Supplementary appendix - The Lancet appendix ... A. Tomova; T. Koynova; Canada: A. Joy; C. Luk; R....

Supplementary appendixThis appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors.

Supplement to: Chan A, Delaloge S, Holmes FA, et al, for the ExteNET Study Group. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2016; published online Feb 10. http://dx.doi.org/10.1016/S1470-2045(15)00551-3.

1

SUPPLEMENTARY APPENDIX

Table of Contents

List of Investigators and Countries ............................................................................................................. ... 2

Academic Steering Committee and Independent Data Monitoring Committee .......................................... ... 4

History of Global Protocol Amendments ................................................................................................... ... 5

Sensitivity Analysis of Early Drop-Outs .................................................................................................... ... 7

Figure S1. Kaplan-Meier Curves Showing Invasive Disease-free Survival in Hormone Receptor–Positive

Patients and in Hormone Receptor–Negative Patients and Disease-free Survival Including Ductal

Carcinoma In Situ in Hormone Receptor–Positive Patients and in Hormone Receptor–Negative Patients

(Intention-to-Treat Population) .................................................................................................................... ... 8

Figure S2. Kaplan-Meier Curves Showing Invasive Disease-free Survival and Disease-free Survival

Including Ductal Carcinoma In Situ (Amended Intention-to-Treat Population) .......................................... ... 9

Figure S3. Kaplan-Meier Curves Showing Invasive Disease-free Survival and Disease-free Survival

Including Ductal Carcinoma In Situ (Centrally-Confirmed HER2-Positive Patients) ................................. . 10

Figure S4. Diarrheal Events by Grade Over Time in Patients Treated with Neratinib ................................ . 11

Figure S5. Mean FACT-B Total Scores and EQ-5D Visual Analog Scale Scores by Treatment Group ..... . 12

Table S1. Efficacy Endpoint Definitions .................................................................................................... . 13

Table S2. Efficacy Endpoint Analyses (Intention-to-Treat Population) ..................................................... . 14

Table S3. Baseline Characteristics of Patients According to Duration of Follow-up (Intention-to-Treat

Population) ................................................................................................................................................. . 15

Table S4. Treatment-Emergent Adverse Events of Grade 3 or Greater in Descending Order of Frequency

(Safety Population) ..................................................................................................................................... . 17

Table S5. Summary of Treatment-Emergent Diarrhea in the ExteNET Study (Safety Population) and Study

5201 ............................................................................................................................................................ . 22

Table S6. Summary of Study Sites, Principle Investigators Responsible for Each Site and the Number of

Patients Enrolled from Each Site ............................................................................................................... . 23

References .................................................................................................................................................. . 34

2

LIST OF INVESTIGATORS AND COUNTRIES

We would like to acknowledge the following investigators who also participated in this trial: Australia: A.

Chan; R. Hui; R. De Boer; T. Healey; P. Mainwaring; D. Kotasek; D. Campbell; W. Patterson; Bahamas: T.

Turnquest; Belgium: G. Jerusalem; J. Mebis; V. Philippe; I. Deleu; M. Borms; J-P. Salmon; A. Bols; R.

D'Hondt; C. Nouwynck; G. Pelgrims; V. Richard; J. Verschuere; K. Geldhof; Brazil: C. Barrios; Bulgaria: P.

Petrov; V. Taskova; C. Timcheva; A. Tomova; T. Koynova; Canada: A. Joy; C. Luk; R. Yasmin; B. Dingle;

S. Sridhar; J. Chang; C. Desbiens; J-P. Ayoub; D. Grenier; P. Dube; S. Chia; B. Lesperance; F. Couture; J.

Wilson; G. Hunt; China: Z-Z. Shen; Q. Sun; X. Wang; Z-S. Tong; J. Yang; B. Xu; Z. Jiang; D-G. Liu; R. Luo;

Colombia: S. Franco; M. E. G. Fernandez; G. Rojas; Croatia: T. Silovski; Z. Vojnovic; D. Gugic; D. Vrbanec;

Czech Republic: K. Petrakova; J. Vanasek; J. Prausova; V. Benesova; P. Garnolova; O. Bednarik; Denmark:

E. H. Jakobsen; S. Cold; A. Luczak; S. Langkjer; P. Sørensen; B. Ejlertsen; E. Harder-Brix; V. Glavicic; L.

Adrian; P. Vestlev; B. Bjerregaard Jensen; V. Haahr; France: S. Delaloge; B. Coudert; C. Levy; D. Khayat; C.

