Jeffrey Weber1, Mario Mandala1, Michele Del Vecchio1, Helen J Gogas1, Ana M Arance1, C Lance Cowey1, Stéphane Dalle1, Michael Schenker1, Vanna Chiarion-Sileni1, Ivan Marquez-Rodas1, Jean-Jacques Grob1, Marcus O Butler1, Mark R Middleton1, Michele Maio1, Victoria Atkinson1, Paola Queirolo1, Rene Gonzalez1, Ragini R Kudchadkar1, Michael Smylie1, Nicolas Meyer1, Laurent Mortier1, Michael B Atkins1, Georgina V Long1, Shailender Bhatia1, Celeste Lebbé1, Piotr Rutkowski1, Kenji Yokota1, Naoya Yamazaki1, Tae M Kim1, Veerle de Pril1, Javier Sabater1, Anila Qureshi1, James Larkin1, Paolo A Ascierto1. 1. From New York University Perlmutter Cancer Center, New York (J.W.); Papa Giovanni XXIII Cancer Center Hospital, Bergamo (M. Mandala), Medical Oncology, National Cancer Institute, Milan (M.D.V.), Oncology Institute of Veneto Istituti di Ricovero e Cura a Carattere Scientifico, Padua (V.C.-S.), Center for Immuno-Oncology, University Hospital of Siena, Istituto Toscano Tumori, Siena (M. Maio), Ospedale Policlinico San Martino, Genoa (P.Q.), and Istituto Nazionale Tumori Fondazione Pascale, Naples (P.A.A.) - all in Italy; National and Kapodistrian University of Athens, Athens (H.J.G.); Hospital Clinic de Barcelona, Barcelona (A.M.A.), and General University Hospital Gregorio Marañón, Madrid (I.M.-R.) - both in Spain; Texas Oncology-Baylor Cancer Center, Dallas (C.L.C.); Hospices Civils de Lyon, Pierre Bénite (S.D.), Aix-Marseille University, Hospital de la Timone, Marseille (J.-J.G.), Institut Universitaire du Cancer de Toulouse and Centre Hospitalier Universitaire (CHU), Toulouse (N.M.), Université Lille, INSERM Unité 1189, CHU Lille, Lille (L.M.), and Assistance Publique-Hôpitaux de Paris, Dermatology and Centres d'Investigation Clinique, INSERM Unité 976, Hôpital Saint Louis, Université Paris Diderot, Paris (C.L.) - all in France; Oncology Center Sf. Nectarie, Craiova, Romania (M. Schenker); Princess Margaret Cancer Centre, University of Toronto, Toronto (M.O.B.), and Cross Cancer Institute, Edmonton, AB (M. Smylie) - both in Canada; the Department of Oncology, University of Oxford, Oxford (M.R.M.), and Royal Marsden NHS Foundation Trust, London (J.L.) - both in the United Kingdom; Gallipoli Medical Research Foundation and University of Queensland, Queensland, VIC (V.A.), and Melanoma Institute Australia, University of Sydney, and Royal North Shore and Mater Hospitals, Sydney (G.V.L.) - all in Australia; University of Colorado, Denver (R.G.); Winship Cancer Institute, Emory University School of Medicine, Atlanta (R.R.K.); Georgetown-Lombardi Comprehensive Cancer Center, Washington DC (M.B.A.); University of Washington, Seattle (S.B.); Maria Sklodowska-Curie Institute-Oncology Center, Warsaw, Poland (P.R.); Nagoya University Graduate School of Medicine, Nagoya (K.Y.), and the National Cancer Center Hospital, Tokyo (N.Y.) - both in Japan; Seoul National University Hospital, Seoul, South Korea (T.M.K.); and Bristol-Myers Squibb, Princeton, NJ (V.P, J.S., A.Q.).
