Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial

• Published in: The lancet oncology 2017-12, Vol.18 (12), p.1688-1700
• Main Authors: Iwata, Hiroji, Chia, Stephen K L, Bashford, Anna, Inoue, Kenichi, Armstrong, Anne C, Wong, Alvin, Buyse, Marc, Harvey, Vernon, Smith, John W., Konstantinovic, Zora Neskovic, Rodriguez, Gladys I., Jáñez Martinez, Noelia, Knoop, Ann Soegaard, De Boer, Richard Hendry, Rai, Yoshiaki, Yamamoto, Naohito, Brincat, Stephen, Papish, Steven William, Manalo, Yvonne, Sorensen, Peter Grundtvig, Aogi, Kenjiro, Shimizu, Satoru, Mainwaring, Paul, Chang, Jose, del Barco Berron, Sonia, Dickerson, Laura C., Klein, Leonard M., Ruxer, Robert, Veyret, Corinne, Wagnerova, Maria, Richards, Donald A., Vasileios, Asskikis, Dourthe, Louis Marie, Lu, Yen-Shen, Greenspan, Andrew R., Gonzalez Santiago, Santiago, Perren, Timothy John, Yau, Chung Cheung Thomas, Pikó, Béla, Sato, Nobuaki, Askoy, Sercan, Altundag, Mustafa Kadri, Saip, Pinar, Bajaj, Rajesh, Vestlev, Peter Michael, Dank, Magdolna, Cinieri, Saverio, Suszko-Kazarnowicz, Malgorzata, Yap, Yoon Sim, Chen, Shin-Cheh, Haley, Barbara Bacsik, Inhorn, Roger C., Koynova, Tatyana, Schneeweiss, Andreas, Cubedo Cervera, Ricardo, Urruticoechea Ribate, Ander, Schwartz, Garry H., Mocharnuk, Robert Scott, Alkhouri, Nabiel, Erickson, Nicholette, Traynor, Ann, Volterra, Fabio, Capo, Gerardo, Flaherty, Lawrence E., Baidas, Said, Lybaert, Willem, Holland, David R., Gonzalez Jimenez, Sonia, Vanlemmens, Laurence, Ruggeri, Enzo Maria, Desai, Ajit, Nixon, David Allen, O'Brien, Edward, Lanier, Keith S., Brescia, Frankie Ann, Richard, Vincent, Geldhof, Kurt, Bednarik, Otakar, Schwedler, Kathrin, Fries, Stefan, Klare, Peter, Griesinger, Frank, Trufflandier, Nathalie, Chetiyawardana, Anula D., Papandreou, Christos, Hornyak, Lajos, Simo, Erzsebet, Im, Seock-Ah, Ruit, Jan B., Ciltas, Aydin, Benekli, Mustafa, Conkright, William A., Ottaviano, Yvonne, Delmas, Andrew, Steele, Heather A., Bova, Abby R., Shirinian, Mihran, O'Rourke, Timothy J., Francisco, Michael, Carrillo Flores, Maria Regina
• Format: Article
• Language: English
• Subjects: Adjuvant therapy; Administration, Oral; Adult; Antibodies, Monoclonal, Humanized - adverse effects; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Biotechnology; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - mortality; Breast Neoplasms - pathology; Breast Neoplasms - surgery; Cancer therapies; Chemotherapy; Chemotherapy, Adjuvant; Disease-Free Survival; Dose-Response Relationship, Drug; Double-Blind Method; Double-blind studies; Drug Administration Schedule; Endocrine therapy; ErbB-2 protein; Estrogens; Female; Follow-Up Studies; Humans; Immunotherapy; Japan; Kaplan-Meier Estimate; Mastectomy - methods; Metastasis; Middle Aged; Monoclonal antibodies; Neoplasm Invasiveness - pathology; Neoplasm Staging; Patients; Proportional Hazards Models; Quinolines - administration & dosage; Quinolines - adverse effects; Receptor, ErbB-2 - metabolism; Risk Assessment; Survival Analysis; Targeted cancer therapy; Time Factors; Trastuzumab; Trastuzumab - administration & dosage; Trastuzumab - adverse effects; Treatment Outcome; Womens health
• ISSN: 1470-2045; 1474-5488
• DOI: 10.1016/S1470-2045(17)30717-9

ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings. In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (≥20 years in Japan) with stage 1–3c (modified to stage 2–3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1–3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat. ExteNET is registered with ClinicalTrials.gov, number NCT00878709, and is closed to new participants. Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420). After a median follow-up of 5·2 years (IQR 2·1–5·3), patients in the neratinib group had significantly fewer invasive disease-free survival events than those in the placebo group (116 vs 163 events; stratified hazard ratio 0·73, 95% CI 0·57–0·92, p=0·0083). The 5-year invasive disease-free survival was 90·2% (95% CI 88·3–91·8) in the neratinib group and 87·7% (85·7–89·4) in the placebo group. Without diarrhoea prophylaxis, the most common grade 3–4 adverse events in the neratinib group, compared with the placebo group, were diarrhoea (561 [40%] grade 3 and one [