Jacob Schachter1, Antoni Ribas2, Georgina V Long3, Ana Arance4, Jean-Jacques Grob5, Laurent Mortier6, Adil Daud7, Matteo S Carlino8, Catriona McNeil9, Michal Lotem10, James Larkin11, Paul Lorigan12, Bart Neyns13, Christian Blank14, Teresa M Petrella15, Omid Hamid16, Honghong Zhou17, Scot Ebbinghaus18, Nageatte Ibrahim18, Caroline Robert19. 1. Division of Oncology, Ella Lemelbaum Institute for Melanoma, Sheba Medical Center, Tel Hashomer, Israel. Electronic address: jacob.schachter@sheba.health.gov.il. 2. Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. 3. Department of Medical Oncology and Translational Research, Melanoma Institute Australia, The University of Sydney, Mater Hospital and Royal North Shore Hospital, Sydney, Australia. 4. Department of Medical Oncology, Hospital Clinic de Barcelona, Barcelona, Spain. 5. Department of Dermatology and Skin Cancer, Aix Marseille University, Hôpital de la Timone, Marseille, France. 6. Department of Dermatology, Université Lille, INSERM U1189, CHU Lille, F-59000, France. 7. Department of Hematology/Oncology, University of California, San Francisco, San Francisco, CA, USA. 8. Department of Medical Oncology, Westmead and Blacktown Hospitals, Melanoma Institute Australia, and The University of Sydney, Sydney, Australia. 9. Department of Medical Oncology, Chris O'Brien Lifehouse, Royal Prince Alfred Hospital, and Melanoma Institute Australia, Camperdown, Australia. 10. Department of Melanoma and Cancer Immunotherapy, Sharett Institute of Oncology, Hadassah Hebrew University Medical Center, Jerusalem, Israel. 11. Department of Medical Oncology, Royal Marsden Hospital, London, UK. 12. Department of Medical Oncology University of Manchester and the Christie NHS Foundation Trust, Manchester, UK. 13. Department of Medical Oncology, Universitair Ziekenhuis Brussel, Brussels, Belgium. 14. Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands. 15. Department of Medicine, Division of Medical Oncology/Hematology, Sunnybrook Health Sciences Center, Toronto, ON, Canada. 16. Department of Hematology/Oncology, The Angeles Clinic and Research Institute, Los Angeles, CA, USA. 17. Department of BARDS, Merck & Co, Kenilworth, NJ, USA. 18. Department of Clinical Oncology, Merck & Co, Kenilworth, NJ, USA. 19. Department of Oncology, Gustave Roussy and Paris-Sud University, Villejuif, France.
Abstract
BACKGROUND: Interim analyses of the phase 3 KEYNOTE-006 study showed superior overall and progression-free survival of pembrolizumab versus ipilimumab in patients with advanced melanoma. We present the final protocol-specified survival analysis. METHODS: In this multicentre, open-label, randomised, phase 3 trial, we recruited patients from 87 academic institutions, hospitals, and cancer centres in 16 countries (Australia, Austria, Belgium, Canada, Chile, Colombia, France, Germany, Israel, Netherlands, New Zealand, Norway, Spain, Sweden, UK, and USA). We randomly assigned participants (1:1:1) to one of two dose regimens of pembrolizumab, or one regimen of ipilimumab, using a centralised, computer-generated allocation schedule. Treatment assignments used blocked randomisation within strata. Eligible patients were at least 18 years old, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, at least one measurable lesion per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), unresectable stage III or IV melanoma (excluding ocular melanoma), and up to one previous systemic therapy (excluding anti-CTLA-4, PD-1, or PD-L1 agents). Secondary eligibility criteria are described later. Patients were excluded if they had active brain metastases or active autoimmune disease requiring systemic steroids. The primary outcome was overall survival (defined as the time from randomisation to death from any cause). Response was assessed per RECIST v1.1 by independent central review at week 12, then every 6 weeks up to week 48, and then every 12 weeks thereafter. Survival was assessed every 12 weeks, and final analysis occurred after all patients were followed up for at least 21 months. Primary analysis was done on the intention-to-treat population (all randomly assigned patients) and safety analyses were done in the treated population (all randomly assigned patients who received at least one dose of study treatment). Data cutoff date for this analysis was Dec 3, 2015. This study was registered with ClinicalTrials.gov, number NCT01866319. FINDINGS: Between Sept 18, 2013, and March 3, 2014, 834 patients with advanced melanoma were enrolled and randomly assigned to receive intravenous pembrolizumab every 2 weeks (n=279), intravenous pembrolizumab every 3 weeks (n=277), or intravenous ipilimumab every 3 weeks (ipilimumab for four doses; n=278). One patient in the pembrolizumab 2 week group and 22 patients in the ipilimumab group withdrew consent and did not receive treatment. A total of 811 patients received at least one dose of study treatment. Median follow-up was 22·9 months; 383 patients died. Median overall survival was not reached in either pembrolizumab group and was 16·0 months with ipilimumab (hazard ratio [HR] 0·68, 95% CI 0·53-0·87 for pembrolizumab every 2 weeks vs ipilimumab; p=0·0009 and 0·68, 0·53-0·86 for pembrolizumab every 3 weeks vs ipilimumab; p=0·0008). 24-month overall survival rate was 55% in the 2-week group, 55% in the 3-week group, and 43% in the ipilimumab group. INTERPRETATION: Substantiating the results of the interim analyses of KEYNOTE-006, pembrolizumab continued to provide superior overall survival versus ipilimumab, with no difference between pembrolizumab dosing schedules. These conclusions further support the use of pembrolizumab as a standard of care for advanced melanoma. FUNDING: Merck & Co.