Abstract
BACKGROUND:Nivolumab and ipilimumab are immune checkpoint inhibitors that have been approved for the treatment of advanced melanoma. In the United States, ipilimumab has also been approved as adjuvant therapy for melanoma on the basis of recurrence-free and overall survival rates that were higher than those with placebo in a phase 3 trial. We wanted to determine the efficacy of nivolumab versus ipilimumab for adjuvant therapy in patients with resected advanced melanoma. METHODS: In this randomized, double-blind, phase 3 trial, we randomly assigned 906 patients (≥15 years of age) who were undergoing complete resection of stage IIIB, IIIC, or IV melanoma to receive anintravenous infusion of either nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks (453 patients) or ipilimumab at a dose of 10 mg per kilogram every 3 weeks for four doses and then every 12 weeks (453 patients). The patients were treated for a period of up to 1 year or until disease recurrence, a report of unacceptable toxic effects, or withdrawal of consent. The primary end point was recurrence-free survival in the intention-to-treat population. RESULTS: At a minimum follow-up of 18 months, the 12-month rate of recurrence-free survival was 70.5% (95% confidence interval [CI], 66.1 to 74.5) in the nivolumab group and 60.8% (95% CI, 56.0 to 65.2) in the ipilimumab group (hazard ratio for disease recurrence or death, 0.65; 97.56% CI, 0.51 to 0.83; P<0.001). Treatment-related grade 3 or 4 adverse events were reported in 14.4% of the patients in the nivolumab group and in 45.9% of those in the ipilimumab group; treatment was discontinued because of any adverse event in 9.7% and 42.6% of the patients, respectively. Two deaths (0.4%) related to toxic effects were reported in the ipilimumab group more than 100 days after treatment. CONCLUSIONS: Among patients undergoing resection of stage IIIB, IIIC, or IV melanoma, adjuvant therapy withnivolumab resulted in significantly longer recurrence-free survival and a lower rate of grade 3 or 4 adverse events than adjuvant therapy with ipilimumab. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 238 ClinicalTrials.gov number, NCT02388906 ; Eudra-CT number, 2014-002351-26 .).
RCT Entities:
BACKGROUND:Nivolumab and ipilimumab are immune checkpoint inhibitors that have been approved for the treatment of advanced melanoma. In the United States, ipilimumab has also been approved as adjuvant therapy for melanoma on the basis of recurrence-free and overall survival rates that were higher than those with placebo in a phase 3 trial. We wanted to determine the efficacy of nivolumab versus ipilimumab for adjuvant therapy in patients with resected advanced melanoma. METHODS: In this randomized, double-blind, phase 3 trial, we randomly assigned 906 patients (≥15 years of age) who were undergoing complete resection of stage IIIB, IIIC, or IV melanoma to receive an intravenous infusion of either nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks (453 patients) or ipilimumab at a dose of 10 mg per kilogram every 3 weeks for four doses and then every 12 weeks (453 patients). The patients were treated for a period of up to 1 year or until disease recurrence, a report of unacceptable toxic effects, or withdrawal of consent. The primary end point was recurrence-free survival in the intention-to-treat population. RESULTS: At a minimum follow-up of 18 months, the 12-month rate of recurrence-free survival was 70.5% (95% confidence interval [CI], 66.1 to 74.5) in the nivolumab group and 60.8% (95% CI, 56.0 to 65.2) in the ipilimumab group (hazard ratio for disease recurrence or death, 0.65; 97.56% CI, 0.51 to 0.83; P<0.001). Treatment-related grade 3 or 4 adverse events were reported in 14.4% of the patients in the nivolumab group and in 45.9% of those in the ipilimumab group; treatment was discontinued because of any adverse event in 9.7% and 42.6% of the patients, respectively. Two deaths (0.4%) related to toxic effects were reported in the ipilimumab group more than 100 days after treatment. CONCLUSIONS: Among patients undergoing resection of stage IIIB, IIIC, or IV melanoma, adjuvant therapy with nivolumab resulted in significantly longer recurrence-free survival and a lower rate of grade 3 or 4 adverse events than adjuvant therapy with ipilimumab. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 238 ClinicalTrials.gov number, NCT02388906 ; Eudra-CT number, 2014-002351-26 .).
Authors: Robyn D Gartrell; Douglas K Marks; Emanuelle M Rizk; Margaret Bogardus; Camille L Gérard; Luke W Barker; Yichun Fu; Camden L Esancy; Gen Li; Jiayi Ji; Shumin Rui; Marc S Ernstoff; Bret Taback; Sarabjot Pabla; Rui Chang; Sandra J Lee; John J Krolewski; Carl Morrison; Basil A Horst; Yvonne M Saenger Journal: Clin Cancer Res Date: 2019-01-15 Impact factor: 12.531
Authors: Jacob S Ankeny; Brian Labadie; Jason Luke; Eddy Hsueh; Jane Messina; Jonathan S Zager Journal: Clin Exp Metastasis Date: 2018-05-02 Impact factor: 5.150
Authors: Mark R Albertini; Richard K Yang; Erik A Ranheim; Jacquelyn A Hank; Cindy L Zuleger; Sharon Weber; Heather Neuman; Greg Hartig; Tracey Weigel; David Mahvi; Mary Beth Henry; Renae Quale; Thomas McFarland; Jacek Gan; Lakeesha Carmichael; KyungMann Kim; Hans Loibner; Stephen D Gillies; Paul M Sondel Journal: Cancer Immunol Immunother Date: 2018-08-03 Impact factor: 6.968
Authors: F C Wright; L H Souter; S Kellett; A Easson; C Murray; J Toye; D McCready; C Nessim; D Ghazarian; N J Look Hong; S Johnson; D P Goldstein; T Petrella Journal: Curr Oncol Date: 2019-08-01 Impact factor: 3.677