Veyret; J-P. Bergerat; E. Bourbouloux; L-M. Dourthe; P. Bougnoux; V. Dieras; J-P. Jacquin; L. Cany; L.

Vanlemmens; M. Espie; D. Machover; D. Mayeur; N. Trufflandier; V. Delacroix; M. Mousseau; J-M. Nabholtz;

Germany: F. Overkamp; N. Marschner; H. Tesch; H-J. Lück; J. Janssen; I. Schwaner; G. von Minckwitz; J.

Hackmann; T. Neunhoeffer; G. Graffunder; P. Bojko; B. Heinrich; A. von der Assen; J. Schilling; K. Apel; C-

H. Koehne; A. Schneeweiss; S. Fuxius; C. Jackisch; M. Neumann; E-M. Grischke; D. Seeger; V. Moebus; A.

Prechtl; M. Kusche; D. Ossenbühl; D. Fischer; R. Repp; P. Klare; F. Griesinger; L. Hanker; B. Schnappauf; J.

Bischoff; R. Neumeister; M. Schmidt; B. Rack; V. Schulz; R. E. Felberbaum; T. Noesselt; Greece: G.

Fountzilas; S. Kakolyris; H. Kalofonos; I. Varthalitis; V. Georgoulias; D. Pectasidis; C. Papandreou; D.

Pectasidis; Hong Kong: W-H Tsang; T-Y. Ng; L. Chow; T. C. C. Yau; Hungary: I. Láng; Z. Pólya; Z. Nagy;

G. Pajkos; É. Somogyiné; Á. Wéber; B. Pikó; M. Dank; E. Simo; Israel: N. Efrat; B. Kaufman; K. Drumea; D.

Geffen; Italy: P. Tassone; M. Nardi; R. Maisano; G. Tonini; D. Giuffrida; G. Cartenì; F. Nuzzo; C. Falci; S.

Cinieri; F. Roila; S. Barni; P. Bidoli; E. Ruggeri; T. Gamucci; F. Cognetti; G. Gorzegno; C. Gridelli; A. Falcone;

H. J. Soto Parra; M. Di Palma; F. Angelini; Japan: N. Masuda; K. Inoue; Y. Rai; Y. Hozumi; K. Higaki; M.

Takahashi; N. Yamamoto; K. Aogi; S. Shimizu; Y. Ito; M. Tanaka; H. Iwata; S. J. Kim; S. Takao; M. Ishitobi;

Y. Tokuda; N. Sato; R. Nishimura; J. Watanabe; O. Shinji; K. Katsumasa; T. Ueno; M. Hirofumi; Lithuania:

A. Ciceniene; E. Juozaityte; Macedonia: S. Smichkoska; Malaysia: A. Z. Bustam; Malta: S. Brincat; Mexico:

B. Sanchez-Llamas; Netherlands: A. Ten Tije; G.S. Madretsma; C. Van Groeningen; M. Dercksen; F.

Erdkamp; J. Braun; J. Ruit; J.E.A. Portielje; New Zealand: V. Harvey; Peru: V. Bermudez; Poland: K.

Lesniewski-Kmak; E. Chmielowska; T. Sarosiek; W. Rogowski; K. Wozniak; M. Wojtukiewicz; J. Jassem; A.

