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1. Effects of neratinib on health-related quality of life in women with HER2-positive early-stage breast cancer: longitudinal analyses from the randomized phase III ExteNET trial

Author

Delaloge, S., Cella, D., Ye, Y., Buyse, M., Chan, A., Barrios, C.H., Holmes, F.A., Mansi, J., Iwata, H., Ejlertsen, B., Moy, B., Chia, S.K.L., Gnant, M., Smichkoska, S., Ciceniene, A., Martinez, N., Filipović, S., Ben-Baruch, N.E., Joy, A.A., Langkjer, S.T., Senecal, F., de Boer, R.H., Moran, S., Yao, B., Bryce, R., Auerbach, A., Fallowfield, L., and Martin, M.

Published
2019
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4. Effects of neratinib on health-related quality of life in women with HER2-positive early-stage breast cancer:longitudinal analyses from the randomized phase III ExteNET trial

Author

S Filipović, Carlos H. Barrios, B Yao, Anil A. Joy, A. Chan, S Chia, S. Moran, Miguel Martin, Beverly Moy, Bent Ejlertsen, R De Boer, Y. Ye, Noa Ben-Baruch, Michael Gnant, Richard A. Bryce, David Cella, Lesley Fallowfield, Sven Tyge Langkjer, Suzette Delaloge, Noelia Martínez, Francis M. Senecal, Frankie A. Holmes, A. Ciceniene, Hiroji Iwata, Janine Mansi, Snezhana Smichkoska, Marc Buyse, and A.H. Auerbach

Subjects
0301 basic medicine, Adult, medicine.medical_specialty, early-stage breast cancer, Receptor, ErbB-2, Population, Antineoplastic Agents, Breast Neoplasms, Placebo, Disease-Free Survival, Placebos, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Breast cancer, Double-Blind Method, Trastuzumab, Internal medicine, HER2, medicine, Adjuvant therapy, Humans, Imputation (statistics), Longitudinal Studies, education, Aged, Neoplasm Staging, Aged, 80 and over, education.field_of_study, business.industry, Cancer, Hematology, Middle Aged, medicine.disease, health-related quality of life, neratinib, 030104 developmental biology, Oncology, Chemotherapy, Adjuvant, patient-reported outcomes, 030220 oncology & carcinogenesis, Neratinib, Quality of Life, Quinolines, Female, business, medicine.drug
Abstract

BACKGROUND: We report longitudinal health-related quality-of-life (HRQoL) data from the international, randomized, double-blind, placebo-controlled phase III ExteNET study, which demonstrated an invasive disease-free survival benefit of extended adjuvant therapy with neratinib over placebo in human epidermal growth factor receptor-2-positive early-stage breast cancer. PATIENTS AND METHODS: Women (N = 2840) with early-stage HER2-positive breast cancer who had completed trastuzumab-based adjuvant therapy were randomly assigned to neratinib 240 mg/day or placebo for 12 months. HRQoL was an exploratory end point. Patients completed the Functional Assessment of Cancer Therapy-Breast (FACT-B) and EuroQol 5-Dimensions (EQ-5D) questionnaires at baseline and months 1, 3, 6, 9, and 12. Changes from baseline were compared using analysis of covariance with no imputation for missing values. Sensitivity analyses used alternative methods. Changes in HRQoL scores were regarded as clinically meaningful if they exceeded previously reported important differences (IDs). RESULTS: Of the 2840 patients (intention-to-treat population), 2407 patients were evaluable for FACT-B (neratinib, N = 1171; placebo, N = 1236) and 2427 patients for EQ-5D (neratinib, N = 1186; placebo, N = 1241). Questionnaire completion rates exceeded 85%. Neratinib was associated with a decrease in global HRQoL scores at month 1 compared with placebo (adjusted mean differences: FACT-B total, -2.9 points; EQ-5D index, -0.02), after which between-group differences diminished at later time-points. Except for the FACT-B physical well-being (PWB) subscale at month 1; all between-group differences were less than reported IDs. The FACT-B breast cancer-specific subscale showed small improvements with neratinib at months 3-9, but all were less than IDs. Sensitivity analyses exploring missing data did not change the results. CONCLUSIONS: Extended adjuvant neratinib was associated with a transient, reversible decrease in HRQoL during the first month of treatment, possibly linked to treatment-related diarrhea. With the exception of the PWB subscale at month 1, all neratinib-related HRQoL changes did not reach clinically meaningful thresholds. ClinicalTrials.gov: NCT00878709.

