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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., Competing Interests: Disclosure NH reports research grants from Eli Lilly and Company to her institution; personal fees and other for lectures and consulting from Amgen, AstraZeneca, Daiichi-Sankyo, Eli Lilly and Company, Merck Sharp & Dohme (MSD), Novartis, Pfizer, Pierre-Fabre, Roche/Genentech, Sandoz, and SeaGen outside the submitted work. SJ reports personal fees from AstraZeneca, Eli Lilly and Company, Novartis, Pfizer, and Puma Biotechnology for consulting and advisory role; personal fees from AstraZeneca, Novartis, Pfizer, Eisai, and Roche/Genentech for speaker’s bureau; personal fees and other from AstraZeneca, Eli Lilly and Company, Novartis, Pfizer, Puma Biotechnology, and Roche/Genentech for research funding, outside the submitted work. PR reports other compensation for travel/accommodations from Eli Lilly and Company, AstraZeneca, and Roche/Genentech; and other non-compensated fees for Ad Board participation, outside the submitted work. MM reports grants from Novartis and personal fees from Amgen, Roche, AstraZeneca, and Pfizer, outside of the submitted work. ZMS, MA, RH, and KT have nothing to disclose. SMT reports grants and personal fees from Eli Lilly and Company, during the conduct of the study; grants and personal fees from Immunomedics/Gilead, AstraZeneca, grants and personal fees from Eli Lilly and Company, Odonate, grants and personal fees from Merck, grants and personal fees from Nektar, grants and personal fees from Novartis, grants and personal fees from Pfizer, grants and personal fees from Genentech/Roche, grants and personal fees from Exelixis, grants and personal fees from Bristol Myers Squibb, grants and personal fees from Eisai, Sanofi, and grants and personal fees from Nanostring; personal fees from Chugai Pharma, Ellipses Pharma, 4D Pharma, BeyondSpring Pharma, OncXerna, Infinity Therapeutics, OncoSec, Seattle Genetics, Celldex, Certara, Mersana Therapeutics, Silverback Therapeutics, Daiichi-Sankyo, G1 Therapeutics, CytomX, Samsung Bioepis Inc., Athenex, OncoPep, Kyowa Kirin Pharmaceuticals, and Puma; grants from Cyclacel, grants and personal fees from Sanofi, personal fees from Celldex, grants and personal fees from Odonate, personal fees from Seattle Genetics, personal fees from Silverback Therapeutics, personal fees from G1 Therapeutics, personal fees from Athenex, personal fees from OncoPep, personal fees from Kyowa Kirin Pharmaceuticals, personal fees from Daiichi-Sankyo, personal fees from CytomX, personal fees from Samsung Bioepis Inc., personal fees from Certara, personal fees from Mersana Therapeutics, grants and personal fees from Immunomedics/Gilead, personal fees from OncoSec, personal fees from Chugai Pharma, personal fees from Ellipses Pharma, personal fees from 4D Pharma, personal fees from BeyondSpring Pharma, personal fees from OncXerna, personal fees from Infinity Therapeutics, outside the submitted work. PAH reports personal fees from Novartis, Pfizer, Daiichi-Sankyo, AstraZeneca, Eisai, MSD, Eli Lilly and Company, Pierre Fabre, Seattle Genetics, Roche/Genentech, and Hexal; and grants from Biontech, and Cepheid, outside of the submitted work. CH reports grants and personal fees for advisory role from Eli Lilly and Company; personal fees and non-financial support for advisory role, speaker’s bureaus, and travel expense from Amgen; and grants, personal fees, and non-financial support for advisory role, speaker bureaus, and travel expenses from Pfizer and Roche/Genentech; grants and personal fees for speaker bureaus from Novartis; grants, personal fees, and non-financial support for travel expenses, and grants from EirGenix, OBI Pharma, MSD, and Daiichi-Sankyo, outside the submitted work. GGJ reports personal fees from Eli Lilly and Company, during the conduct of the study; personal fees from Amgen, AstraZeneca, Clinigen, Egis, Eli Lilly and Company, Exact Sciences, Novartis, Oncompass Medicine, Pfizer, Pierre Fabre, Roche/Genentech, Sandoz, Samsung, and TLC Biopharmaceuticals, outside the submitted work. AT reports personal fees and non-financial support from Eli Lilly and