Piktel; K. Krzemieniecki; R. Banas; Romania: D. Lungulescu; P. Iorga; A. Eniu; Serbia: Z. Neskovic-

Konstantinovic; S. Filipovic; Singapore: Y-S. Yap; Slovakia: S. Spanik; M. Wagnerova; M. Kakalejcik; South

Korea: S-B. Kim; Y-H. Im; K. H. Park; J. S. Ro; S-A. Im; Spain: A. G. Zotano; N. Martinez; A. Murias-

Rosales; S. Morales; M. Ruiz-Borrego; M. Martin Jimenez; A. Arance; J. García-Sáenz; C. Jara Sanchez; M.

Lomas-Garrido; J. R. De La Haba Rodriguez; A. Avella Mestre; S. del Barco Berron; I. Calvo Plaza; A. A.

Torres; E. Martínez de Dueñas; B. Bermejo de las Heras; M. Ramos-Vázquez; S. Gonzalez Santiago; A.

Rodriguez Lescure; R. Cubedo Cervera; J. Valero Alvarez Gallego; A. Arcusa; M. del Pilar Lopez Alvarez; J.

Florian Gerico; C. Saura Manich; A. Sanchez-Muñoz; S. González; J. Cassinello; S. Pernas Simón; M. Margeli

Vila; N. Batista; M. Angel de la Cruz Mora; J. C. Toral-Pena; J. Baena Canadá; P. Martinez del Prado; Sweden:

N. Loman; Switzerland: D. Rauch; R. Popescu; W. Mingrone; C. Clemens; Taiwan: Y-S. Lu; S-C. Chen; M-

F. Hou; Turkey: E. Gokmen; I. Somali; S. Turhal; K. Altundag; P. Saip; A. Sevinc; M. Ozguroglu; N. Alkis;

M. Benekli; T. Evrensel; United Kingdom: A. Armstrong; A. Anand; S. Khan; R. Coleman; M. J. Rolles; J.

Mansi; A. Robinson; W. Ella; H. Algurafi; J. Bishop; T. Perren; I. Boiangiu; J. Stebbing; R. R. Roylance; A.

Harnett; A. D. Chetiyawarda; J. Barret; United States of America: S. Sawhney; M. A. Ghraowi; P. M.

Blanchet; J. J. Choate; M. Venigalla; R. Rao; J. A. Berman; F. Qazi; M. A. Danso; N. Robert; I. Gore; J. Smith;

W. Harker; N. Iannotti; G. Rodriguez; B. Hellerstedt; J. Link; J. Means-Powell; F. Senecal; M. Bhandari; C.

Osborne; V. Hansen; V. Rao; B. Moy; M. Gupta; R. Birhiray; M. Citron; W. Berry; Y. Manalo; J. Smith; I.

Vaziri; S. Papish; R. Somer; P. Flynn; M. Wilkinson; N. Green; A. Sidrys; D. Testori; L. Dickerson; J. Mace;

S. Hallmeyer; R. Rivera; L. Klein; R. Ruxer; S. Wilks; D. Richards; E. Tran-Chiu; C. Henderson; V. Holden;

3

C. Croot; A. Dekker; N. Belman; R. Michaelson; S. Chui; K. Nahum; F. Holmes; J. Nichols; C. Encarnacion;

T. Niederman; R. Gordon; A. Greenspan; M. Ali; J. Wade; J. Chien; Y. Novik; C. Jani; R. L. Rice; R. Bajaj; D.

Brandt; R. Greenberg; A. Eiseman; R. Droder; R. Abbasi; M. Vaysburd; B. Haley; E. L. Robin; R. Inhorn; D.

Hufnagle; E. Spremulli; P. Silverman; S. Jain; M. Keaton; R. Weigand; G. Kimmick; H. Caldera; E. Gartner;

L. Flaherty; E. Ibrahim; P. Hergenroeder; A. Mahmood; E. Kaplan; D. Patel; B. W. Clowney; K. Hoelzer; G.

Schwartz; J. Abraham; R. Mocharnuk; L. Schlabach; S. McCachren; T. Cosgriff; L. P. Dreibach; L. Pawl; J.