Published
2019

5. 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

Author

Miguel Martin, Frankie A Holmes, Bent Ejlertsen, Suzette Delaloge, Beverly Moy, Hiroji Iwata, Gunter von Minckwitz, Stephen K L Chia, Janine Mansi, Carlos H Barrios, Michael Gnant, Zorica Tomašević, Neelima Denduluri, Robert Šeparović, Erhan Gokmen, Anna Bashford, Manuel Ruiz Borrego, Sung-Bae Kim, Erik Hugger Jakobsen, Audrone Ciceniene, Kenichi Inoue, Friedrich Overkamp, Joan B Heijns, Anne C Armstrong, John S Link, Anil Abraham Joy, Richard Bryce, Alvin Wong, Susan Moran, Bin Yao, Feng Xu, Alan Auerbach, Marc Buyse, Arlene Chan, Vernon Harvey, Rudolf Tomek, Nicholas J. Robert, Ira Gore, John W. Smith, Norikazu Masuda, S. Di Sean Kendall, William Graydon Harker, Katarina Petrakova, Angel Guerrero Zotano, Amparo Ruiz Simon, Zora Neskovic Konstantinovic, Nicholas O. Iannotti, Pierfrancesco Tassone, Gladys I. Rodriguez, Noelia Jáñez Martinez, Carmen Crespo Massieu, Snezana Smickoska, Isil Somali, Ugur Yilmaz, Mirta Garcia Alonso, Adolfo Murias Rosales, Soeren Cold, Ann Soegaard Knoop, Debra Patt, Beth A. Hellerstedt, Serafin Morales Murillo, Ingrid A. Mayer, Julie Ann Means-Powell, Rina Hui, Francis M. Senecal, Richard Hendry De Boer, Zhenzhou Shen, Adam Andrzej Luczak, Joanna W.Y. Chui, Janice Wing-hang Tsang, Istvan Lang, Yoshiaki Rai, Yasuo Hozumi, Albert J. Ten Tije, Manish Bhandari, Cynthia R.C. Osborne, Shoichiro Ohtani, Kenji Higaki, Kenichi Watanabe, Kazunori Taguchi, Masato Takahashi, Sladjana Filipovic, Vincent L. Hansen, Vijayarama Phooshkooru Rao, Manish Gupta, Petar Petrov, Bruno Coudert, Zeljko Vojnovic, Zsofia Polya, Toshiko Miyaki, Naohito Yamamoto, Stephen Brincat, Krzysztof Lesniewski-Kmak, Ewa Chmielowska, Ruemu E. Birhiray, Marc L. Citron, Steven William Papish, William R. Berry, Sven Tyge Langkjer, José Angel Garcia Sáenz, Ana Maria Arance, Noa Efrat, Tomasz Sarosiek, Lukasz Grzeda, Yvonne Manalo, Julie C. Smith, Irfan Vaziri, Tabitha Healey, Yasmin Rahim, Cynthia Luk, Brian Dingle, Sandra Franco, Peter Grundtvig Sorensen, Anjana Anand, Sarah Khan, George Fountzilas, Kenjiro Aogi, Satoru Shimizu, Milada Mikulova, Stanislav Spanik, Robert A. Somer, Patrick J. Flynn, Jermaine Coward, Paul Mainwaring, Guy Jerusalem, Carine Segura-Ojezzar, Christelle Levy, Thierry Delozier, David Khayat, Robert E. Coleman, Martin J. Rolles, Robert Maisano, Mario Nardi, Yoshinori Ito, Perran Fulden Yumuk, Gul Basaran, Nazim Serdar Turhal, Mary J. Wilkinson, Nathan B. Green, Algis P. Sidrys, Sigrun Hallmeyer, Douglas J. Testori, Srikala Sridhar, Jose Chang, Qiang Sun, Carlos Jara-Sanchez, Xabier Rubio, Maria Lomas Garrido, Juan Rafael De La Haba Rodriguez, Antonia Perello Martorell, Antoni Avelia Mestre, Julio Rifa Ferrer, Sonia del Barco Berron, Zsuzsanna Nagy, Maki Tanaka, Young-Hyuck Im, Robert R. Carroll, Laura C. Dickerson, Joseph R. Mace, Ragene Rivera, Leonard M. Klein, Robert Ruxer, Sharon T. Wilks, Dusan Kotasek, Vasil Popov, Violina Taskova, Violetka Marinova-Venkova, Constanta Timcheva, Christine Desbiens, Jean-Pierre Ayoub, Debjani Grenier, Norbert Marschner, Hans Tesch, Hans-Joachim Lueck, Jan Janssen, Ingo Schwaner, Stine Wahlstrom, Eva Harder Brix, Susanne Vallentin, Dan Kristensen, Anna Andreeva, Vesna Glavicic, Isabel Calvo Plaza, Antonio Anton Torres, Corinne Veyret, Jean-Pierre Bergerat, Emmanuelle Bourbouloux, Wendy Ann Ella, Hafiz Algurafi, Anne Robinson, Seung Jin Kim, Tetsuya Taguchi, Elona Juozaityte, Stanley Madretsma, Sandra Radema, Malgorzata Czerniawska-Meier, Wojciech Rogowski, Maria Wagnerova, Donald A. Richards, Elizabeth Tan-Chiu, Asskikis Vasileios, Charles Arthur Henderson, Viran Roger Holden, Xiaojia Wang, Zhongsheng Tong, Junlan Yang, Manuel Enrique Gonzalez, Mahdi Rezai, John Hackmann, Eduardo Martinez de Dueñas, Begoña Bermejo de las Heras, Louis Marie Dourthe, Dorothee Chocteau-Bouju, Philippe Bougnoux, Stylianos Kakolyris, Haralabos Kalofonos, Dimitrios Pectasidis, Ting Ying Ng, Gabor Pajkos, Eva Ezer Somogyine, Giuseppe Tonini, Dario Giuffrida, Shintaro Takao, Makoto Ishitobi, Hideo Inaji, Yutaka Tokuda, Katarzyna Wozniak, Dan Lungulescu, Yen-Shen Lu, King-Jen Chang, Julian Hill, Christopher Charles Croot, Albert Dekker, Neil D. Belman, Miguel Conde, Richard A. Michaelson, Kathleen Kemmer, Stephen Chui, Shiuh-Wen Luoh, Kenneth Nahum, Andrew R. Greenspan, Joni C. Nichols, Carlos A. Encarnacion, Thomas M.J. Niederman, Theresa Lee, Roland Alexander, Robert Gordon, Antoanet Tomova, Daniel Rauch, Razvan Andrei Popescu, Gustavo Adolfo Rojas, Jaroslav Vanasek, Tanja Neunhoeffer, Jana Barinoff, Gerd Graffunder, Abenhardt Wolfgang, Peter Bojko, Bernhard Heinrich, Albert von der Assen, Bogovic Jurij Antonovic, Lene Adrian, Manuel Ramos Vazquez, Santiago Gonzalez Santiago, Veronique Dieras, Jill Mercia Bishop, Timothy John Perren, Ioannis Varthalitis, Dimitris Mavroudis, Vassilis Georgoulias, Louis W.C. Chow, Chung Cheung Thomas Yau, Raymond Hin-Suen Liang, Béla Pikó, Agnes Wéber, Bella Kaufman, Karen Drumea, Francesco Nuzzo, Andrea De Matteis, Giacomo Carteni, Eriko Tokunaga, Mayumi Ishida, Shinji Ohno, Nobuaki Sato, Katsumasa Kuroi, Reiki Nishimura, Junichiro Watanabe, Yoon Ji Choi, Kyong Hwa Park, Marek Wojtukiewicz, Jacek Jassem, Niklas Loman, Sercan Askoy, Mustafa Kadri Altundag, Pinar Saip, Muhammad Amjad Ali, James Lloyd Wade, Amy Jo Chien, Debra Brandt, Yelena Novik, Chirag Jani, Robert L. Rice, Yousuf A. R Gaffar, Mark R. Keaton, Rajesh Bajaj, Gretchen Kimmick, David Campbell, Theodore Turnquest, Sideras Lucas, Pierre Dube, Binghe Xu, Joerg Schilling, Klaus Apel, Peter Michael Vestlev, Brita Bjerregaard Jensen, Vera Haahr, Alvaro Rodriguez Lescure, Begona Grana Suarez, Cristina Saura Manich, Jean-Philippe