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N Engl J Med. 2018 May 10;378(19):1789-1801. doi: 10.1056/NEJMoa1802357. Epub 2018 Apr 15.

Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma.

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From the Gustave Roussy Cancer Campus Grand Paris and University Paris-Saclay, Villejuif (A.M.M.E., C.R.), Hospices Civils de Lyon Cancer Institute, Cancer Research Center of Lyon, Lyon University, Lyon (S.D.), and Aix-Marseille University, Hôpital de la Timone, Assistance Publique-Hôpitaux de Marseille, Marseille (J.-J.G.) - all in France; Netherlands Cancer Institute-Antoni van Leeuwenhoek (C.U.B., A.C.J.A.) and VU University Medical Center (A.J.M.E.), Amsterdam, and Radboud University Medical Center Nijmegen, Nijmegen (R.K.) - all in the Netherlands; Azienda Ospedaliera Papa Giovanni XXIII, Bergamo (M. Mandala), Istituto Nazionale Tumori Istituto di Ricovero e Cura a Carattere Scientifico Fondazione G. Pascale, Naples (P.A.A.), and Universita Degli Studi Di Siena-Policlinico le Scotte, Siena (M. Maio) - all in Italy; Melanoma Institute Australia, the University of Sydney, and Mater and Royal North Shore Hospitals (G.V.L.) and Westmead and Blacktown Hospitals, Melanoma Institute Australia and the University of Sydney (M.S.C.), Sydney, Princess Alexandra Hospital, University of Queensland, Brisbane (V.A.), Alfred Hospital (A.H.) and Peter MacCallum Cancer Centre (S. Sandhu), Melbourne, VIC, and Fiona Stanley Hospital-University of Western Australia-Edith Cowan University Perth, Perth (A.K.) - all in Australia; Cancer Research Center, Moscow (M.L.); Royal Marsden Hospital, London (J.L.); Hospital Clinic Universitari de Barcelona, Barcelona (S.P.); Maria Sklodowska-Curie Institute-Oncology Center, Warsaw, Poland (P.R.); University Hospital Essen, Essen and German Cancer Consortium, Heidelberg (D.S.), and the Skin Cancer Center, Department of Dermatology, Hannover Medical School, Hannover (R.G.) - all in Germany; Washington University School of Medicine, St. Louis (L.H.-A.); Centre Hospitalier de l'Université de Montréal (CHUM), Centre de Recherche du CHUM, Montreal (R.J.); Christie NHS Foundation Trust, Manchester, United Kingdom (P.L.); Merck, Kenilworth, NJ (N.I.); and the European Organization for the Research and Treatment of Cancer Headquarters, Brussels (S.M., S. Suciu).



The programmed death 1 (PD-1) inhibitor pembrolizumab has been found to prolong progression-free and overall survival among patients with advanced melanoma. We conducted a phase 3 double-blind trial to evaluate pembrolizumab as adjuvant therapy in patients with resected, high-risk stage III melanoma.


Patients with completely resected stage III melanoma were randomly assigned (with stratification according to cancer stage and geographic region) to receive 200 mg of pembrolizumab (514 patients) or placebo (505 patients) intravenously every 3 weeks for a total of 18 doses (approximately 1 year) or until disease recurrence or unacceptable toxic effects occurred. Recurrence-free survival in the overall intention-to-treat population and in the subgroup of patients with cancer that was positive for the PD-1 ligand (PD-L1) were the primary end points. Safety was also evaluated.


At a median follow-up of 15 months, pembrolizumab was associated with significantly longer recurrence-free survival than placebo in the overall intention-to-treat population (1-year rate of recurrence-free survival, 75.4% [95% confidence interval {CI}, 71.3 to 78.9] vs. 61.0% [95% CI, 56.5 to 65.1]; hazard ratio for recurrence or death, 0.57; 98.4% CI, 0.43 to 0.74; P<0.001) and in the subgroup of 853 patients with PD-L1-positive tumors (1-year rate of recurrence-free survival, 77.1% [95% CI, 72.7 to 80.9] in the pembrolizumab group and 62.6% [95% CI, 57.7 to 67.0] in the placebo group; hazard ratio, 0.54; 95% CI, 0.42 to 0.69; P<0.001). Adverse events of grades 3 to 5 that were related to the trial regimen were reported in 14.7% of the patients in the pembrolizumab group and in 3.4% of patients in the placebo group. There was one treatment-related death due to myositis in the pembrolizumab group.


As adjuvant therapy for high-risk stage III melanoma, 200 mg of pembrolizumab administered every 3 weeks for up to 1 year resulted in significantly longer recurrence-free survival than placebo, with no new toxic effects identified. (Funded by Merck; number, NCT02362594 ; EudraCT number, 2014-004944-37 .).

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