Paolo A Ascierto1, Georgina V Long2,3,4, Caroline Robert5, Benjamin Brady6, Caroline Dutriaux7, Anna Maria Di Giacomo8, Laurent Mortier9, Jessica C Hassel10, Piotr Rutkowski11, Catriona McNeil12,13, Ewa Kalinka-Warzocha14, Kerry J Savage15, Micaela M Hernberg16, Celeste Lebbé17, Julie Charles18,19, Catalin Mihalcioiu20, Vanna Chiarion-Sileni21, Cornelia Mauch22, Francesco Cognetti23, Lars Ny24, Ana Arance25, Inge Marie Svane26,27, Dirk Schadendorf28,29, Helen Gogas30, Abdel Saci31, Joel Jiang31, Jasmine Rizzo32, Victoria Atkinson33,34. 1. Melanoma, Cancer Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy. 2. Melanoma Institute Australia, Sydney, New South Wales, Australia. 3. Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia. 4. Department of Medical Oncology, Northern Sydney Cancer Centre, Royal North Shore Hospital, Sydney, New South Wales, Australia. 5. Department of Medicine, Institute Gustave Roussy, Villejuif, France. 6. Medical Oncology and Haematology, Cabrini Health, Melbourne, Victoria, Australia. 7. Dermatology Service, University Hospital of Bordeaux, Bordeaux, France. 8. UOC Oncological Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy. 9. Clinique de Dermatologie, Unité d'Onco-Dermatologie, Institut National de la Santé et de la Recherche Médicale (INSERM) U1189, Centre Hospitalier Régional Universitaire de Lille, Lille, France. 10. Department of Dermatology, University Hospital Heidelberg and National Center for Tumor Diseases, Heidelberg, Germany. 11. Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Institute-Oncology Center, Warsaw, Poland. 12. Chris O'Brien Lifehouse, Melanoma Institute Australia, Camperdown, New South Wales. 13. Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia. 14. Polish Mother's Memorial Hospital Research Institute, Lodz, Poland. 15. Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, British Columbia, Canada. 16. Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland. 17. Assistance Publique-Hôpitaux de Paris Dermatology and Centre d'Investigation Clinique, University Paris Diderot INSERM U976, Saint Louis Hospital, Paris, France. 18. Institute for Advanced Biosciences, Université Grenoble Alpes/INSERM U1209/CNRS UMR 5309 Joint Research Center, Grenoble, France. 19. Dermatology Department, Grenoble Alpes University Hospital, Grenoble, France. 20. Department of Oncology, McGill University, Montreal, Quebec, Canada. 21. Melanoma Cancer Unit, Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico, Padua, Italy. 22. Department of Dermatology, University Hospital Cologne, Cologne, Germany. 23. Division of Oncology, Regina Elena Institute, Rome, Italy. 24. Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden. 25. Hospital Clinic and Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain. 26. Center for Cancer Immune Therapy, Herlev Hospital, Herlev, Denmark. 27. Department of Oncology, Copenhagen University Hospital, Herlev, Denmark. 28. Department of Dermatology, University Hospital Essen, Essen, Germany. 29. German Cancer Consortium, Heidelberg, Germany. 30. First Department of Medicine, Laiko General Hospital, National and Kapodistrian University of Athens School of Medicine, Athens, Greece. 31. Global Biometric Sciences, Bristol-Myers Squibb, Princeton, New Jersey. 32. Oncology Clinical Development, Bristol-Myers Squibb, Princeton, New Jersey. 33. Princess Alexandra Hospital, University of Queensland, Woolloongabba, Queensland, Australia. 34. Gallipoli Medical Research Foundation, Greenslopes Private Hospital, Greenslopes, Queensland, Australia.