Jacquin, Ahmed Samreen, Ion Boiangiu, Magdolna Dank, Cristina Falci, Antonio Jirillo, Saverio Cinieri, Takayuki Ueno, Fumiaki Sato, Hiroyasu Yamashiro, Tomoharu Sugie, Keun Seok Lee, Jung Sil Ro, In Hae Park, Anita Zarina Bustam, Malgorzata Suszko-Kazarnowicz, Artur Piktel, Krzysztof Krzemieniecki, Polizenia Georgeta Iorga, Yoon Sim Yap, Marian Kakalejcik, Alper Sevinc, Mustafa Ozguroglu, Shin-Cheh Chen, Richard H. Greenberg, Allan Daniel Eisemann, Robert Droder, M. Rashid Abbasi, Marina Vaysburd, Humberto Jose Caldera, Barbara Bacsik Haley, Erwin Robin, Roger C. Inhorn, David Hufnagel, Peter D. Kenyon, Ellen Spremulli, Paula Silverman, Sharad Jain, Robert Weigand, Jeroen Mebis, Tatyana Koynova, Bernard Lesperance, Jana Prausova, Claus-Henning Kohne, Andreas Schneeweiss, Christian Jackisch, Stefan Fuxius, Ricardo Cubedo Cervera, Ander Urruticoechea Ribate, Sonia Pernas Simon, Jose Valero Gallego, Angels Arcusa Lanza, Maria del Pilar Alvarez, Jesus Florian Gerico, Laurent Cany, Justin Stebbing, Dejan Labudovic, Damir Gugic, Damir Vrbanec, Fausto Roila, Sandro Barni, Paolo Bidoli, Hirofumi Mukai, Vanessa Bermudez, Alexandru Eniu, Barry C. Mirtsching, Emad Ibrahim, Joan Trey, Paul Francis Hergenroeder, Aftab Mahmood, Anneliese Gonzalez, Edward H. Kaplan, Stacy Ban, Dhimant Patel, Billy Clowney, Karen Hoelzer, Garry H. Schwartz, Mohamed Salkeni, Jame Abraham, Sunil Narula, Khaled Jabboury, Robert Scott Mocharnuk, Richard H. McDonough, David H. Sikes, Ronald H. Kawanchi, Larry Schlabach, Samuel Spence McCachren, Thomas M. Cosgriff, Luke Dreisbach, Angela DeMichele, Lawrence Pawl, Jennifer Lucas, Lowell C. Shinn, Nabiel Alkhouri, Manish Monga, Deborah L. Lindquist, Thomas C. Anderson, Humera Khurshid, Sabrina Witherby, Nicholette Erickson, Ann Traynor, Ron Bose, Timothy J. Pluard, Michael C. Jones, Sucharu Prakash, Fabio Volterra, Gerardo Capo, Lawrence E. Flaherty, Elaina Gartner, Said Baidas, Ian Okazaki, Bichlien Nguyen, Thomas Rakowski, Ira Oliff, Joseph W. Leach, Daniel Anderson, Kendra Kubiak, Michaela Tsai, Philippe Vroman, Ines Deleu, Willem Lybaert, Marleen Borms, Felix Couture, Jonathan J. Wilson, Gordon Hunt, David R. Holland, Walter Mingrone, Shusen Wang, Donggeng Liu, Zefei Jiang, Vera Benesova, Martin Smakal, Petra Garnolova, Anne-Sophie Vesper, Monika Neumann, Wolfgang Janni, Cornelia Liedtke, Dorothea Fischer, Eva-Maria Grischke, Dietmar Seeger, Volker Moebus, Anita Prechtl, Juan Carlos Camara Toral, Alfonso Sanchez Munoz, Sonia Gonzalez Jimenez, Javier Cassinello Espinosa, Beatriz Cirauqui, Mireia Margeli Vila, Norberto Batista Lopez, Jose Ignacio Chacon Lopez-Muniz, Miguel Angel de la Cruz Mora, Audrey Mailliez, Laurence Vanlemmens, Damien Pouessel, Marc Espie, John Conibear, Rebecca Roylance, Adrian Harnett, David Geffen, Enzo Maria Ruggeri, Teresa Gamucci, Cees J. Van Groeningen, Renata Banas, Necati Alkis, Ming-Feng Hou, Amy K. Krie, Nandagopal S. Vrindavanam, Orion M. Howard, Dennis Citrin, Mark S. Morginstin, Ajit Desai, Ines J. Sanchez, David Allen Nixon, Patrick G. Beatty, Kathryn Edmiston, Marilyn McLaughlin, Jonathan D. Eneman, Cynthia A. Lynch, Edward O'Brien, Justin A. Call, Keith S. Lanier, Alison Conlin, Donald J. Brooks, Kristi McIntyre, Marc A. Saltzman, Michael J. Castine, Gregory L. Ortega, Young M. Choi, Craig H. Reynolds, Frankie Ann Brescia, Rita Kramer, Aimee D. Kohn, John P. Micha, Jessica M. Rhee, Satish Shah, David A. Riseberg, William Kevin Patterson, Jean-Paul Salmon, Chantal Andre, Alain Bols, Randal D'hondt, Sylvie Luce, Claire Nouwynck, Gino Pelgrims, Vincent Richard, Johan Verschuere, Kurt Geldhof, Clemens Caspar, Rongcheng Luo, Otakar Bednarik, Kathrin Schwedler, Marcus Schmidt, Romy Neumeister, Joachim Bischoff, Brigitte Rack, Roland Repp, Stefan Fries, Ralf Adrion, Volker Schulz, Peter Klare, Mahmoud Danei, Dirk Ossenbuhl, Jakob Manfred Kusche, Frank Griesinger, Jose Manuel Baena Canada, Purificacion Martinez del Prado, David Machover, Didier Mayeur, Nathalie Trufflandier, Valerie Delecroix, Mireille Mousseau, Marie-Ange Mouret-Reynier, Jean-Marc Nabholtz, Anula D. Chetiyawardana, Christos Papandreou, Lajos Hornyak, Zsolt Faluhelyi, Erzsebet Simo, Mario Di Palma, Francesco Cognetti, Gabriella Gorzegno, Luigi Dogliotti, Cesare Gridelli, Alfredo Falcone, Hector Soto Parra, Calogero Buscarino, Seock-Ah Im, Benito Sanchez Llamas, Wouter Dercksen, Franciscus Erdkamp, Jan B. Ruit, Hans Braun, Joanneke E.A. Portielje, Aydin Ciltas, Suleyman Buyukberber, Mustafa Benekli, Andrew J. Zahalsky, Rebecca Jaslow, Gary W. Thomas, Archana Maini, Israel Wiznitzer, Ali Khojasteh, Manuel Francisco Gonzalez, Lynn R. Kong, Aruna Padmanabhan, William A. Conkright, Sandra M. Swain, Douglas E. Faig, Kirti Jain, Ronald H. Yanagihara, Yvonne Ottaviano, Andrew Delmas, Heather A. Steele, Gordon K. Rainey, Penelope J. Harris, Jason K. Burris, Erik J. Rupard, Esther Tan, Pat W. Whitworth, Abby R. Bova, Ian C. Anderson, Mihran Shirinian, Caesar Tin-u, Timothy J. O'Rourke, Michael S. Roberts, Michael Francisco, A. Scott Pierson, Peter D. Byeff, Peter A. Kovach, John R. Caton, Mark Urban Rarick, William G. Schimidt, Alison T. Stopeck, Rachel Swart, Maria Regina Carrillo Flores, Carlos A. Alemany, Brennely Lozada, Paul L. Weinstein, Wei Wang, Michael Porubcin, David M. Ellison, George F. Geils, Edgardo Rivera, Mahmoud Charif, Martin, M, Holmes, F, Ejlertsen, B, Delaloge, S, Moy, B, Iwata, H, von Minckwitz, G, Chia, S, Mansi, J, Barrios, C, Gnant, M, Tomasevic, Z, Denduluri, N, Separovic, R, Gokmen, E, Bashford, A, Borrego, M, Kim, S, Jakobsen, E, Ciceniene, A, Inoue, K, Overkamp, F, Heijns, J, Armstrong, A, Link, J, Abraham, A, Bryce, J, Wong, A, Moran, S, Yao, B, Xu, F, Auerbach, A, Buyse, M, Chan, A, and Bidoli, P

