Format

Send to

Choose Destination
Lancet Oncol. 2017 Dec;18(12):1688-1700. doi: 10.1016/S1470-2045(17)30717-9. Epub 2017 Nov 13.

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.

Collaborators (592)

Harvey V, Tomek R, Robert NJ, Gore I Jr., Smith JW 2nd, Masuda N, Di Sean Kendall S, Harker WG, Petrakova K, Guerrero Zotano A, Simon AR, Konstantinovic ZN, Iannotti NO, Tassone P, Rodriguez GI, Jáñez Martinez N, Crespo Massieu C, Smickoska S, Somali I, Yilmaz U, Alonso MG, Rosales AM, Cold S, Knoop AS, Patt D, Hellerstedt BA, Morales Murillo S, Mayer IA, Means-Powell JA, Hui R, Senecal FM, De Boer RH, Shen Z, Luczak AA, Chui JWY, Tsang JW, Lang I, Rai Y, Hozumi Y, Ten Tije AJ, Bhandari M, Osborne CRC, Ohtani S, Higaki K, Watanabe K, Taguchi K, Takahashi M, Filipovic S, Hansen VL, Rao VP, Gupta M, Petrov P, Coudert B, Vojnovic Z, Polya Z, Miyaki T, Yamamoto N, Brincat S, Lesniewski-Kmak K, Chmielowska E, Birhiray RE, Citron ML, Papish SW, Berry WR, Langkjer ST, Garcia Sáenz JA, Arance AM, Efrat N, Sarosiek T, Grzeda L, Manalo Y, Smith JC, Vaziri I, Healey T, Rahim Y, Luk C, Dingle B, Franco S, Sorensen PG, Anand A, Khan S, Fountzilas G, Aogi K, Shimizu S, Mikulova M, Spanik S, Somer RA, Flynn PJ, Coward J, Mainwaring P, Jerusalem G, Segura-Ojezzar C, Levy C, Delozier T, Khayat D, Coleman RE, Rolles MJ, Maisano R, Nardi M, Ito Y, Yumuk PF, Basaran G, Serdar Turhal N, Wilkinson MJ, Green NB, Sidrys AP, Hallmeyer S, Testori DJ, Sridhar S, Chang J, Sun Q, Jara-Sanchez C, Rubio X, Garrido ML, De La Haba Rodriguez JR, Perello Martorell A, Avelia Mestre A, Rifa Ferrer J, Del Barco Berron S, Nagy Z, Tanaka M, Im YH, Carroll RR, Dickerson LC, Mace JR, Rivera R, Klein LM, Ruxer R, Wilks ST, Kotasek D, Popov V, Taskova V, Marinova-Venkova V, Timcheva C, Desbiens C, Ayoub JP, Grenier D, Marschner N, Tesch H, Lueck HJ, Janssen J, Schwaner I, Wahlstrom S, Brix EH, Vallentin S, Kristensen D, Andreeva A, Glavicic V, Calvo Plaza I, Anton Torres A, Veyret C, Bergerat JP, Bourbouloux E, Ella WA, Algurafi H, Robinson A, Kim SJ, Taguchi T, Juozaityte E, Madretsma S, Radema S, Czerniawska-Meier M, Rogowski W, Wagnerova M, Richards DA, Tan-Chiu E, Vasileios A, Henderson CA, Holden VR, Wang X, Tong Z, Yang J, Gonzalez ME, Rezai M, Hackmann J, de Dueñas EM, de Las Heras BB, Dourthe LM, Chocteau-Bouju D, Bougnoux P, Kakolyris S, Kalofonos H, Pectasidis D, Ng TY, Pajkos G, Somogyine EE, Tonini G, Giuffrida D, Takao S, Ishitobi M, Inaji H, Tokuda Y, Wozniak K, Lungulescu D, Lu YS, Chang KJ, Hill J, Croot CC, Dekker A, Belman ND, Conde M, Michaelson RA, Kemmer K, Chui S, Luoh SW, Nahum K, Greenspan AR, Nichols JC, Encarnacion CA, Niederman TMJ, Lee T, Alexander R, Gordon R, Tomova A, Rauch D, Popescu RA, Rojas GA, Vanasek J, Neunhoeffer T, Barinoff J, Graffunder G, Wolfgang A, Bojko P, Heinrich B, von der Assen A, Antonovic BJ, Adrian L, Ramos Vazquez M, Gonzalez Santiago S, Dieras V, Bishop JM, Perren TJ, Varthalitis I, Mavroudis D, Georgoulias V, Chow LWC, Yau CCT, Liang RH, Pikó B, Wéber A, Kaufman B, Drumea K, Nuzzo F, De Matteis A, Nuzzo F, Carteni G, Tokunaga E, Ishida M, Ohno S, Sato N, Kuroi K, Nishimura R, Watanabe J, Choi YJ, Park KH, Wojtukiewicz M, Jassem J, Loman N, Askoy S, Altundag MK, Saip P, Ali MA, Wade JL 3rd, Chien AJ, Brandt D, Novik Y, Jani C, Rice RL, Gaffar YAR, Keaton MR, Bajaj R, Kimmick G, Campbell D, De Boer RH, Turnquest T, Lucas S, Dube P, Xu B, Schilling J, Apel K, Sorensen PG, Vestlev PM, Jensen BB, Haahr V, Lescure AR, Grana Suarez B, Saura Manich C, Jacquin JP, Samreen A, Boiangiu I, Dank M, Falci C, Jirillo A, Cinieri S, Ueno T, Sato F, Yamashiro H, Sugie T, Lee KS, Ro JS, Park IH, Bustam