Lucas; L. Shinn; D. Lindquist; T. Anderson; S. Witherby; N. Erickson; R. Bose; S. Prakahs; F. Volterra; G.

Capo; S. Baidas; I. Okazaki; B. Nguyen; T. Rakowski; I. Oliff; M. Kubiak; B. Mirtsching; S. Narula; K.

Jabboury; R. McDonough; A. DeMichele; A. Krie; N. Vrindavanam; O. Howard; D. Citrin; I. J. Sanchez-

Rivera; D. Nixon; P. Beatty; K. Edmiston; J. Eneman; C. Lynch; J. Call; A. Conlin; D. Brooks; C. Jones; K.

McIntyre; M. Saltzman; M. Castine III; G. Ortega; Y. Choi; C. Reynolds; R. M. Kramer; A. Kohn; J. Micha;

S. Shah; D. Riseberg; M. Morginstin; A. Desai; A. Zahalsky; R. Jaslow; G. Thomas; A. Maini; A. Khojasteh;

M. Gonzalez; L. R. Kong; A. Padmanabha; S. Swain; D. Faig; K. K. Jain; R. Yanagihara; O. Yvonne; E. Tan;

P. Whitworth; A. Bova; I. Anderson; M. Shirinian; C. K. Tin-U; T. O'Rourke; M. S. Roberts; M. Francisco; P.

Byeff; P. Kovach; M. Rarick; W. G. Schmidt; A. Stopeck; M. R. Flores; P. Weinstein; W. Wang; M. Porubcin;

D. Ellison; M. Charif; W. Conkright; E. Rivera; I. Oliff.

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ACADEMIC STEERING COMMITTEE

Carlos Barrios, MD (Pontifical Catholic University of Rio Grande do Sul School of Medicine, Porto Alegre,

Brazil); Arlene Chan, MD (Breast Cancer Research Centre-WA & Curtin University, Perth, Australia); Stephen

Chia, MD (BC Cancer Agency, Vancouver, BC, Canada); Suzette Delaloge, MD (Institut Gustave Roussy,

Villejuif, France); Bent Ejlertsen, MD (Rigshospitalet, Copenhagen, Denmark); Michael Gnant, MD

(Department of Surgery and Comprehensive Cancer Centre, Medical University of Vienna, Vienna, Austria);

Frankie Ann Holmes, MD (Texas Oncology, P.A., Houston, TX, USA); James Ingle*; Hiroji Iwata, MD (Aichi

Cancer Center, Chikusa-ku, Nagoya, Japan); Janine Mansi, MD (Guy's Hospital, London, BRC, King's College,

London, United Kingdom); Miguel Martin, MD (Instituto de Investigación Sanitaria Gregorio Marañón,

Universidad Complutense de Madrid, Madrid, Spain); Beverly Moy, MD (Massachusetts General Hospital

Cancer Center, Boston, MA, USA); Gunter von Minckwitz, MD (Luisenkrankenhaus, German Breast Group

Forschungs GmbH, Düsseldorf, Neu-lsenburg, Germany); Marc Buyse, ScD (International Drug Development

Institute (IDDI), Louvain-la-Neuve, Belgium).

*Original ASC only.

INDEPENDENT DATA MONITORING COMMITTEE

Joanne Mortimer, MD (City of Hope, CA, USA); Mohammad Jahanzeb, MD (University of Miami, FL, USA);

Jack di Palma, MD (USA Gastroenterology, Mobile, AL, USA); Kendra Schmid, PhD (University of Nebraska

Medical Center, NE, USA).

5

HISTORY OF GLOBAL PROTOCOL AMENDMENTS

There were a total of six global protocol amendments over the course of the study under the supervision of three

sponsors. Three of the global protocol amendments, described below, affected the original study design.