Subjects
0301 basic medicine, Time Factors, Receptor, ErbB-2, Clinical Trial, Phase III, Receptor, ErbB-2/metabolism, Administration, Oral, Kaplan-Meier Estimate, exteNET, 0302 clinical medicine, Japan, Trastuzumab, Antineoplastic Combined Chemotherapy Protocols, pan-HER tyrosine kinase inhibitor, Mastectomy, Antineoplastic Combined Chemotherapy Protocols/administration & dosage, Middle Aged, neratinib, trastuzumab, breast cancer, adjuvant, Multicenter Study, Treatment Outcome, Oncology, Antibodies, Monoclonal, Humanized/adverse effects, Chemotherapy, Adjuvant, 030220 oncology & carcinogenesis, Randomized Controlled Trial, Neratinib, Quinolines, Neoplasm Invasiveness/pathology, Female, medicine.drug, Adult, medicine.medical_specialty, Quinolines/administration & dosage, Breast Neoplasms, Placebo, Antibodies, Monoclonal, Humanized, Risk Assessment, Disease-Free Survival, Drug Administration Schedule, Trastuzumab/administration & dosage, 03 medical and health sciences, Breast cancer, Breast Neoplasms/drug therapy, Double-Blind Method, Internal medicine, Journal Article, medicine, Adjuvant therapy, Humans, Comparative Study, Neoplasm Invasiveness, HER2-positive breast cancer, Neoplasm Staging, Proportional Hazards Models, Intention-to-treat analysis, Dose-Response Relationship, Drug, business.industry, medicine.disease, Survival Analysis, Mastectomy/methods, Surgery, Clinical trial, Regimen, 030104 developmental biology, business, Follow-Up Studies
Abstract