RCT Entities:
BACKGROUND: Interim analyses of the phase 3 KEYNOTE-006 study showed superior overall and progression-free survival of pembrolizumab versus ipilimumab in patients with advanced melanoma. We present the final protocol-specified survival analysis. METHODS: In this multicentre, open-label, randomised, phase 3 trial, we recruited patients from 87 academic institutions, hospitals, and cancer centres in 16 countries (Australia, Austria, Belgium, Canada, Chile, Colombia, France, Germany, Israel, Netherlands, New Zealand, Norway, Spain, Sweden, UK, and USA). We randomly assigned participants (1:1:1) to one of two dose regimens of pembrolizumab, or one regimen of ipilimumab, using a centralised, computer-generated allocation schedule. Treatment assignments used blocked randomisation within strata. Eligible patients were at least 18 years old, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, at least one measurable lesion per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), unresectable stage III or IV melanoma (excluding ocular melanoma), and up to one previous systemic therapy (excluding anti-CTLA-4, PD-1, or PD-L1 agents). Secondary eligibility criteria are described later. Patients were excluded if they had active brain metastases or active autoimmune disease requiring systemic steroids. The primary outcome was overall survival (defined as the time from randomisation to death from any cause). Response was assessed per RECIST v1.1 by independent central review at week 12, then every 6 weeks up to week 48, and then every 12 weeks thereafter. Survival was assessed every 12 weeks, and final analysis occurred after all patients were followed up for at least 21 months. Primary analysis was done on the intention-to-treat population (all randomly assigned patients) and safety analyses were done in the treated population (all randomly assigned patients who received at least one dose of study treatment). Data cutoff date for this analysis was Dec 3, 2015. This study was registered with ClinicalTrials.gov, number NCT01866319. FINDINGS: Between Sept 18, 2013, and March 3, 2014, 834 patients with advanced melanoma were enrolled and randomly assigned to receive intravenous pembrolizumab every 2 weeks (n=279), intravenous pembrolizumab every 3 weeks (n=277), or intravenous ipilimumab every 3 weeks (ipilimumab for four doses; n=278). One patient in the pembrolizumab 2 week group and 22 patients in the ipilimumab group withdrew consent and did not receive treatment. A total of 811 patients received at least one dose of study treatment. Median follow-up was 22·9 months; 383 patients died. Median overall survival was not reached in either pembrolizumab group and was 16·0 months with ipilimumab (hazard ratio [HR] 0·68, 95% CI 0·53-0·87 for pembrolizumab every 2 weeks vs ipilimumab; p=0·0009 and 0·68, 0·53-0·86 for pembrolizumab every 3 weeks vs ipilimumab; p=0·0008). 24-month overall survival rate was 55% in the 2-week group, 55% in the 3-week group, and 43% in the ipilimumab group. INTERPRETATION: Substantiating the results of the interim analyses of KEYNOTE-006, pembrolizumab continued to provide superior overall survival versus ipilimumab, with no difference between pembrolizumab dosing schedules. These conclusions further support the use of pembrolizumab as a standard of care for advanced melanoma. FUNDING: Merck & Co.
Authors: Judith Lacey; Anna J Lomax; Catriona McNeil; Michael Marthick; David Levy; Steven Kao; Theresa Nielsen; Haryana M Dhillon Journal: Support Care Cancer Date: 2018-11-03 Impact factor: 3.603
Authors: Diwakar Davar; Hong Wang; Joe-Marc Chauvin; Ornella Pagliano; Julien J Fourcade; Mignane Ka; Carmine Menna; Amy Rose; Cindy Sander; Amir A Borhani; Arivarasan Karunamurthy; Ahmad A Tarhini; Hussein A Tawbi; Qing Zhao; Blanca H Moreno; Scott Ebbinghaus; Nageatte Ibrahim; John M Kirkwood; Hassane M Zarour Journal: J Clin Oncol Date: 2018-10-25 Impact factor: 44.544