Arlene Chan1, Beverly Moy2, Janine Mansi3, Bent Ejlertsen4, Frankie Ann Holmes5, Stephen Chia6, Hiroji Iwata7, Michael Gnant8, Sibylle Loibl9, Carlos H Barrios10, Isil Somali11, Snezhana Smichkoska12, Noelia Martinez13, Mirta Garcia Alonso14, John S Link15, Ingrid A Mayer16, Søren Cold17, Serafin Morales Murillo18, Francis Senecal19, Kenichi Inoue20, Manuel Ruiz-Borrego21, Rina Hui22, Neelima Denduluri23, Debra Patt24, Hope S Rugo25, Stephen R D Johnston26, Richard Bryce27, Bo Zhang27, Feng Xu27, Alvin Wong27, Miguel Martin28. 1. Breast Clinical Trials Unit, Breast Cancer Research Centre-WA & Curtin University, Perth, Australia. Electronic address: arlenechan@me.com. 2. Breast Oncology Program, Massachusetts General Hospital Cancer Center, Boston, MA. 3. Oncology & Haematology Clinical Trials, Guy's and St Thomas Hospital NHS Foundation Trust and Biomedical Research Centre, King's College, London, United Kingdom. 4. Department of Oncology, Rigshospitalet, Copenhagen, Denmark. 5. Texas Oncology/US Oncology Research, Houston, TX. 6. Medical Oncology, BC Cancer Agency, Vancouver, BC, Canada. 7. Clinical Oncology, Aichi Cancer Center, Chikusa-ku, Nagoya, Japan. 8. Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria. 9. Center for Hematology and Oncology Bethanien, Frankfurt, Germany. 10. Centro de Pesquisa em Oncologia, Hospital São Lucas, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil. 11. Department of Oncology, Dokuz Eylul Universitesi Tip Fakultesi Hastanesi Tibbi Onkoloji Anabilim Dali Mithatpaşa, Balçova, Izmir, Turkey. 12. University Clinic for Radiotherapy and Oncology, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia. 13. Department of Medical Oncology, Hospital Universitario Ramón y Cajal, Madrid, Spain. 14. Oncología Médica, Hospital Universitario Nuestra Señora de la Candelaria Ctra. Del Rosario, Sta. Cruz De Tenerife, Canarias. 15. Breastlink Medical Group, Inc, Santa Ana, CA. 16. Division of Hematology/Oncology, Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Nashville, TN. 17. Onkologisk Afdeling R, Odense University Hospital, Odense, Denmark. 18. Hospital Universitario Arnau Vilanova Servei d'Oncologia Mèdica i Hematologia, Lleida, Spain. 19. Physician Medical Center, Northwest Medical Specialties PLLC, Tacoma, WA. 20. Breast Oncology, Saitama Cancer Center, Kita-Adachi, Japan. 21. Oncología, Hospital Universitario Virgen del Rocio, Seville, Spain. 22. Crown Princess Mary Cancer Centre, Westmead Hospital and University of Sydney, Sydney, NSW, Australia. 23. Virginia Cancer Specialists, Arlington, VA. 24. Texas Oncology - Round Rock, Austin, TX. 25. Department of Medicine (Hematology/Oncology), University of California San Francisco Comprehensive Cancer Center, San Francisco, CA. 26. The Breast Unit, Royal Marsden NHS Foundation Trust, London, United Kingdom. 27. Puma Biotechnology Inc., Los Angeles, CA. 28. Medical Oncology Service, Instituto de Investigación Sanitaria Gregorio Marañón, CIBERONC, GEICAM, Universidad Complutense, Madrid, Spain.