BACKGROUND: 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. METHODS: 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. FINDINGS: 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 [BACKGROUND: 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.METHODS: 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.FINDINGS: 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 [INTERPRETATION: At the 5-year follow-up, 1 year of extended adjuvant therapy with neratinib, administered after chemotherapy and trastuzumab, significantly reduced the proportion of clinically relevant breast cancer relapses-ie, those that might lead to death, such as distant and locoregional relapses outside the preserved breast-without increasing the risk of long-term toxicity. An analysis of overall survival is planned after 248 events.FUNDING: Wyeth, Pfizer, and Puma Biotechnology.

Published
2017

6. 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

Author

Martin, Miguel, primary, Holmes, Frankie A, additional, Ejlertsen, Bent, additional, Delaloge, Suzette, additional, Moy, Beverly, additional, Iwata, Hiroji, additional, von Minckwitz, Gunter, additional, Chia, Stephen K L, additional, Mansi, Janine, additional, Barrios, Carlos H, additional, Gnant, Michael, additional, Tomašević, Zorica, additional, Denduluri, Neelima, additional, Šeparović, Robert, additional, Gokmen, Erhan, additional, Bashford, Anna, additional, Ruiz Borrego, Manuel, additional, Kim, Sung-Bae, additional, Jakobsen, Erik Hugger, additional, Ciceniene, Audrone, additional, Inoue, Kenichi, additional, Overkamp, Friedrich, additional, Heijns, Joan B, additional, Armstrong, Anne C, additional, Link, John S, additional, Joy, Anil Abraham, additional, Bryce, Richard, additional, Wong, Alvin, additional, Moran, Susan, additional, Yao, Bin, additional, Xu, Feng, additional, Auerbach, Alan, additional, Buyse, Marc, additional, Chan, Arlene, additional, Harvey, Vernon, additional, Tomek, Rudolf, additional, Robert, Nicholas J., additional, Gore, Ira, additional, Smith, John W., additional, Masuda, Norikazu, additional, Di Sean Kendall, S., additional, Harker, William Graydon, additional, Petrakova, Katarina, additional, Guerrero Zotano, Angel, additional, Simon, Amparo Ruiz, additional, Konstantinovic, Zora Neskovic, additional, Iannotti, Nicholas O., additional, Tassone, Pierfrancesco, additional, Rodriguez, Gladys I., additional, Jáñez Martinez, Noelia, additional, Crespo Massieu, Carmen, additional, Smickoska, Snezana, additional, Somali, Isil, additional, Yilmaz, Ugur, additional, Alonso, Mirta Garcia, additional, Rosales, Adolfo Murias, additional, Cold, Soeren, additional, Knoop, Ann Soegaard, additional, Patt, Debra, additional, Hellerstedt, Beth A., additional, Morales Murillo, Serafin, additional, Mayer, Ingrid A., additional, Means-Powell, Julie Ann, additional, Hui, Rina, additional, Senecal, Francis M., additional, De Boer, Richard Hendry, additional, Shen, Zhenzhou, additional, Luczak, Adam Andrzej, additional, Chui, Joanna W.Y., additional, Tsang, Janice Wing-hang, additional, Lang, Istvan, additional, Rai, Yoshiaki, additional, Hozumi, Yasuo, additional, Ten Tije, Albert J., additional, Bhandari, Manish, additional, Osborne, Cynthia R.C., additional, Ohtani, Shoichiro, additional, Higaki, Kenji, additional, Watanabe, Kenichi, additional, Taguchi, Kazunori, additional, Takahashi, Masato, additional, Filipovic, Sladjana, additional, Hansen, Vincent L., additional, Rao, Vijayarama Phooshkooru, additional, Gupta, Manish, additional, Petrov, Petar, additional, Coudert, Bruno, additional, Vojnovic, Zeljko, additional, Polya, Zsofia, additional, Miyaki, Toshiko, additional, Yamamoto, Naohito, additional, Brincat, Stephen, additional, Lesniewski-Kmak, Krzysztof, additional, Chmielowska, Ewa, additional, Birhiray, Ruemu E., additional, Citron, Marc L., additional, Papish, Steven William, additional, Berry, William R., additional, Langkjer, Sven Tyge, additional, Garcia Sáenz, José Angel, additional, Arance, Ana Maria, additional, Efrat, Noa, additional, Sarosiek, Tomasz, additional, Grzeda, Lukasz, additional, Manalo, Yvonne, additional, Smith, Julie C., additional, Vaziri, Irfan, additional, Healey, Tabitha, additional, Rahim, Yasmin, additional, Luk, Cynthia, additional, Dingle, Brian, additional, Franco, Sandra, additional, Sorensen, Peter Grundtvig, additional, Anand, Anjana, additional, Khan, Sarah, additional, Fountzilas, George, additional, Aogi, Kenjiro, additional, Shimizu, Satoru, additional, Mikulova, Milada, additional, Spanik, Stanislav, additional, Somer, Robert A., additional, Flynn, Patrick J., additional, Coward, Jermaine, additional, Mainwaring, Paul, additional, Jerusalem, Guy, additional, Segura-Ojezzar, Carine, additional, Levy, Christelle, additional, Delozier, Thierry, additional, Khayat, David, additional, Coleman, Robert E., additional, Rolles, Martin J., additional, Maisano, Robert, additional, Nardi, Mario, additional, Ito, Yoshinori, additional, Yumuk, Perran Fulden, additional, Basaran, Gul, additional, Serdar Turhal, Nazim, additional, Wilkinson, Mary J., additional, Green, Nathan B., additional, Sidrys, Algis P., additional, Hallmeyer, Sigrun, additional, Testori, Douglas J., additional, Sridhar, Srikala, additional, Chang, Jose, additional, Sun, Qiang, additional, Jara-Sanchez, Carlos, additional, Rubio, Xabier, additional, Garrido, Maria Lomas, additional, De La Haba Rodriguez, Juan Rafael, additional, Perello Martorell, Antonia, additional, Avelia Mestre, Antoni, additional, Rifa Ferrer, Julio, additional, del Barco Berron, Sonia, additional, Nagy, Zsuzsanna, additional, Tanaka, Maki, additional, Im, Young-Hyuck, additional, Carroll, Robert R., additional, Dickerson, Laura C., additional, Mace, Joseph R., additional, Rivera, Ragene, additional, Klein, Leonard M., additional, Ruxer, Robert, additional, Wilks, Sharon T., additional, Kotasek, Dusan, additional, Popov, Vasil, additional, Taskova, Violina, additional, Marinova-Venkova, Violetka, additional, Timcheva, Constanta, additional, Desbiens, Christine, additional, Ayoub, Jean-Pierre, additional, Grenier, Debjani, additional, Marschner, Norbert, additional, Tesch, Hans, additional, Lueck, Hans-Joachim, additional, Janssen, Jan, additional, Schwaner, Ingo, additional, Wahlstrom, Stine, additional, Brix, Eva Harder, additional, Vallentin, Susanne, additional, Kristensen, Dan, additional, Andreeva, Anna, additional, Glavicic, Vesna, additional, Calvo Plaza, Isabel, additional, Anton Torres, Antonio, additional, Veyret, Corinne, additional, Bergerat, Jean-Pierre, additional, Bourbouloux, Emmanuelle, additional, Ella, Wendy