Original Protocol (29-Apr-2009, Wyeth)

The primary objective of the study was to compare invasive disease free survival (iDFS) of women with early-

stage HER2 overexpressed/amplified breast cancer following trastuzumab in the extended adjuvant setting,

receiving neratinib versus that of women receiving placebo. Secondary objectives were to compare the

following additional endpoints for subjects receiving neratinib versus those subjects receiving placebo: disease

free survival including ductal carcinoma in situ (DFS-DCIS), time to distant recurrence (TTDR), distant

disease-free survival (DDFS), incidence of central nervous system (CNS) recurrence, overall survival (OS) and

the short- and long-term safety (including incidence of grade 3 or higher diarrhea). Additional exploratory

objectives encompassed health outcomes and biomarker assessments.

The primary endpoint iDFS, was planned to be analyzed using a 1-sided log-rank test to compare the two

treatment groups. Statistical significance of the log-rank test was used to determine the stopping boundaries for

the 2 planned interim analyses at approximately 135 and 236 iDFS events, respectively, while the final analysis

was planned at approximately 337 iDFS events. The study was designed to provide approximately 90% power

to detect a difference in iDFS between the 2 treatment arms assuming a hazard ratio (HR) of 0·70 based upon

a 1-sided log-rank test controlling the type I error at 0·025.

The required study sample size of 3850 subjects was established by assuming a placebo arm hazard rate of

0·056 events per year per subject, assuming a peak accrual rate of 240 subjects per month and 1 year time for

accrual ramp-up, and assuming a 15% dropout rate in the first year and a 5% annual dropout rate thereafter.

Accrual was projected to last for approximately 2 years and the study was projected to reach the planned number

of iDFS events in 3·6 years from randomization of the first subject.

Global Protocol Amendment 3 (25-Feb-2010, Pfizer)

After study commencement, long-term follow-up data were presented for two adjuvant trastuzumab trials,

NCCTG N98311 and BCIRG 006.2 In both trials, the 5-year DFS rate was reported as approximately 84% for

the subjects treated with the most common concurrent trastuzumab regimen (adjuvant chemotherapy, followed

by a taxane plus trastuzumab, AC-TH), confirming there remained a substantial risk of tumor recurrence for

subjects who have completed adjuvant trastuzumab therapy. However, the 5-year DFS rate for node-negative

subjects treated with AC-TH was reported from the BCIRG 006 study as 93%, indicating the risk of tumor

recurrence was lower than expected when this study was originally designed. Additional efficacy data from

more mature pivotal adjuvant trastuzumab trials suggested that subjects were at higher risk of recurrence closer

to completion of adjuvant trastuzumab, and the risk of recurrence may decrease over time. As a result of the

aforementioned reported data, the study eligibility criteria were updated. Global Amendment 3 only included

subjects with a higher risk of recurrence and to comply with scientific advice provided by the Committee for

Medicinal Products for Human Use (CHMP), and subjects were to be randomized within one year of completion

of trastuzumab therapy.

Approximately 3300 subjects with a higher risk of recurrence were expected to be enrolled under Amendment

3 or if enrolled prior to this amendment satisfy 2 key eligibility criteria: node-positive disease and randomization

within one year from completion of prior trastuzumab therapy. The study was expected to have 90% power to

detect a difference in iDFS if the hazard ratio of the neratinib arm vs the placebo arm was 0·713, based on a 1-

sided log-rank test controlling the type 1 error at 0·025.

The primary efficacy analysis population was changed from the ITT to the amended ITT (aITT). The aITT

population consisted of subjects deemed to be at higher risk of disease recurrence (viz. node positive, had

residual invasive disease following neoadjuvant chemotherapy and had completed adjuvant trastuzumab up to

12 months earlier).

6

Global Protocol Amendment 9 (14-Oct-2011, Pfizer)

Pfizer chose to stop enrollment of new subjects immediately with Global Amendment 9. Furthermore, the

follow-up period was limited to 2 years after randomization and data for the exploratory objectives were no

longer collected, ie, tumor samples for pharmacogenetics and patient-reported health outcomes assessment data

ceased to be collected upon implementation of this amendment. The consequences of this amendment impacted

the original study objectives of evaluating the long-term efficacy of neratinib in the extended adjuvant setting.