Abstract
Importance: This analysis provides long-term follow-up in patients with BRAF wild-type advanced melanoma receiving first-line therapy based on anti-programmed cell death 1 receptor inhibitors. Objective: To compare the 3-year survival with nivolumab vs that with dacarbazine in patients with previously untreated BRAF wild-type advanced melanoma. Design, Setting, and Participants: This follow-up of a randomized phase 3 trial analyzed 3-year overall survival data from the randomized, controlled, double-blind CheckMate 066 phase 3 clinical trial. For this ongoing, multicenter academic institution trial, patients were enrolled from January 2013 through February 2014. Eligible patients were 18 years or older with confirmed unresectable previously untreated stage III or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 but without a BRAF mutation. Interventions: Patients were treated until progression or unacceptable toxic events with nivolumab (3 mg/kg every 2 weeks plus dacarbazine-matched placebo every 3 weeks) or dacarbazine (1000 mg/m2 every 3 weeks plus nivolumab-matched placebo every 2 weeks). Main Outcome and Measure: Overall survival. Results: At minimum follow-ups of 38.4 months among 210 participants in the nivolumab group (median age, 64 years [range, 18-86 years]; 57.6% male) and 38.5 months among 208 participants in the dacarbazine group (median age, 66 years [range, 25-87 years]; 60.1% male), 3-year overall survival rates were 51.2% (95% CI, 44.1%-57.9%) and 21.6% (95% CI, 16.1%-27.6%), respectively. The median overall survival was 37.5 months (95% CI, 25.5 months-not reached) in the nivolumab group and 11.2 months (95% CI, 9.6-13.0 months) in the dacarbazine group (hazard ratio, 0.46; 95% CI, 0.36-0.59; P < .001). Complete and partial responses, respectively, were reported for 19.0% (40 of 210) and 23.8% (50 of 210) of patients in the nivolumab group compared with 1.4% (3 of 208) and 13.0% (27 of 208) of patients in the dacarbazine group. Additional analyses were performed on outcomes with subsequent therapies. Treatment-related grade 3/4 adverse events occurred in 15.0% (31 of 206) of nivolumab-treated patients and in 17.6% (36 of 205) of dacarbazine-treated patients. There were no deaths due to study drug toxic effects. Conclusions and Relevance: Nivolumab led to improved 3-year overall survival vs dacarbazine in patients with previously untreated BRAF wild-type advanced melanoma. Trial Registration: ClinicalTrials.gov identifier: NCT01721772.
RCT Entities:
Importance: This analysis provides long-term follow-up in patients with BRAF wild-type advanced melanoma receiving first-line therapy based on anti-programmed cell death 1 receptor inhibitors. Objective: To compare the 3-year survival with nivolumab vs that with dacarbazine in patients with previously untreated BRAF wild-type advanced melanoma. Design, Setting, and Participants: This follow-up of a randomized phase 3 trial analyzed 3-year overall survival data from the randomized, controlled, double-blind CheckMate 066 phase 3 clinical trial. For this ongoing, multicenter academic institution trial, patients were enrolled from January 2013 through February 2014. Eligible patients were 18 years or older with confirmed unresectable previously untreated stage III or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 but without a BRAF mutation. Interventions: Patients were treated until progression or unacceptable toxic events with nivolumab (3 mg/kg every 2 weeks plus dacarbazine-matched placebo every 3 weeks) or dacarbazine (1000 mg/m2 every 3 weeks plus nivolumab-matched placebo every 2 weeks). Main Outcome and Measure: Overall survival. Results: At minimum follow-ups of 38.4 months among 210 participants in the nivolumab group (median age, 64 years [range, 18-86 years]; 57.6% male) and 38.5 months among 208 participants in the dacarbazine group (median age, 66 years [range, 25-87 years]; 60.1% male), 3-year overall survival rates were 51.2% (95% CI, 44.1%-57.9%) and 21.6% (95% CI, 16.1%-27.6%), respectively. The median overall survival was 37.5 months (95% CI, 25.5 months-not reached) in the nivolumab group and 11.2 months (95% CI, 9.6-13.0 months) in the dacarbazine group (hazard ratio, 0.46; 95% CI, 0.36-0.59; P < .001). Complete and partial responses, respectively, were reported for 19.0% (40 of 210) and 23.8% (50 of 210) of patients in the nivolumab group compared with 1.4% (3 of 208) and 13.0% (27 of 208) of patients in the dacarbazine group. Additional analyses were performed on outcomes with subsequent therapies. Treatment-related grade 3/4 adverse events occurred in 15.0% (31 of 206) of nivolumab-treated patients and in 17.6% (36 of 205) of dacarbazine-treated patients. There were no deaths due to study drug toxic effects. Conclusions and Relevance: Nivolumab led to improved 3-year overall survival vs dacarbazine in patients with previously untreated BRAF wild-type advanced melanoma. Trial Registration: ClinicalTrials.gov identifier: NCT01721772.