Ann, additional, Algurafi, Hafiz, additional, Robinson, Anne, additional, Kim, Seung Jin, additional, Taguchi, Tetsuya, additional, Juozaityte, Elona, additional, Madretsma, Stanley, additional, Radema, Sandra, additional, Czerniawska-Meier, Malgorzata, additional, Rogowski, Wojciech, additional, Wagnerova, Maria, additional, Richards, Donald A., additional, Tan-Chiu, Elizabeth, additional, Vasileios, Asskikis, additional, Henderson, Charles Arthur, additional, Holden, Viran Roger, additional, Wang, Xiaojia, additional, Tong, Zhongsheng, additional, Yang, Junlan, additional, Gonzalez, Manuel Enrique, additional, Rezai, Mahdi, additional, Hackmann, John, additional, de Dueñas, Eduardo Martinez, additional, de las Heras, Begoña Bermejo, additional, Dourthe, Louis Marie, additional, Chocteau-Bouju, Dorothee, additional, Bougnoux, Philippe, additional, Kakolyris, Stylianos, additional, Kalofonos, Haralabos, additional, Pectasidis, Dimitrios, additional, Ng, Ting Ying, additional, Pajkos, Gabor, additional, Somogyine, Eva Ezer, additional, Tonini, Giuseppe, additional, Giuffrida, Dario, additional, Takao, Shintaro, additional, Ishitobi, Makoto, additional, Inaji, Hideo, additional, Tokuda, Yutaka, additional, Wozniak, Katarzyna, additional, Lungulescu, Dan, additional, Lu, Yen-Shen, additional, Chang, King-Jen, additional, Hill, Julian, additional, Croot, Christopher Charles, additional, Dekker, Albert, additional, Belman, Neil D., additional, Conde, Miguel, additional, Michaelson, Richard A., additional, Kemmer, Kathleen, additional, Chui, Stephen, additional, Luoh, Shiuh-Wen, additional, Nahum, Kenneth, additional, Greenspan, Andrew R., additional, Nichols, Joni C., additional, Encarnacion, Carlos A., additional, Niederman, Thomas M.J., additional, Lee, Theresa, additional, Alexander, Roland, additional, Gordon, Robert, additional, Tomova, Antoanet, additional, Rauch, Daniel, additional, Popescu, Razvan Andrei, additional, Rojas, Gustavo Adolfo, additional, Vanasek, Jaroslav, additional, Neunhoeffer, Tanja, additional, Barinoff, Jana, additional, Graffunder, Gerd, additional, Wolfgang, Abenhardt, additional, Bojko, Peter, additional, Heinrich, Bernhard, additional, von der Assen, Albert, additional, Antonovic, Bogovic Jurij, additional, Adrian, Lene, additional, Ramos Vazquez, Manuel, additional, Gonzalez Santiago, Santiago, additional, Dieras, Veronique, additional, Bishop, Jill Mercia, additional, Perren, Timothy John, additional, Varthalitis, Ioannis, additional, Mavroudis, Dimitris, additional, Georgoulias, Vassilis, additional, Chow, Louis W.C., additional, Yau, Chung Cheung Thomas, additional, Liang, Raymond Hin-Suen, additional, Pikó, Béla, additional, Wéber, Agnes, additional, Kaufman, Bella, additional, Drumea, Karen, additional, Nuzzo, Francesco, additional, De Matteis, Andrea, additional, Carteni, Giacomo, additional, Tokunaga, Eriko, additional, Ishida, Mayumi, additional, Ohno, Shinji, additional, Sato, Nobuaki, additional, Kuroi, Katsumasa, additional, Nishimura, Reiki, additional, Watanabe, Junichiro, additional, Choi, Yoon Ji, additional, Park, Kyong Hwa, additional, Wojtukiewicz, Marek, additional, Jassem, Jacek, additional, Loman, Niklas, additional, Askoy, Sercan, additional, Altundag, Mustafa Kadri, additional, Saip, Pinar, additional, Ali, Muhammad Amjad, additional, Wade, James Lloyd, additional, Chien, Amy Jo, additional, Brandt, Debra, additional, Novik, Yelena, additional, Jani, Chirag, additional, Rice, Robert L., additional, Gaffar, Yousuf A. R, additional, Keaton, Mark R., additional, Bajaj, Rajesh, additional, Kimmick, Gretchen, additional, Campbell, David, additional, Turnquest, Theodore, additional, Lucas, Sideras, additional, Dube, Pierre, additional, Xu, Binghe, additional, Schilling, Joerg, additional, Apel, Klaus, additional, Vestlev, Peter Michael, additional, Jensen, Brita Bjerregaard, additional, Haahr, Vera, additional, Lescure, Alvaro Rodriguez, additional, Grana Suarez, Begona, additional, Saura Manich, Cristina, additional, Jacquin, Jean-Philippe, additional, Samreen, Ahmed, additional, Boiangiu, Ion, additional, Dank, Magdolna, additional, Falci, Cristina, additional, Jirillo, Antonio, additional, Cinieri, Saverio, additional, Ueno, Takayuki, additional, Sato, Fumiaki, additional, Yamashiro, Hiroyasu, additional, Sugie, Tomoharu, additional, Lee, Keun Seok, additional, Ro, Jung Sil, additional, Park, In Hae, additional, Bustam, Anita Zarina, additional, Suszko-Kazarnowicz, Malgorzata, additional, Piktel, Artur, additional, Krzemieniecki, Krzysztof, additional, Iorga, Polizenia Georgeta, additional, Yap, Yoon Sim, additional, Kakalejcik, Marian, additional, Sevinc, Alper, additional, Ozguroglu, Mustafa, additional, Chen, Shin-Cheh, additional, Greenberg, Richard H., additional, Eisemann, Allan Daniel, additional, Droder, Robert, additional, Abbasi, M. Rashid, additional, Vaysburd, Marina, additional, Caldera, Humberto Jose, additional, Haley, Barbara Bacsik, additional, Robin, Erwin, additional, Inhorn, Roger C., additional, Hufnagel, David, additional, Kenyon, Peter D., additional, Spremulli, Ellen, additional, Silverman, Paula, additional, Jain, Sharad, additional, Weigand, Robert, additional, Mebis, Jeroen, additional, Koynova, Tatyana, additional, Lesperance, Bernard, additional, Prausova, Jana, additional, Kohne, Claus-Henning, additional, Schneeweiss, Andreas, additional, Jackisch, Christian, additional, Fuxius, Stefan, additional, Cubedo Cervera, Ricardo, additional, Urruticoechea Ribate, Ander, additional, Pernas Simon, Sonia, additional, Valero Gallego, Jose, additional, Arcusa Lanza, Angels, additional, del Pilar Alvarez, Maria, additional, Florian Gerico, Jesus, additional, Cany, Laurent, additional, Stebbing, Justin, additional, Labudovic, Dejan, additional, Gugic, Damir, additional, Vrbanec, Damir, additional, Roila, Fausto, additional, Barni, Sandro, additional, Bidoli, Paolo, additional, Mukai, Hirofumi, additional, Bermudez, Vanessa, additional, Eniu, Alexandru, additional, Mirtsching, Barry C., additional, Ibrahim, Emad, additional, Trey, Joan, additional, Hergenroeder, Paul Francis, additional, Mahmood, Aftab, additional, Gonzalez, Anneliese, additional, Kaplan, Edward H., additional, Ban, Stacy, additional, Patel, Dhimant, additional, Clowney, Billy, additional, Hoelzer, Karen, additional, Schwartz, Garry H., additional, Salkeni, Mohamed, additional, Abraham, Jame, additional, Narula, Sunil, additional, Jabboury, Khaled, additional, Mocharnuk, Robert Scott, additional, McDonough, Richard H., additional, Sikes, David H., additional, Kawanchi, Ronald H., additional, Schlabach, Larry, additional, McCachren, Samuel