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    Original Investigation
    January 2, 2020

    Association Between Immune-Related Adverse Events and Recurrence-Free Survival Among Patients With Stage III Melanoma Randomized to Receive Pembrolizumab or Placebo: A Secondary Analysis of a Randomized Clinical Trial

    Author Affiliations
    • 1Gustave Roussy Cancer Campus Grand Paris, Universite Paris-Saclay, Villejuif, France
    • 2European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium
    • 3Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands
    • 4Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy
    • 5Melanoma Institute Australia, University of Sydney and Mater and Royal North Shore Hospitals, Sydney, New South Wales, Australia
    • 6Princess Alexandra Hospital, University of Queensland, Brisbane, Queensland, Australia
    • 7Hospices Civils de Lyon Cancer Institute, Lyon University, Lyon, France
    • 8Alfred Hospital, Melbourne, Victoria, Australia
    • 9Fiona Stanley Hospital, University of Western Australia, Perth, Washington, Australia
    • 10Westmead and Blacktown Hospitals, Melanoma Institute Australia and the University of Sydney, New South Wales, Australia
    • 11Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
    • 12Royal Marsden Hospital, London, United Kingdom
    • 13Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain
    • 14Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Naples, Italy
    • 15Maria Sklodowska-Curie Institute Cancer Centre and Institute of Oncology, Warsaw, Poland
    • 16University Hospital Essen, Essen, Germany
    • 17Germany and German Cancer Consortium of Translational Cancer Research, Heidelberg, Germany
    • 18Radboud University Medical Center Nijmegen, Nijmegen, Netherlands
    • 19Washington University School of Medicine, St Louis, Missouri
    • 20Center for Immuno-Oncology, University Hospital of Siena, Siena, Italy
    • 21Vrije Universiteit Medical Center Amsterdam, Amsterdam, Netherlands
    • 22Hopital de la Timone, Aix-Marseille University, Marseille, France
    • 23Skin Cancer Center, Hannover Medical School, Hannover, Germany
    • 24Centre de Recherche, Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada
    • 25Christie NHS Foundation Trust, Manchester, United Kingdom
    • 26Merck & Co, Kenilworth, New Jersey
    JAMA Oncol. Published online January 2, 2020. doi:10.1001/jamaoncol.2019.5570
    Key Points

    Question  Are immune-related adverse events associated with recurrence-free survival in patients with high-risk stage III melanoma treated with pembrolizumab therapy compared with placebo?

    Findings  In this secondary analysis of a randomized clinical trial of 1019 adults with stage III melanoma, the occurrence of an immune-related adverse event was associated with longer recurrence-free survival among both men and women in the pembrolizumab arm. However, in the placebo arm, this association was not significant.

    Meaning  These findings suggest that the occurrence of an immune-related adverse event is an indicator of pembrolizumab activity in patients with high-risk stage III melanoma.

    Abstract

    Importance  Whether immune-related adverse events (irAEs) indicate drug activity in patients treated with immune checkpoint inhibitors remains unknown.

    Objective  To investigate the association between irAEs and recurrence-free survival (RFS) in the double-blind EORTC 1325/KEYNOTE-054 clinical trial comparing pembrolizumab therapy and placebo for the treatment of patients with high-risk stage III melanoma.

    Design, Setting, and Participants  A total of 1019 adults with stage III melanoma were randomly assigned on a 1:1 ratio to receive treatment with pembrolizumab therapy or placebo. Eligible patients were adults 18 years and older with complete resection of cutaneous melanoma metastatic to lymph nodes, classified with stage IIIA (at least 1 micrometastasis measuring >1 mm in greatest diameter), IIIB, or IIIC (without in-transit metastasis) cancer. Patients were randomized from August 26, 2015, to November 14, 2016. The clinical cutoff for the data set was October 2, 2017. Analyses were then performed on the database, which was locked on November 28, 2017.

    Interventions  Participants were scheduled to receive 200 mg of pembrolizumab or placebo every 3 weeks for a total of 18 doses for approximately 1 year or until disease recurrence, unacceptable toxic effects, major protocol violation, or withdrawal of consent.

    Main Outcomes and Measures  The association between irAEs and RFS was estimated using a Cox model adjusted for sex, age, and AJCC-7 stage, with a time-varying covariate that had a value of 0 before irAE onset and 1 after irAE onset.

    Results  Of 1011 patients who began treatment with pembrolizumab therapy or placebo, 622 (61.5%) were men and 389 (38.5%) were women; 386 patients (38.2%) were aged 50 to 64 years, 377 (37.3%) were younger than 50 years, and 248 (24.5%) were 65 years and older. Consistent with the reported main analysis in the intent-to-treat population, RFS was longer in the pembrolizumab arm compared with the placebo arm (hazard ratio [HR], 0.56; 98.4% CI, 0.43-0.74) among patients who started treatment. The incidence of irAEs was 190 (37.4%) in the pembrolizumab arm (n = 509) and 45 (9.0%) in the placebo arm (n = 502); in each treatment group, the incidence was similar for men and women. The occurrence of an irAE was associated with a longer RFS in the pembrolizumab arm (HR, 0.61; 95% CI, 0.39-0.95; P = .03) in both men and women. However, in the placebo arm, this association was not significant. Compared with the placebo arm, the reduction in the hazard of recurrence or death in the pembrolizumab arm was greater after the onset of an irAE than without or before an irAE (HR, 0.37; 95% CI, 0.24-0.57 vs HR, 0.61; 95% CI, 0.49-0.77, respectively; P = .03).

    Conclusions and Relevance  In this study, the occurrence of an irAE was associated with a longer RFS in the pembrolizumab arm.

    Trial Registrations  ClinicalTrials.gov identifier: NCT02362594; EudraCT identifier: 2014-004944-37

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