AZ, Suszko-Kazarnowicz M, Piktel A, Krzemieniecki K, Iorga PG, Yap YS, Kakalejcik M, Sevinc A, Ozguroglu M, Chen SC, Greenberg RH, Eisemann AD, Droder R, Abbasi MR, Vaysburd M, Caldera HJ, Haley BB, Robin E, Inhorn RC, Hufnagel D, Kenyon PD, Spremulli E, Silverman P, Jain S, Weigand R, Mebis J, Koynova T, Lesperance B, Prausova J, Kohne CH, Schneeweiss A, Jackisch C, Fuxius S, Cubedo Cervera R, Urruticoechea Ribate A, Pernas Simon S, Valero Gallego J, Arcusa Lanza A, Del Pilar Alvarez M, Florian Gerico J, Cany L, Stebbing J, Labudovic D, Gugic D, Vrbanec D, Roila F, Barni S, Bidoli P, Mukai H, Bermudez V, Eniu A, Mirtsching BC, Ibrahim E, Trey J, Hergenroeder PF, Mahmood A, Gonzalez A, Kaplan EH, Ban S, Patel D, Clowney B, Hoelzer K, Schwartz GH, Salkeni M, Abraham J, Narula S, Jabboury K, Mocharnuk RS, McDonough RH, Sikes DH, Kawanchi RH, Schlabach L, McCachren SS Jr., Cosgriff TM, Dreisbach L, DeMichele A, Pawl L, Lucas J, Shinn LC, Alkhouri N, Monga M, Lindquist DL, Anderson TC, Khurshid H, Witherby S, Erickson N, Traynor A, Bose R, Pluard TJ, Jones MC, Prakash S, Volterra F, Capo G, Flaherty LE, Gartner E, Baidas S, Okazaki I, Nguyen B, Rakowski T, Oliff I, Leach JW, Anderson D, Kubiak K, Tsai M, Vroman P, Deleu I, Lybaert W, Borms M, Couture F, Wilson JJ, Hunt G, Holland DR, Mingrone W, Wang S, Liu D, Jiang Z, Benesova V, Smakal M, Garnolova P, Vesper AS, Neumann M, Janni W, Liedtke C, Fischer D, Grischke EM, Seeger D, Moebus V, Prechtl A, Carlos Camara Toral J, Sanchez Munoz A, Gonzalez Jimenez S, Cassinello Espinosa J, Cirauqui B, Margeli Vila M, Batista Lopez N, Chacon Lopez-Muniz JI, de la Cruz Mora MA, Mailliez A, Vanlemmens L, Pouessel D, Espie M, Conibear J, Roylance R, Harnett A, Geffen D, Ruggeri EM, Gamucci T, Van Groeningen CJ, Banas R, Loman N, Alkis N, Hou MF, Krie AK, Vrindavanam NS, Howard OM, Citrin D, Morginstin MS, Desai A, Sanchez IJ, Nixon DA Jr., Beatty PG, Edmiston K, McLaughlin M, Eneman JD, Lynch CA, O'Brien E, Call JA, Lanier KS, Conlin A, Brooks DJ, McIntyre K, Saltzman MA, Castine MJ 3rd, Ortega GL, Choi YM, Reynolds CH, Brescia FA, Kramer R, Kohn AD, Micha JP, Rhee JM, Shah S, Riseberg DA, Patterson WK, Salmon JP, Andre C, Bols A, D'hondt R, Luce S, Nouwynck C, Pelgrims G, Richard V, Verschuere J, Geldhof K, Caspar C, Luo R, Bednarik O, Schwedler K, Schmidt M, Neumeister R, Bischoff J, Rack B, Repp R, Fries S, Adrion R, Schulz V, Klare P, Danei M, Ossenbuhl D, Kusche JM, Griesinger F, Baena Canada JM, Martinez Del Prado P, Machover D, Mayeur D, Trufflandier N, Delecroix V, Mousseau M, Mouret-Reynier MA, Nabholtz JM, Chetiyawardana AD, Papandreou C, Hornyak L, Faluhelyi Z, Simo E, Di Palma M, Cognetti F, Gorzegno G, Dogliotti L, Gridelli C, Falcone A, Soto Parra H, Buscarino C, Im SA, Sanchez Llamas B, Dercksen W, Erdkamp F, Ruit JB, Braun H, Portielje JEA, Ciltas A, Buyukberber S, Benekli M, Zahalsky AJ, Jaslow R, Thomas GW, Maini A, Wiznitzer I, Khojasteh A, Francisco Gonzalez M, Kong LR, Padmanabhan A, Conkright WA, Swain SM, Faig DE, Jain K, Yanagihara RH, Ottaviano Y, Delmas A, Steele HA, Rainey GK, Harris PJ, Burris JK, Rupard EJ, Tan E, Whitworth PW, Bova AR, Anderson IC, Shirinian M, Tin-U C, O'Rourke TJ, Roberts MS, Francisco M, Pierson AS, Byeff PD, Kovach PA, Caton JR Jr., Rarick MU, Schimidt WG Jr., Stopeck AT, Swart R, Carrillo Flores MR, Alemany CA, Lozada B, Weinstein PL, Wang W, Porubcin M, Ellison DM, Geils GF, Rivera E, Charif M.

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 [<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.

PMID:
29146401
DOI:
10.1016/S1470-2045(17)30717-9
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center