Authors: Caroline Robert; Georgina V Long; Benjamin Brady; Caroline Dutriaux; Michele Maio; Laurent Mortier; Jessica C Hassel; Piotr Rutkowski; Catriona McNeil; Ewa Kalinka-Warzocha; Kerry J Savage; Micaela M Hernberg; Celeste Lebbé; Julie Charles; Catalin Mihalcioiu; Vanna Chiarion-Sileni; Cornelia Mauch; Francesco Cognetti; Ana Arance; Henrik Schmidt; Dirk Schadendorf; Helen Gogas; Lotta Lundgren-Eriksson; Christine Horak; Brian Sharkey; Ian M Waxman; Victoria Atkinson; Paolo A Ascierto Journal: N Engl J Med Date: 2014-11-16 Impact factor: 91.245
Authors: F Stephen Hodi; Jason Chesney; Anna C Pavlick; Caroline Robert; Kenneth F Grossmann; David F McDermott; Gerald P Linette; Nicolas Meyer; Jeffrey K Giguere; Sanjiv S Agarwala; Montaser Shaheen; Marc S Ernstoff; David R Minor; April K Salama; Matthew H Taylor; Patrick A Ott; Christine Horak; Paul Gagnier; Joel Jiang; Jedd D Wolchok; Michael A Postow Journal: Lancet Oncol Date: 2016-09-09 Impact factor: 41.316
Authors: Caroline Robert; Jacob Schachter; Georgina V Long; Ana Arance; Jean Jacques Grob; Laurent Mortier; Adil Daud; Matteo S Carlino; Catriona McNeil; Michal Lotem; James Larkin; Paul Lorigan; Bart Neyns; Christian U Blank; Omid Hamid; Christine Mateus; Ronnie Shapira-Frommer; Michele Kosh; Honghong Zhou; Nageatte Ibrahim; Scot Ebbinghaus; Antoni Ribas Journal: N Engl J Med Date: 2015-04-19 Impact factor: 91.245
Authors: James Larkin; Vanna Chiarion-Sileni; Rene Gonzalez; Jean Jacques Grob; C Lance Cowey; Christopher D Lao; Dirk Schadendorf; Reinhard Dummer; Michael Smylie; Piotr Rutkowski; Pier F Ferrucci; Andrew Hill; John Wagstaff; Matteo S Carlino; John B Haanen; Michele Maio; Ivan Marquez-Rodas; Grant A McArthur; Paolo A Ascierto; Georgina V Long; Margaret K Callahan; Michael A Postow; Kenneth Grossmann; Mario Sznol; Brigitte Dreno; Lars Bastholt; Arvin Yang; Linda M Rollin; Christine Horak; F Stephen Hodi; Jedd D Wolchok Journal: N Engl J Med Date: 2015-05-31 Impact factor: 91.245
Authors: Jeffrey S Weber; Sandra P D'Angelo; David Minor; F Stephen Hodi; Ralf Gutzmer; Bart Neyns; Christoph Hoeller; Nikhil I Khushalani; Wilson H Miller; Christopher D Lao; Gerald P Linette; Luc Thomas; Paul Lorigan; Kenneth F Grossmann; Jessica C Hassel; Michele Maio; Mario Sznol; Paolo A Ascierto; Peter Mohr; Bartosz Chmielowski; Alan Bryce; Inge M Svane; Jean-Jacques Grob; Angela M Krackhardt; Christine Horak; Alexandre Lambert; Arvin S Yang; James Larkin Journal: Lancet Oncol Date: 2015-03-18 Impact factor: 41.316
Authors: Fred R Hirsch; Abigail McElhinny; Dave Stanforth; James Ranger-Moore; Malinka Jansson; Karina Kulangara; William Richardson; Penny Towne; Debra Hanks; Bharathi Vennapusa; Amita Mistry; Rasika Kalamegham; Steve Averbuch; James Novotny; Eric Rubin; Kenneth Emancipator; Ian McCaffery; J Andrew Williams; Jill Walker; John Longshore; Ming Sound Tsao; Keith M Kerr Journal: J Thorac Oncol Date: 2016-11-29 Impact factor: 15.609
Authors: E A Eisenhauer; P Therasse; J Bogaerts; L H Schwartz; D Sargent; R Ford; J Dancey; S Arbuck; S Gwyther; M Mooney; L Rubinstein; L Shankar; L Dodd; R Kaplan; D Lacombe; J Verweij Journal: Eur J Cancer Date: 2009-01 Impact factor: 9.162
Authors: Jedd D Wolchok; Vanna Chiarion-Sileni; Rene Gonzalez; Piotr Rutkowski; Jean-Jacques Grob; C Lance Cowey; Christopher D Lao; John Wagstaff; Dirk Schadendorf; Pier F Ferrucci; Michael Smylie; Reinhard Dummer; Andrew Hill; David Hogg; John Haanen; Matteo S Carlino; Oliver Bechter; Michele Maio; Ivan Marquez-Rodas; Massimo Guidoboni; Grant McArthur; Celeste Lebbé; Paolo A Ascierto; Georgina V Long; Jonathan Cebon; Jeffrey Sosman; Michael A Postow; Margaret K Callahan; Dana Walker; Linda Rollin; Rafia Bhore; F Stephen Hodi; James Larkin Journal: N Engl J Med Date: 2017-09-11 Impact factor: 91.245
Authors: J D Wolchok; J S Weber; M Maio; B Neyns; K Harmankaya; K Chin; L Cykowski; V de Pril; R Humphrey; C Lebbé Journal: Ann Oncol Date: 2013-05-10 Impact factor: 32.976
Authors: I Landego; D Hewitt; I Hibbert; D Dhaliwal; W Pieterse; D Grenier; R Wong; J Johnston; V Banerji Journal: Curr Oncol Date: 2020-06-01 Impact factor: 3.677