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 - 30/12/17
Doi : 10.1016/S1470-2045(17)30717-9
Miguel Martin, ProfMD a, ⁎ 
, Frankie A Holmes, MD b, Bent Ejlertsen, MD c, Suzette Delaloge, MD d, Beverly Moy, MD e, Hiroji Iwata, MD f, Gunter von Minckwitz, ProfMD g, Stephen K L Chia, MD h, Janine Mansi, MD i, Carlos H Barrios, ProfMD j, Michael Gnant, ProfMD k, Zorica Tomašević, MD l, Neelima Denduluri, MD m, Robert Šeparović, MD n, Erhan Gokmen, MD o, Anna Bashford, MBChB p, Manuel Ruiz Borrego, MD p, Sung-Bae Kim, ProfMD r, Erik Hugger Jakobsen, MD s, Audrone Ciceniene, MD t, Kenichi Inoue, MD u, Friedrich Overkamp, MD v, Joan B Heijns, MD w, Anne C Armstrong, MBChB x, John S Link, MD y, Anil Abraham Joy, ProfMD z, Richard Bryce, MBChB aa, Alvin Wong, PharmD aa, Susan Moran, MD aa, Bin Yao, MS aa, Feng Xu, MS aa, Alan Auerbach, MS aa, Marc Buyse, ScD ab, Arlene Chan, ProfMD ac, ad
for the
, Frankie A Holmes, MD b, Bent Ejlertsen, MD c, Suzette Delaloge, MD d, Beverly Moy, MD e, Hiroji Iwata, MD f, Gunter von Minckwitz, ProfMD g, Stephen K L Chia, MD h, Janine Mansi, MD i, Carlos H Barrios, ProfMD j, Michael Gnant, ProfMD k, Zorica Tomašević, MD l, Neelima Denduluri, MD m, Robert Šeparović, MD n, Erhan Gokmen, MD o, Anna Bashford, MBChB p, Manuel Ruiz Borrego, MD p, Sung-Bae Kim, ProfMD r, Erik Hugger Jakobsen, MD s, Audrone Ciceniene, MD t, Kenichi Inoue, MD u, Friedrich Overkamp, MD v, Joan B Heijns, MD w, Anne C Armstrong, MBChB x, John S Link, MD y, Anil Abraham Joy, ProfMD z, Richard Bryce, MBChB aa, Alvin Wong, PharmD aa, Susan Moran, MD aa, Bin Yao, MS aa, Feng Xu, MS aa, Alan Auerbach, MS aa, Marc Buyse, ScD ab, Arlene Chan, ProfMD ac, adfor the
ExteNET Study Group†
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, Francesco Nuzzo, 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, Richard Hendry De Boer, Theodore Turnquest, Sideras Lucas, Pierre Dube, Binghe Xu, Joerg Schilling, Klaus Apel, Peter Grundtvig Sorensen, 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, Niklas Loman, 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
a Instituto de Investigación Sanitaria Gregorio Marañón, Grupo Español de Investigación en Cáncer de Mama (GEICAM), Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Universidad Complutense, Madrid, Spain
b Texas Oncology, Houston, TX, USA
c Rigshospitalet, Copenhagen, Denmark
d Institut Gustave Roussy, Villejuif, France
e Massachusetts General Hospital Cancer Center, Boston, MA, USA
f Aichi Cancer Center, Chikusa-ku, Nagoya, Japan
g Luisenkrankenhaus, German Breast Group Forschungs GmbH, Düsseldorf, Neulsenburg, Germany
h BC Cancer Agency, Vancouver, BC, Canada
i Guy’s and St Thomas’ Hospital National Health Service Foundation Trust and Biomedical Research Centre, King’s College, London, UK
j Pontifical Catholic University of Rio Grande do Sul School of Medicine, Porto Alegre, Brazil
k Department of Surgery and Comprehensive Cancer Centre, Medical University of Vienna, Vienna, Austria
l Daily Chemotherapy Hospital, Institute for Oncology and Radiology of Serbia, Belgrade, Serbia
m Virginia Cancer Specialists, Arlington, VA, USA
n University Hospital for Tumors, University Hospital Center “Sestre milosrdnice”, Zagreb, Croatia
o Ege University Faculty of Medicine, Izmir, Turkey
p Auckland Hospital, Auckland, New Zealand
p Oncology Department, Hospital Universitario Virgen del Rocio, Seville, Spain
r Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
s Department of Oncology, Lillebaelt Hospital, Vejle, Denmark
t Oncology Institute of Vilnius University, Vilnius, Lithuania
u Breast Oncology, Saitama Cancer Center, Kita-Adachi, Japan
v Oncologianova GmbH, Recklinghausen, Germany
w Department of Medical Oncology, Amphia Hospital, Breda, Netherlands
x Department of Oncology, Christie Hospital Manchester, Manchester, UK
y Breastlink Medical Group Inc, Santa Ana, CA, USA
z University of Alberta, Department of Oncology, Cross Cancer Institute, Edmonton, AB, Canada
aa Puma Biotechnology Inc, Los Angeles, CA, USA
ab International Drug Development Institute, Louvain-la-Neuve, Belgium
ac Breast Cancer Research Centre–Western Australia, Perth, WA, Australia
ad Curtin University, Perth, WA, Australia
* Correspondence to: Prof Miguel Martin Instituto de Investigación Sanitaria Gregorio Marañón, Grupo Español de Investigación en Cáncer de Mama (GEICAM), Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Universidad Complutense, Madrid, 28007, Spain Correspondence to: Prof Miguel Martin Instituto de Investigación Sanitaria Gregorio Marañón Grupo Español de Investigación en Cáncer de Mama (GEICAM) Centro de Investigación Biomédica en Red de Cáncer (CIBERONC) Universidad Complutense Madrid 28007 Spain
Summary |
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 [<1%] grade 4 with neratinib vs 23 [2%] grade 3 with placebo), vomiting (grade 3: 47 [3%] vs five [<1%]), and nausea (grade 3: 26 [2%] vs two [<1%]). Treatment-emergent serious adverse events occurred in 103 (7%) women in the neratinib group and 85 (6%) women in the placebo group. No evidence of increased risk of long-term toxicity or long-term adverse consequences of neratinib-associated diarrhoea were identified with neratinib compared with placebo.
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.
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Vol 18 - N° 12
P. 1688-1700 - décembre 2017 Retour au numéro
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