Alexander M M Eggermont1, Christian U Blank2, Mario Mandala3, Georgina V Long4, Victoria G Atkinson5, Stéphane Dalle6, Andrew Haydon7, Mikhail Lichinitser8, Adnan Khattak9, Matteo S Carlino10, Shahneen Sandhu11, James Larkin12, Susana Puig13, Paolo A Ascierto14, Piotr Rutkowski15, Dirk Schadendorf16, Rutger Koornstra17, Leonel Hernandez-Aya18, Anna Maria Di Giacomo19, Alfonsus Jm van den Eertwegh20, Jean-Jacques Grob21, Ralf Gutzmer22, Rahima Jamal23, Paul C Lorigan24, Robert Lupinacci25, Clemens Krepler25, Nageatte Ibrahim25, Michal Kicinski26, Sandrine Marreaud26, Alexander C van Akkooi2, Stefan Suciu26, Caroline Robert27. 1. Gustave Roussy Cancer Campus Grand Paris, Villejuif, France. Electronic address: alexander.eggermont@gustaveroussy.fr. 2. Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, the Netherlands. 3. Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy. 4. Melanoma Institute Australia, The University of Sydney, and Mater and Royal North Shore Hospitals, Sydney, NSW, Australia. 5. Princess Alexandra Hospital, Brisbane, QLD, Australia. 6. Hospices Civils de Lyon Cancer Institute, Lyon, France. 7. Alfred Hospital, Melbourne, VIC, Australia. 8. Russian Oncology Scientific Centre, Moscow, Russia. 9. Fiona Stanley Hospital/University of Western Australia, Perth, WA, Australia. 10. Westmead and Blacktown Hospitals, Melanoma Institute Australia and the University of Sydney, Sydney, NSW, Australia. 11. Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. 12. Royal Marsden Hospital, London, United Kingdom. 13. Hospital Clinic Universitari de Barcelona, Barcelona, Spain. 14. Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", Naples, Italy. 15. Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland. 16. Universitaetsklinikum - University Essen, Essen, Germany. 17. Radboud University Medical Center Nijmegen, Nijmegen, the Netherlands. 18. Washington University School of Medicine, St. Louis, MO, USA. 19. Center for Immuno-Oncology, University Hospital of Siena, Siena, Italy. 20. Amsterdam University Medical Center, Location VUMC, Amsterdam, the Netherlands. 21. Aix Marseille University, Hôpital de la Timone, Marseille, France. 22. Skin Cancer Center, Hannover Medical School, Hannover, Germany. 23. Centre Hospitalier de l'Université de Montréal (CHUM), Centre de recherche du CHUM, Montreal, QC, Canada. 24. Christie NHS Foundation Trust, Manchester, United Kingdom. 25. Merck & Co., Inc., Kenilworth, NJ, United States. 26. EORTC Headquarters, Brussels, Belgium. 27. Gustave Roussy Cancer Campus Grand Paris, Villejuif, France.
Abstract
BACKGROUND: The American Joint Committee on Cancer-8 (AJCC) classification of melanoma was implemented in January 2018. It was based on data gathered when checkpoint inhibitors were not used as adjuvant therapy in stage III melanoma. The European Organization for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 double-blind phase III trial evaluated pembrolizumab vs placebo in AJCC-7 stage IIIA (excluding lymph node metastasis ≤1 mm), IIIB or IIIC (without in-transit metastasis) patients after complete lymphadenectomy. PATIENTS, METHODS AND RESULTS:Patients (n = 1019) were randomised 1:1 to pembrolizumab 200 mg or placebo every 3 weeks (total of 18 doses, ∼1 year). At 1.25-year median follow-up, pembrolizumab prolonged relapse-free survival (RFS) in the total population (1-year RFS rate: 75.4% vs 61.0%; hazard ratio [HR] 0.57; logrank P < 0.0001) and consistently in the AJCC-7 subgroups. Prognostic and predictive values of AJCC-8 for RFS were evaluated in this study. Patient distribution according to the AJCC-8 stage subgroups was 8% (IIIA), 34.7% (IIIB), 49.7% (IIIC), 3.7% (IIID) and 3.8% (unknown). AJCC-8 classification was strongly associated with RFS (HRs for stage IIIB, IIIC and IIID vs IIIA were 4.0, 5.7 and 12.2, respectively) but showed no predictive importance for the treatment comparison regarding RFS (test for interaction: P = 0.68). The 1-year RFS rate for pembrolizumab vs placebo and the HRs (99% confidence interval) within each AJCC-8 subgroup were as follows: stage IIIA (92.7% vs 92.5%; 0.76 [0.11-5.43]), IIIB (79.0% vs 65.5%; 0.59 [0.35-0.99]), IIIC (73.6% vs 53.9%; 0.48 [0.33-0.70]) and IIID (50.0% vs 33.3%; 0.69 [0.24-2.00]). CONCLUSIONS: AJCC-8 staging had a strong prognostic importance for RFS but no predictive importance: the RFS benefit of pembrolizumab was observed across AJCC-8 subgroups in resected high-risk stage III melanoma patients. Crown
RCT Entities:
BACKGROUND: The American Joint Committee on Cancer-8 (AJCC) classification of melanoma was implemented in January 2018. It was based on data gathered when checkpoint inhibitors were not used as adjuvant therapy in stage III melanoma. The European Organization for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 double-blind phase III trial evaluated pembrolizumab vs placebo in AJCC-7 stage IIIA (excluding lymph node metastasis ≤1 mm), IIIB or IIIC (without in-transit metastasis) patients after complete lymphadenectomy. PATIENTS, METHODS AND RESULTS:Patients (n = 1019) were randomised 1:1 to pembrolizumab 200 mg or placebo every 3 weeks (total of 18 doses, ∼1 year). At 1.25-year median follow-up, pembrolizumab prolonged relapse-free survival (RFS) in the total population (1-year RFS rate: 75.4% vs 61.0%; hazard ratio [HR] 0.57; logrank P < 0.0001) and consistently in the AJCC-7 subgroups. Prognostic and predictive values of AJCC-8 for RFS were evaluated in this study. Patient distribution according to the AJCC-8 stage subgroups was 8% (IIIA), 34.7% (IIIB), 49.7% (IIIC), 3.7% (IIID) and 3.8% (unknown). AJCC-8 classification was strongly associated with RFS (HRs for stage IIIB, IIIC and IIID vs IIIA were 4.0, 5.7 and 12.2, respectively) but showed no predictive importance for the treatment comparison regarding RFS (test for interaction: P = 0.68). The 1-year RFS rate for pembrolizumab vs placebo and the HRs (99% confidence interval) within each AJCC-8 subgroup were as follows: stage IIIA (92.7% vs 92.5%; 0.76 [0.11-5.43]), IIIB (79.0% vs 65.5%; 0.59 [0.35-0.99]), IIIC (73.6% vs 53.9%; 0.48 [0.33-0.70]) and IIID (50.0% vs 33.3%; 0.69 [0.24-2.00]). CONCLUSIONS: AJCC-8 staging had a strong prognostic importance for RFS but no predictive importance: the RFS benefit of pembrolizumab was observed across AJCC-8 subgroups in resected high-risk stage III melanomapatients. Crown
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