Company, Bayer and Novartis, Bristol Myers Squibb, MSD, Biocad, and Merck; personal fees from AstraZeneca, Eisai Co., Ltd, and Amgen, outside the submitted work. MPG receives consulting fees to institution from Eagle pharmaceuticals, Eli Lilly and Company, Biovica, Novartis, Sermonix, Context Pharm, Pfizer, and Biotheranostics; and grants from Pfizer, and Eli Lilly and Company; and grants to institution from Sermonix, outside the submitted work. HSR reports grants to institution from Pfizer, Merck, Novartis, Eli Lilly and Company, Roche/Genentech, OBI, Odonate, Daiichi-Sankyo, Seattle Genetics, Eisai, MacroGenics, Sermonix, Immunomedics, and AstraZeneca; non-financial travel support for educational meeting from Daiichi-Sankyo, Mylan, Pfizer, Merck, AstraZeneca, Novartis, and MacroGenics; personal fees for honoraria from Puma and Mylan; other fees for limited consulting from Samsung, outside of the submitted work. ES reports personal fees for honoraria from Amgen, AstraZeneca, Clinigen, Egis, Eli Lilly and Company, Exact Sciences, Novartis, Oncompas Medicine, Pfizer, Pierre Fabre, Roche/Genentech, Sandoz, and TLC Biopharmaceuticals; personal fees for travel support from Amgen, AstraZeneca, Egis, Novartis, Pfizer, and Roche/Genentech; personal fees for clinical research from Amgen, AstraZeneca, Novartis, Pfizer, and Roche/Genentech, and Samsung, outside the submitted work. LT reports other fees for non-CME received directly from commercial interest or their agents from Eli Lilly and Company, Novartis, Pfizer, Roche/Genentech, and Libbs; and personal fees for travel from Pfizer, Roche/Genentech, Libbs, and United Medical. LDM reports grant for research from Eli Lilly and Company; personal fees from Eli Lilly and Company, Novartis, Roche, MSD, Pfizer, Genomic Health, Pierre Fabre, Daiichi-Sankyo, AstraZeneca, Seattle Genetics, Eisai, and Ipsen; and non-financial support from Roche, Pfizer, and Eisai, outside the submitted work. GGS reports personal fees and non-financial support from Novartis, Pfizer, AstraZeneca, and Roche; non-financial support from Teva; personal fees from Astro Pharma; and grants from Roche, outside the submitted work. HK reports personal fees for lectures and presentations during professional and scientific meetings from AstraZeneca, Genomic Health, Roche/Genentech, and Pfizer, outside the submitted work. JS reports research grant funding to institution from MSD, Roche, Novartis, AstraZeneca, Eli Lilly, Pfizer, GlaxoSmithKline (GSK), Daiichi Sankyo, Sanofi, and Boehringer Ingelheim, outside the submitted work. VG reports personal fees from Eli Lilly and Company, Novartis, Roche, and MSD an advisory board role and speaker’s bureau, outside the submitted work, and grant to institution from Roche, outside the submitted work. JC reports fees from Roche, Celgene, Cellestia, AstraZeneca, Biothera Pharmaceuticals, Merus, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Eli Lilly and Company, Servier, MSD, GSK, Leuko, Bioasis, Clovis Oncology, and Boehringer Ingelheim for consulting and advisory role; honoraria from Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Eli Lilly and Company, MSD, Daiichi Sankyo; research funding to institution from Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta, GMBH/Servier Affaires, Bayer Healthcare, Eisai, F. Hoffman-La Roche, Guardant Health, MSD, Pfizer, Piqur Therapeutics, Puma C, and Queen Mary University of London; stock, patents, and intellectual property from MedSIR; and travel, accommodation, and expenses from Roche, Novartis, Eisai, Pfizer, and Daiichi Sankyo, outside the submitted work. EH reports grants from Eli Lilly and Company, during the conduct of the study; grants and other from Pfizer, Silverback Therapeutics, Black Diamond, Daiichi, AstraZeneca, Novartis, Mersana, Cascadian Therapeutics, and Genentech/Roche; personal fees from Flatiron Health; grants and other from Cascadian Therapeutics, grants from Hutchinson MediPharma, grants from OncoMed, grants from MedImmune, grants from StemCentrx, grants from Abbvie, grants from Curis, grants from Verastem, grants from Zymeworks, grants from Syndax, grants from Lycera, grants from Rgenix, grants and other from