Abstract
BACKGROUND: The ExteNET trial demonstrated improved invasive disease-free survival (iDFS) with neratinib, an irreversible pan-HER tyrosine kinase inhibitor, versus placebo in patients with human epidermal growth factor receptor 2-positive (HER2+)/hormone receptor-positive (HR+) early-stage breast cancer (eBC). PATIENTS AND METHODS: ExteNET was a multicenter, randomized, double-blind, phase III trial of 2840 patients with HER2+ eBC after neoadjuvant/adjuvant trastuzumab-based therapy. Patients were stratified by HR status and randomly assigned 1-year oral neratinib 240 mg/day or placebo. The primary endpoint was iDFS. Descriptive analyses were performed in patients with HR+ eBC who initiated treatment ≤ 1 year (HR+/≤ 1-year) and > 1 year (HR+/> 1-year) post-trastuzumab. RESULTS: HR+/≤ 1-year and HR+/> 1-year populations comprised 1334 (neratinib, n = 670; placebo, n = 664) and 297 (neratinib, n = 146; placebo, n = 151) patients, respectively. Absolute iDFS benefits at 5 years were 5.1% in HR+/≤ 1-year (hazard ratio, 0.58; 95% confidence interval [CI], 0.41-0.82) and 1.3% in HR+/>1-year (hazard ratio, 0.74; 95% CI, 0.29-1.84). In HR+/≤ 1-year, neratinib was associated with a numerical improvement in overall survival (OS) at 8 years (absolute benefit, 2.1%; hazard ratio, 0.79; 95% CI, 0.55-1.13). Of 354 patients in the HR+/≤ 1-year group who received neoadjuvant therapy, 295 had residual disease, and results showed absolute benefits of 7.4% at 5-year iDFS (hazard ratio, 0.60; 95% CI, 0.33-1.07) and 9.1% at 8-year OS (hazard ratio, 0.47; 95% CI, 0.23-0.92). There were fewer central nervous system events with neratinib. Adverse events were similar to those previously reported. CONCLUSION: Neratinib significantly improved iDFS in the HER2+/HR+/≤ 1-year population, and a similar trend was observed in patients with residual disease following neoadjuvant treatment. Numerical improvements in central nervous system events and OS were consistent with iDFS benefits and suggest long-term benefit for neratinib in this population.
RCT Entities:
BACKGROUND: The ExteNET trial demonstrated improved invasive disease-free survival (iDFS) with neratinib, an irreversible pan-HER tyrosine kinase inhibitor, versus placebo in patients with humanepidermal growth factor receptor 2-positive (HER2+)/hormone receptor-positive (HR+) early-stage breast cancer (eBC). PATIENTS AND METHODS: ExteNET was a multicenter, randomized, double-blind, phase III trial of 2840 patients with HER2+ eBC after neoadjuvant/adjuvant trastuzumab-based therapy. Patients were stratified by HR status and randomly assigned 1-year oral neratinib 240 mg/day or placebo. The primary endpoint was iDFS. Descriptive analyses were performed in patients with HR+ eBC who initiated treatment ≤ 1 year (HR+/≤ 1-year) and > 1 year (HR+/> 1-year) post-trastuzumab. RESULTS: HR+/≤ 1-year and HR+/> 1-year populations comprised 1334 (neratinib, n = 670; placebo, n = 664) and 297 (neratinib, n = 146; placebo, n = 151) patients, respectively. Absolute iDFS benefits at 5 years were 5.1% in HR+/≤ 1-year (hazard ratio, 0.58; 95% confidence interval [CI], 0.41-0.82) and 1.3% in HR+/>1-year (hazard ratio, 0.74; 95% CI, 0.29-1.84). In HR+/≤ 1-year, neratinib was associated with a numerical improvement in overall survival (OS) at 8 years (absolute benefit, 2.1%; hazard ratio, 0.79; 95% CI, 0.55-1.13). Of 354 patients in the HR+/≤ 1-year group who received neoadjuvant therapy, 295 had residual disease, and results showed absolute benefits of 7.4% at 5-year iDFS (hazard ratio, 0.60; 95% CI, 0.33-1.07) and 9.1% at 8-year OS (hazard ratio, 0.47; 95% CI, 0.23-0.92). There were fewer central nervous system events with neratinib. Adverse events were similar to those previously reported. CONCLUSION:Neratinib significantly improved iDFS in the HER2+/HR+/≤ 1-year population, and a similar trend was observed in patients with residual disease following neoadjuvant treatment. Numerical improvements in central nervous system events and OS were consistent with iDFS benefits and suggest long-term benefit for neratinib in this population.
Authors: Lisi M Dredze; Michael Friger; Samuel Ariad; Michael Koretz; Bertha Delgado; Ruthy Shaco-Levy; Margarita Tokar; Michael Bayme; Ravit Agassi; Maia Rosenthal; Victor Dyomin; Olga Belochitski; Shai Libson; Tamar Mizrahi; David B Geffen Journal: Breast Cancer Res Treat Date: 2022-04-22 Impact factor: 4.872
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Authors: Alvaro Moreno-Aspitia; Eileen M Holmes; Christian Jackisch; Evandro de Azambuja; Frances Boyle; David W Hillman; Larissa Korde; Debora Fumagalli; Miguel A Izquierdo; Ann E McCullough; Antonio C Wolff; Kathleen I Pritchard; Michael Untch; Sébastien Guillaume; Michael S Ewer; Zhimin Shao; Sung Hoon Sim; Zeba Aziz; Georgia Demetriou; Ajay O Mehta; Michael Andersson; Masakazu Toi; Istvan Lang; Binghe Xu; Ian E Smith; Carlos H Barrios; Jose Baselga; Richard D Gelber; Martine Piccart-Gebhart Journal: Eur J Cancer Date: 2021-03-23 Impact factor: 9.162
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