus ipilimumab group versus placebo group was 0·23 (97·5% CI 0·12–0·45; p
ISSN:0140-6736
1474-547X
DOI:10.1016/S0140-6736(20)30417-7