Spence, additional, Cosgriff, Thomas M., additional, Dreisbach, Luke, additional, DeMichele, Angela, additional, Pawl, Lawrence, additional, Lucas, Jennifer, additional, Shinn, Lowell C., additional, Alkhouri, Nabiel, additional, Monga, Manish, additional, Lindquist, Deborah L., additional, Anderson, Thomas C., additional, Khurshid, Humera, additional, Witherby, Sabrina, additional, Erickson, Nicholette, additional, Traynor, Ann, additional, Bose, Ron, additional, Pluard, Timothy J., additional, Jones, Michael C., additional, Prakash, Sucharu, additional, Volterra, Fabio, additional, Capo, Gerardo, additional, Flaherty, Lawrence E., additional, Gartner, Elaina, additional, Baidas, Said, additional, Okazaki, Ian, additional, Nguyen, Bichlien, additional, Rakowski, Thomas, additional, Oliff, Ira, additional, Leach, Joseph W., additional, Anderson, Daniel, additional, Kubiak, Kendra, additional, Tsai, Michaela, additional, Vroman, Philippe, additional, Deleu, Ines, additional, Lybaert, Willem, additional, Borms, Marleen, additional, Couture, Felix, additional, Wilson, Jonathan J., additional, Hunt, Gordon, additional, Holland, David R., additional, Mingrone, Walter, additional, Wang, Shusen, additional, Liu, Donggeng, additional, Jiang, Zefei, additional, Benesova, Vera, additional, Smakal, Martin, additional, Garnolova, Petra, additional, Vesper, Anne-Sophie, additional, Neumann, Monika, additional, Janni, Wolfgang, additional, Liedtke, Cornelia, additional, Fischer, Dorothea, additional, Grischke, Eva-Maria, additional, Seeger, Dietmar, additional, Moebus, Volker, additional, Prechtl, Anita, additional, Carlos Camara Toral, Juan, additional, Sanchez Munoz, Alfonso, additional, Gonzalez Jimenez, Sonia, additional, Cassinello Espinosa, Javier, additional, Cirauqui, Beatriz, additional, Margeli Vila, Mireia, additional, Batista Lopez, Norberto, additional, Chacon Lopez-Muniz, Jose Ignacio, additional, de la Cruz Mora, Miguel Angel, additional, Mailliez, Audrey, additional, Vanlemmens, Laurence, additional, Pouessel, Damien, additional, Espie, Marc, additional, Conibear, John, additional, Roylance, Rebecca, additional, Harnett, Adrian, additional, Geffen, David, additional, Ruggeri, Enzo Maria, additional, Gamucci, Teresa, additional, Van Groeningen, Cees J., additional, Banas, Renata, additional, Alkis, Necati, additional, Hou, Ming-Feng, additional, Krie, Amy K., additional, Vrindavanam, Nandagopal S., additional, Howard, Orion M., additional, Citrin, Dennis, additional, Morginstin, Mark S., additional, Desai, Ajit, additional, Sanchez, Ines J., additional, Nixon, David Allen, additional, Beatty, Patrick G., additional, Edmiston, Kathryn, additional, McLaughlin, Marilyn, additional, Eneman, Jonathan D., additional, Lynch, Cynthia A., additional, O'Brien, Edward, additional, Call, Justin A., additional, Lanier, Keith S., additional, Conlin, Alison, additional, Brooks, Donald J., additional, McIntyre, Kristi, additional, Saltzman, Marc A., additional, Castine, Michael J., additional, Ortega, Gregory L., additional, Choi, Young M., additional, Reynolds, Craig H., additional, Brescia, Frankie Ann, additional, Kramer, Rita, additional, Kohn, Aimee D., additional, Micha, John P., additional, Rhee, Jessica M., additional, Shah, Satish, additional, Riseberg, David A., additional, Patterson, William Kevin, additional, Salmon, Jean-Paul, additional, Andre, Chantal, additional, Bols, Alain, additional, D'hondt, Randal, additional, Luce, Sylvie, additional, Nouwynck, Claire, additional, Pelgrims, Gino, additional, Richard, Vincent, additional, Verschuere, Johan, additional, Geldhof, Kurt, additional, Caspar, Clemens, additional, Luo, Rongcheng, additional, Bednarik, Otakar, additional, Schwedler, Kathrin, additional, Schmidt, Marcus, additional, Neumeister, Romy, additional, Bischoff, Joachim, additional, Rack, Brigitte, additional, Repp, Roland, additional, Fries, Stefan, additional, Adrion, Ralf, additional, Schulz, Volker, additional, Klare, Peter, additional, Danei, Mahmoud, additional, Ossenbuhl, Dirk, additional, Kusche, Jakob Manfred, additional, Griesinger, Frank, additional, Baena Canada, Jose Manuel, additional, Martinez del Prado, Purificacion, additional, Machover, David, additional, Mayeur, Didier, additional, Trufflandier, Nathalie, additional, Delecroix, Valerie, additional, Mousseau, Mireille, additional, Mouret-Reynier, Marie-Ange, additional, Nabholtz, Jean-Marc, additional, Chetiyawardana, Anula D., additional, Papandreou, Christos, additional, Hornyak, Lajos, additional, Faluhelyi, Zsolt, additional, Simo, Erzsebet, additional, Di Palma, Mario, additional, Cognetti, Francesco, additional, Gorzegno, Gabriella, additional, Dogliotti, Luigi, additional, Gridelli, Cesare, additional, Falcone, Alfredo, additional, Soto Parra, Hector, additional, Buscarino, Calogero, additional, Im, Seock-Ah, additional, Sanchez Llamas, Benito, additional, Dercksen, Wouter, additional, Erdkamp, Franciscus, additional, Ruit, Jan B., additional, Braun, Hans, additional, Portielje, Joanneke E.A., additional, Ciltas, Aydin, additional, Buyukberber, Suleyman, additional, Benekli, Mustafa, additional, Zahalsky, Andrew J., additional, Jaslow, Rebecca, additional, Thomas, Gary W., additional, Maini, Archana, additional, Wiznitzer, Israel, additional, Khojasteh, Ali, additional, Francisco Gonzalez, Manuel, additional, Kong, Lynn R., additional, Padmanabhan, Aruna, additional, Conkright, William A., additional, Swain, Sandra M., additional, Faig, Douglas E., additional, Jain, Kirti, additional, Yanagihara, Ronald H., additional, Ottaviano, Yvonne, additional, Delmas, Andrew, additional, Steele, Heather A., additional, Rainey, Gordon K., additional, Harris, Penelope J., additional, Burris, Jason K., additional, Rupard, Erik J., additional, Tan, Esther, additional, Whitworth, Pat W., additional, Bova, Abby R., additional, Anderson, Ian C., additional, Shirinian, Mihran, additional, Tin-u, Caesar, additional, O'Rourke, Timothy J., additional, Roberts, Michael S., additional, Francisco, Michael, additional, Pierson, A. Scott, additional, Byeff, Peter D., additional, Kovach, Peter A., additional, Caton, John R., additional, Rarick, Mark Urban, additional, Schimidt, William G., additional, Stopeck, Alison T., additional, Swart, Rachel, additional, Carrillo Flores, Maria Regina, additional, Alemany, Carlos A., additional, Lozada, Brennely, additional, Weinstein, Paul L., additional, Wang, Wei, additional, Porubcin, Michael, additional, Ellison, David M., additional, Geils, George F., additional, Rivera, Edgardo, additional, and Charif, Mahmoud, additional