Novartis, grants and other from Mersana, grants from TapImmune, grants from BerGenBio, grants from Tesaro, grants from Medivation, grants from Kadmon, grants from Boehringer Ingelheim, grants from Eisai, grants from H3 Biomedicine, grants from Radius Health, grants from Acerta, grants from Takeda, grants from MacroGenics, grants from Immunomedics, grants from FujiFilm, grants from Effector, grants from Syros, grants from Unum, grants and other from Daiichi, grants and other from AstraZeneca, grants from Sutro, grants from Aravive, grants from Deciphera, grants from Clovis, grants from Sermonix, grants from Zenith, grants from Arvinas, grants from ArQule, grants from Torque, grants from Harpoon, grants from Fochon, grants from Orinove, grants from Molecular Template, grants and other from Silverback Therapeutics, grants and other from Black Diamond, grants from Seattle Genetics, outside the submitted work. VA, RW, SB, SS, TF, SCN, BSA, MM, AS are full-time employees of Eli Lilly and Company and/or Eli Lilly and Company shareholders. MT reports grants and personal fees for research and honoraria from Chugai, Takeda, Pfizer, Kyowa-Kirin, Taiho, Eisai, Daiichi-Sankyo, AstraZeneca, Shimadzu, Yakult, and Nippon Kayaku; other fees for advisory role for drug development from Kyowa-Kirin and Daiichi-Sankyo; research grants from JBCRG association, Astellas, AFI Technologies, Shionogi, and GL Science; personal and other fees from Eli Lilly and Company for advisory role; personal fees for honoraria from MSD, Exact Science, and Novartis; personal fees and other for honoraria and advisory role from Konica Minolta; other fees for honoraria and advisory role from Bristol Myers Squibb; other fees for advisory role from Athenex Oncology, Bertis, Terumo, and Kansai Medical Net; and serves as a board of director for JBCRG association, Organisation for Oncology and Translational Research, and Kyoto Breast Cancer Research Network, outside the submitted work. JO reports personal fees from Abbvie, Aptitude Health, AstraZeneca, Agendia, Bristol Myers Squibb, Celgene, Eisai, G1 Therapeutics, Genentech, Immunomedics, Eli Lilly and Company, Merck, Novartis, Pfizer, Puma Biotechnology, Roche/Genentech, and Seattle Genentech, outside the submitted work., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Response rates in HER2-overexpressing EBC treated with neoadjuvant chemotherapy and trastuzumab (T) have been improved by addition of pertuzumab (P). The prospective, phase II, neoadjuvant WSG-ADAPT HER2+/HR- trial assessed whether patients with strong early response to dual blockade alone might achieve pathological complete response (pCR) comparable to that of patients receiving dual blockade and chemotherapy., Patients and Methods: Female patients with HER2+/HR- EBC (M0) were randomized (5:2) to 12 weeks of T + P ± weekly paclitaxel (pac) at 80 mg/m2. Early response was defined as proliferation decrease ≥30% of Ki-67 (versus baseline) or low cellularity (<500 invasive tumor cells) in the 3-week biopsy. The trial was designed to test non-inferiority for pCR in early responding patients of the T + P arm versus all chemotherapy-treated patients., Results: From February 2014 to December 2015, 160 patients were screened, 92 were randomized to T + P and 42 to T + P+pac. Baseline characteristics were well balanced (median age 54 versus 51.5 years, cT2 51.1 versus 52.4%, cN0 54.3 versus 61.9%); 91.3% of patients completed T + P per protocol and 92.9% T + P+pac. The pCR rate in the T + P+pac arm was 90.5%, compared with 36.3% in the T + P arm as a whole. In the T + P arm, 24/92 were classified as non-responders, and their pCR rate was only 8.3% compared with 44.7% in responders (38/92) and 42.9% in patients with unclassified early response (30/92). No new safety signals were observed in the study population., Conclusion: Addition of taxane monotherapy to dual HER2 blockade in a 12-week neoadjuvant setting substantially increases pCR rates in HER2+/HR- EBC compared with dual blockade alone, even within early responders to dual blockade. Early non-response under dual blockade strongly predicts failure to achieve pCR., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)