The expected sample size for the study was approximately 1700 subjects for the aITT population. For each

subject, the follow-up from randomization was approximately 2 years. There was no pre-specified total number

of iDFS events. Assuming a hazard ratio of 0·667, the study was expected to have 83% power to detect a

difference in iDFS between the 2 treatment arms based on a 1-sided log-rank test controlling the Type 1 error

at 0·05.

Global Protocol Amendment 13 (Oct-2013, Puma Biotechnology)

The rationale for Global Amendment 13 was made following results from the I-SPY2 study, which

demonstrated that the pathological complete response rate for the combination of paclitaxel plus neratinib was

higher than the pathological complete response rate for the combination of paclitaxel plus trastuzumab in a

randomized study. Amendment 13 restored the study to its primary intention, ie, obtain iDFS and OS data for

all randomized subjects in order to evaluate the long-term efficacy of neratinib in the extended adjuvant setting.

The sponsor extended the collection of recurrent disease events and deaths to 5 years post-randomization and

will conduct long-term survival follow-up. Additionally, the primary efficacy analysis population was returned

to ITT, based on a 1-sided log-rank test controlling the Type 1 error at 0·025.

7

SENSITIVITY ANALYSIS OF EARLY DROP-OUTS

One hundred and twenty-seven patients in the neratinib arm dropped out within 3 months of treatment for

reasons other than recurrent disease compared to 44 patients in the placebo arm. The baseline disease

characteristics were balanced between patients who dropped out early and patients who were followed up for

longer in both treatment arms (Table S3).

To assess the potential impact of the early drop-outs (censored <3 months) on the primary analysis, the

following sensitivity analysis was performed. Patients who dropped out early in the neratinib group were

assumed to have iDFS events following the distribution observed in the placebo group. Specifically, imputation

of iDFS events for the neratinib early drop-out patients was achieved via resampling from the placebo patients

by matching hormone receptor status, nodal status and prior trastuzumab regimen (i.e. concurrent vs

sequential). The resampling was done 10,000 times. On average, 9 additional iDFS events were observed in the

resampled populations, ranging from 0 to 24 events. The average hazard ratio was 0·685 with standard deviation

of 0·021. Among the 10,000 resampled populations, 99·8% of the times the stratified log-rank test yielded

statistically significant result with a P-value less than or equal to 0·05.

8

Figure S1. Kaplan-Meier Curves Showing Invasive Disease-free Survival in Hormone Receptor–Positive

Patients (Panel A) and in Hormone Receptor–Negative Patients (Panel B), and Disease-free Survival

Including Ductal Carcinoma In Situ in Hormone Receptor–Positive Patients (Panel C) and in Hormone

Receptor–Negative Patients (Panel D) (Intention-to-Treat Population).

9

Figure S2. Kaplan-Meier Curves Showing Invasive Disease-free Survival (Panel A) and Disease-free

Survival Including Ductal Carcinoma In Situ (Panel B) (Amended Intention-to-Treat Population).

The amended intent-to-treat population consisted of all subjects with node-positive disease and who were

randomized within 1 year of completion of prior trastuzumab.

10

Figure S3. Kaplan-Meier Curves Showing Invasive Disease-free Survival (Panel A) and Disease-free

Survival Including Ductal Carcinoma In Situ (Panel B) (Centrally-Confirmed HER2-Positive Patients).

11

Figure S4. Diarrheal Events by Grade Over Time in Patients Treated with Neratinib.

12

Figure S5. Mean FACT-B Total Scores (Panel A) and EQ-5D Visual Analog Scale Scores (Panel

B) by Treatment Group.

