N Harbeck1, P Rastogi2, M Martin3, S M Tolaney4, Z M Shao5, P A Fasching6, C S Huang7, G G Jaliffe8, A Tryakin9, M P Goetz10, H S Rugo11, E Senkus12, L Testa13, M Andersson14, K Tamura15, L Del Mastro16, G G Steger17, H Kreipe18, R Hegg19, J Sohn20, V Guarneri21, J Cortés22, E Hamilton23, V André24, R Wei24, S Barriga24, S Sherwood24, T Forrester24, M Munoz24, A Shahir24, B San Antonio24, S C Nabinger24, M Toi25, S R D Johnston26, J O'Shaughnessy27. 1. Breast Center, Department of OB & GYN and CCC Munich, LMU University Hospital, Munich, Germany. Electronic address: Nadia.Harbeck@med.uni-muenchen.de. 2. University of Pittsburgh/UPMC, NSABP Foundation, Pittsburgh, USA. 3. Hospital General Universitario Gregorio Marañon, Universidad Complutense, CIBERONC, GEICAM, Madrid, Spain. 4. Dana-Farber Cancer Institute, Boston, USA. 5. Fudan University Shanghai Cancer Center, Shanghai, China. 6. University Hospital Erlangen, Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany. 7. National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan. 8. Grupo Medico Camino S.C., Mexico City, Mexico. 9. N.N.Blokhin Russian Cancer Research Center, Moscow, Russia. 10. Mayo Clinic, Rochester, USA. 11. Department of Medicine (Hematology/Oncology), University of California San Francisco, San Francisco, USA. 12. Department of Oncology & Radiotherapy, Medical University of Gdańsk, Gdańsk, Poland. 13. Instituto D'Or de Pesquisa e Ensino (IDOR), Sao Paulo, Brazil. 14. Rigshospitalet, Copenhagen, Denmark. 15. National Cancer Center Hospital, Tokyo, Japan. 16. IRCSS Ospedale Policlinico San Martino, UO Breast Unit, Genoa, Italy; Università di Genova, Department of Internal Medicine and Medical Specialties (DIM), Genoa, Italy. 17. Medical University of Vienna, Vienna, Austria. 18. Medizinische Hochschule Hannover, Hannover, Germany. 19. Clin. Pesq. e Centro São Paulo, São Paulo, Brazil. 20. Yonsei Cancer Center, Seoul, Korea. 21. Department of Surgery, Oncology and Gastroenterology, University of Padova, Padua, Italy; Istituto Oncologico Veneto IOV-IRCCS, Padua, Italy. 22. International Breast Cancer Center (IBCC), Madrid & Barcelona, and Vall d'Hebron Institute of Oncology, Barcelona, Spain; Universidad Europea de Madrid, Faculty of Biomedical and Health Sciences, Department of Medicine, Madrid, Spain. 23. Sarah Cannon Research Institute/Tennessee Oncology, Nashville, USA. 24. Eli Lilly and Company, Indianapolis, USA. 25. Kyoto University Hospital, Kyoto, Japan. 26. Royal Marsden NHS Foundation Trust, London, UK. 27. Baylor University Medical Center, Texas Oncology, US Oncology, Dallas, USA.
Abstract
BACKGROUND: Adjuvant abemaciclib combined with endocrine therapy (ET) previously demonstrated clinically meaningful improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer at the second interim analysis, however follow-up was limited. Here, we present results of the prespecified primary outcome analysis and an additional follow-up analysis. PATIENTS AND METHODS: This global, phase III, open-label trial randomized (1 : 1) 5637 patients to adjuvant ET for ≥5 years ± abemaciclib for 2 years. Cohort 1 enrolled patients with ≥4 positive axillary lymph nodes (ALNs), or 1-3 positive ALNs and either grade 3 disease or tumor ≥5 cm. Cohort 2 enrolled patients with 1-3 positive ALNs and centrally determined high Ki-67 index (≥20%). The primary endpoint was IDFS in the intent-to-treat population (cohorts 1 and 2). Secondary endpoints were IDFS in patients with high Ki-67, DRFS, overall survival, and safety. RESULTS: At the primary outcome analysis, with 19 months median follow-up time, abemaciclib + ET resulted in a 29% reduction in the risk of developing an IDFS event [hazard ratio (HR) = 0.71, 95% confidence interval (CI) 0.58-0.87; nominal P = 0.0009]. At the additional follow-up analysis, with 27 months median follow-up and 90% of patients off treatment, IDFS (HR = 0.70, 95% CI 0.59-0.82; nominal P < 0.0001) and DRFS (HR = 0.69, 95% CI 0.57-0.83; nominal P < 0.0001) benefit was maintained. The absolute improvements in 3-year IDFS and DRFS rates were 5.4% and 4.2%, respectively. Whereas Ki-67 index was prognostic, abemaciclib benefit was consistent regardless of Ki-67 index. Safety data were consistent with the known abemaciclib risk profile. CONCLUSION: Abemaciclib + ET significantly improved IDFS in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer, with an acceptable safety profile. Ki-67 index was prognostic, but abemaciclib benefit was observed regardless of Ki-67 index. Overall, the robust treatment benefit of abemaciclib extended beyond the 2-year treatment period.
BACKGROUND: Adjuvant abemaciclib combined with endocrine therapy (ET) previously demonstrated clinically meaningful improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer at the second interim analysis, however follow-up was limited. Here, we present results of the prespecified primary outcome analysis and an additional follow-up analysis. PATIENTS AND METHODS: This global, phase III, open-label trial randomized (1 : 1) 5637 patients to adjuvant ET for ≥5 years ± abemaciclib for 2 years. Cohort 1 enrolled patients with ≥4 positive axillary lymph nodes (ALNs), or 1-3 positive ALNs and either grade 3 disease or tumor ≥5 cm. Cohort 2 enrolled patients with 1-3 positive ALNs and centrally determined high Ki-67 index (≥20%). The primary endpoint was IDFS in the intent-to-treat population (cohorts 1 and 2). Secondary endpoints were IDFS in patients with high Ki-67, DRFS, overall survival, and safety. RESULTS: At the primary outcome analysis, with 19 months median follow-up time, abemaciclib + ET resulted in a 29% reduction in the risk of developing an IDFS event [hazard ratio (HR) = 0.71, 95% confidence interval (CI) 0.58-0.87; nominal P = 0.0009]. At the additional follow-up analysis, with 27 months median follow-up and 90% of patients off treatment, IDFS (HR = 0.70, 95% CI 0.59-0.82; nominal P < 0.0001) and DRFS (HR = 0.69, 95% CI 0.57-0.83; nominal P < 0.0001) benefit was maintained. The absolute improvements in 3-year IDFS and DRFS rates were 5.4% and 4.2%, respectively. Whereas Ki-67 index was prognostic, abemaciclib benefit was consistent regardless of Ki-67 index. Safety data were consistent with the known abemaciclib risk profile. CONCLUSION: Abemaciclib + ET significantly improved IDFS in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer, with an acceptable safety profile. Ki-67 index was prognostic, but abemaciclib benefit was observed regardless of Ki-67 index. Overall, the robust treatment benefit of abemaciclib extended beyond the 2-year treatment period.
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