Published
2017
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7. 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

Author

Martin, M, Holmes, F, Ejlertsen, B, Delaloge, S, Moy, B, Iwata, H, von Minckwitz, G, Chia, S, Mansi, J, Barrios, C, Gnant, M, Tomasevic, Z, Denduluri, N, Separovic, R, Gokmen, E, Bashford, A, Borrego, M, Kim, S, Jakobsen, E, Ciceniene, A, Inoue, K, Overkamp, F, Heijns, J, Armstrong, A, Link, J, Abraham, A, Bryce, J, Wong, A, Moran, S, Yao, B, Xu, F, Auerbach, A, Buyse, M, Chan, A, Bidoli, P, Holmes, FA, Chia, SKL, Barrios, CH, Borrego, MR, Kim, SB, Jakobsen, EH, Heijns, JB, Armstrong, AC, Link, JS, Bryce, JR, Martin, M, Holmes, F, Ejlertsen, B, Delaloge, S, Moy, B, Iwata, H, von Minckwitz, G, Chia, S, Mansi, J, Barrios, C, Gnant, M, Tomasevic, Z, Denduluri, N, Separovic, R, Gokmen, E, Bashford, A, Borrego, M, Kim, S, Jakobsen, E, Ciceniene, A, Inoue, K, Overkamp, F, Heijns, J, Armstrong, A, Link, J, Abraham, A, Bryce, J, Wong, A, Moran, S, Yao, B, Xu, F, Auerbach, A, Buyse, M, Chan, A, Bidoli, P, Holmes, FA, Chia, SKL, Barrios, CH, Borrego, MR, Kim, SB, Jakobsen, EH, Heijns, JB, Armstrong, AC, Link, JS, and Bryce, JR

Abstract

Background 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. Methods 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. Findings 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

Published
2017

8. 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

Author

Martin, M., Holmes, F., Ejlertsen, B., Delaloge, S., Moy, B., Iwata, H., von Minckwitz, G., Chia, S., Mansi, J., Barrios, C., Gnant, M., Tomaševic, Z., Denduluri, N., Šeparovic, R., Gokmen, E., Bashford, A., Ruiz Borrego, M., Kim, S., Jakobsen, E., Ciceniene, A., Inoue, K., Overkamp, F., Heijns, J., Armstrong, A., Link, J., Joy, A., Bryce, R., Wong, A., Moran, S., Yao, B., Xu, F., Auerbach, A., Buyse, M., Chan, Arlene, ExteNET Study Group, Martin, M., Holmes, F., Ejlertsen, B., Delaloge, S., Moy, B., Iwata, H., von Minckwitz, G., Chia, S., Mansi, J., Barrios, C., Gnant, M., Tomaševic, Z., Denduluri, N., Šeparovic, R., Gokmen, E., Bashford, A., Ruiz Borrego, M., Kim, S., Jakobsen, E., Ciceniene, A., Inoue, K., Overkamp, F., Heijns, J., Armstrong, A., Link, J., Joy, A., Bryce, R., Wong, A., Moran, S., Yao, B., Xu, F., Auerbach, A., Buyse, M., Chan, Arlene, and ExteNET Study Group

Abstract

Background: 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. Methods: 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. Findings: 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), patien

Published
2017

9. Effects of neratinib (N) on health-related quality of life (HRQoL) in early-stage HER2+ breast cancer (BC): longitudinal analyses from the phase III ExteNET trial

Author

Delaloge, S., primary, Ye, Y., additional, Cella, D., additional, Buyse, M., additional, Chan, A., additional, Barrios, C., additional, Holmes, F.A., additional, Mansi, J., additional, Iwata, H., additional, Ejlertsen, B., additional, Moy, B., additional, von Minckwitz, G., additional, Chia, S., additional, Gnant, M., additional, Smichkoska, S., additional, Ciceniene, A., additional, Moran, S., additional, Auerbach, A.H., additional, Fallowfield, L., additional, and Martin Jimenez, M., additional

Published
2017
Full Text
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10. Effects of neratinib (N) on health-related quality of life (HRQoL) in early-stage HER2+ breast cancer (BC): longitudinal analyses from the phase III ExteNET trial

Author

S Chia, H. Iwata, A.H. Auerbach, M. Martin Jimenez, Beverly Moy, Marc Buyse, David Cella, A. Ciceniene, Snezhana Smichkoska, A. Chan, Suzette Delaloge, Janine Mansi, Y. Ye, Frankie A. Holmes, S. Moran, Carlos H. Barrios, Bent Ejlertsen, Lesley Fallowfield, Michael Gnant, and G. von Minckwitz

Subjects
0301 basic medicine, Health related quality of life, Oncology, Gynecology, medicine.medical_specialty, business.industry, Hematology, medicine.disease, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Breast cancer, 030220 oncology & carcinogenesis, Internal medicine, Neratinib, medicine, Stage (cooking), business, medicine.drug
Published
2017

12. P-771 Surgical treatment of small cell lung cancer during 1980–2003years

Author

A. Jackevičius, A. Ciceniene, E. Aleknavičius, and Saulius Cicenas

Subjects
Pulmonary and Respiratory Medicine, Oncology, Cancer Research, medicine.medical_specialty, business.industry, Internal medicine, medicine, Cancer, Non small cell, medicine.disease, business, Surgical treatment
Published
2005

15. Induction chemoterapy gemcitabine(G)-cisplatin(C) versus etoposide(E)-cisplatin(C) in IIIA/IIIB stages non — small cell lung cancer (NSCLC) patients with intermittent radiotherapy

Author

Terese Pipiriene-Zelviene, Audrone Ciceniene, Arvydas Burneckis, and Saulius Cicenas

Subjects
Pulmonary and Respiratory Medicine, Oncology, Cisplatin, Cancer Research, medicine.medical_specialty, business.industry, medicine.medical_treatment, non-small cell lung cancer (NSCLC), medicine.disease, Gemcitabine, Radiation therapy, Internal medicine, Medicine, business, Etoposide, medicine.drug
Published
2003

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