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. In the patient population with early-stage human epidermal growth factor receptor 2-positive/hormone receptor-positive breast cancer who initiate neratinib within 1 year of trastuzumab-based therapy, the absolute 5-year invasive disease-free survival benefit versus placebo is 5.1%, and absolute 8-year overall survival benefit is 2.1%. Among those with residual disease after neoadjuvant therapy (non-pathologic complete response), absolute gains with neratinib are 7.4% and 9.1%, respectively.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Clinical Breast Cancer |
| Vol/bind | 21 |
| Udgave nummer | 1 |
| Sider (fra-til) | 80-91.e7 |
| ISSN | 1526-8209 |
| DOI | |
| Status | Udgivet - feb. 2021 |
Finansiering
B. Moy reports grants from Puma Biotechnology Inc during the conduct of the study, and personal fees from Motus outside the submitted work. B. Ejlertsen reports grants from NanoString , Roche , Novartis , and Oncology-Venture , and non-financial support from MSD outside the submitted work. F. A. Holmes reports personal fees from Puma Biotechnology Inc during the conduct of the study. Stephen Chia reports grants from AstraZeneca , Genentech , and Roche , grants and personal fees from Genomic Health and Novartis , and personal fees from Pfizer outside the submitted work. H. Iwata reports grants and personal fees from AstraZeneca , Chugai Pharma , Daiichi-Sankyo , Eisai , Kyowa Hakko Kirin , Lilly Japan, Novartis , and Pfizer , and grants from Bayer , GlaxoSmithKline , MSD , and Nihonkayaku outside the submitted work. M. Gnant reports personal fees/travel support from Amgen, AstraZeneca, Daiichi-Sankyo, Eli Lilly, LifeBrain, Nanostring, Novartis, and TLC Biopharmaceuticals all outside the submitted work; an immediate family member is employed by Sandoz. S. Loibl reports grants and non-financial support from Immunomedics during the conduct of the study, grants and other from Abbvie , Amgen , AstraZeneca , Celgene , Daiichi-Sankyo , Novartis , Pfizer , and Roche , other from BMS, Eirgenix, Lilly, MSD, PriME/Medscape, Puma Biotechnology Inc, Samsung, and Seattle Genetics, and personal fees from Chugai, and grants from Teva and Vifor from outside the submitted work. In addition, S. Loibl has a patent (EP14153692.0) pending. C. H. Barrios reports grants from Abbvie , Amgen , Astellas , AstraZeneca , BMS , Celgene , Covance , Lilly , Medivation , MSD , Merck Serono , Novartis , Pfizer , PharmaMar , and Roche , and personal fees from AstraZeneca, Bayer, BMS, Beringer, Eisai, GSK, Lilly, MSD, Novartis, Pfizer, and Roche outside the submitted work. S. Smichkoska reports personal fees from Pfizer and Roche outside the submitted work. I. A. Mayer reports personal fees from Puma Biotechnology Inc during the conduct of the study, grants and personal fees from Genentech , Novartis , and Pfizer , and personal fees from Abbvie, AstraZeneca, Eisai, GSK, Immunomedics, Lilly, Macrogenics, and Seattle Genetics, outside the submitted work. K. Inoue reports a grant from Puma Biotechnology Inc during the conduct of the study, and grants from Chugai Pharma , Lilly , MSD , Novartis , and Pfizer outside the submitted work. R. Hui reports personal fees from AstraZeneca, BMS, Eli Lilly, MSD, Novartis, and Roche outside the submitted work. N. Denduluri reports other from Genentech, Immunomedics, Merck, Novartis, and Seattle Genetics, and personal fees and other from Daiichi outside the submitted work. H. S. Rugo reports personal fees from Puma Biotechnology Inc during the conduct of the study, and grants and personal fees from Daiichi , Macrogenics , Merck , and Pfizer , grants from Eisai , Genentech , Immunomedics , Lilly , Novartis , OBI , Odonate , Seattle Genetics , and Sermonix , and personal fees from AstraZeneca and Samsung outside the submitted work. S. R. D. Johnston reports grants and personal fees from Puma Biotechnology Inc during the conduct of the study, grants and personal fees from AstraZeneca , Eisai , Eli Lilly , Novartis , Pfizer , and Roche /Genentech outside the submitted work. R. Bryce, B. Zhang, F. Xu, and A. Wong are employees of Puma Biotechnology Inc, and own stock in Puma Biotechnology Inc. Miguel Martin reports grants and personal fees from Novartis and Roche /Genentech, and personal fees from Amgen, AstraZeneca, Lilly, Pfizer, Pharmamar, and Puma Biotechnology Inc. outside the submitted work. The remaining authors have stated that they have no conflicts of interest. The authors thank the Independent Data Monitoring Committee, study investigators, research staff, clinical research organizations, and other vendors, as well as the patients who participated in the ExteNET trial. The authors would like to acknowledge statistical programming support provided by Janine Lu, Yan Yan, and Dan DiPrimeo ( Puma Biotechnology ). The authors also thank Deepa Lalla and Bethann Hromatka (Puma Biotechnology) for review and revision of the manuscript, and Lee Miller and Harriet Lamb (Miller Medical Communications Ltd) for writing/editorial support. This work was supported by Puma Biotechnology Inc , Los Angeles, CA. The funders of the study designed the trial, were responsible for data collection, data integrity and analyses, and interpretation of the data with oversight from the authors. The manuscript was written with input from authors, and with review and input from the sponsor. The lead and senior authors were responsible for the final decision regarding manuscript contents and submission. Puma Biotechnology Inc funded the provision of editorial support provided by Miller Medical Communications .