FACT-B is a 37-item questionnaire with 4 subscales of FACT-G assessing physical, social, emotional, and

functional well-being, with an additional breast cancer-specific subscale (9 items). The FACT-B score range is

from 0 to 144, with a minimally important difference of 7-8 points.3 On EQ-5D, general health is measured via

a vertical visual analog scale (0-100), with a minimally important difference of 7-10 units.4 For both

instruments, a higher score indicates a better quality of life. Numbers shown reflect the actual available data.

Adjusted mean changes from baseline are estimated when both the visit and baseline values are available.

13

Table S1. Efficacy Endpoint Definitions.

Endpoint Definition

Primary

Invasive disease-free survival Time from randomization to the first occurrence of the following disease-

free survival events:

(a) Invasive ipsilateral breast tumor recurrence

(b) Invasive contralateral breast cancer

(c) Local/regional invasive recurrence

(d) Distant recurrence

(e) Death from any cause.

Any patient for whom an event had not been observed by the data cut-off

were censored at the date of their last physical examination.

Secondary

Disease-free survival including ductal carcinoma in situ Time from randomization to the first occurrence of a disease-free survival

event or ductal carcinoma in situ event. Disease-free survival including

ductal carcinoma in situ events include ductal carcinoma in situ and all

disease-free survival events. For subjects who have a ductal carcinoma in

situ diagnosis followed by a disease-free survival event, the date of event

for disease-free survival including ductal carcinoma in situ is the date of

ductal carcinoma in situ. Any patient for whom an event had not been

observed by the data cut-off were censored at the date of their last

physical examination.

Time to distant recurrence Time between randomization and the date of the first distance recurrence

or death from breast cancer. Time to distant recurrence events include

distant recurrence and death from breast cancer. Any patient for whom an

event had not been observed by the cut-off date were censored at the date

of their last physical examination.

Distant disease-free survival Time from randomization to the first occurrence of distant recurrence or

death from any cause. Distant disease-free survival events include distant

recurrence and death from any cause. Any patient for whom an event had

not been observed by the data cut-off were censored at the date of their

last physical examination.

Central nervous system recurrence Cumulative incidence of central nervous system recurrences as first

distant recurrence (either isolated central nervous system metastases, or

diagnosed concurrently with other sites of metastatic disease) defined as

time from randomization to central nervous system recurrence as first

distant recurrence. Any patient who was alive and for whom distant

recurrence had not been observed by the data cut-off as censored at the

date of their last physical examination.

14

Table S2. Efficacy Endpoint Analyses (Intention-to-Treat Population).

Variable Estimated event-free survival rate at 2 years

(95% CI), %*

Hazard ratio

(95 percent

confidence interval)†

P Value‡

Neratinib

(N = 1420)

Placebo

(N = 1420)

Invasive disease-free survival 93·9 (92·4-95·2) 91·6 (90·0-93·0) 0·67 (0·50, 0·91) 0·0091

Disease-free survival including ductal

carcinoma in situ

93·9 (92·4-95·2) 91·0 (89·3-92·5) 0·63 (0·46, 0·84) 0·0017

Distant disease-free survival 95·1 (93·7-96·2) 93·7 (92·2-94·9) 0·75 (0·53, 1·04) 0·089

Time to distant recurrence 95·4 (94·1-96·5) 93·9 (92·4-95·0) 0·71 (0·50, 1·00) 0·054

CNS recurrence 0·91 (0·49-1·59) 1·25 (0·75-1·99) – 0·44

CI = confidence interval; CNS = central nervous system.

* Event-free rates for all endpoints, except for CNS recurrence for which cumulative incidence is reported.

† Stratified Cox proportional hazards model.

‡ Stratified 2-sided log-rank test for all endpoints, except for CNS recurrence for which Gray’s method was used.

15

Table S3. Baseline Characteristics of Patients According to Duration of Follow-up (Intention-to-Treat

Population).

Variable

Neratinib Placebo

≤3 months

(N = 127)

>3 months

(N = 1291)

≤3 months

(N = 44)

>3 months

(N = 1367)

Region – no. (%)

North America 49 (38·6) 469 (36·3) 16 (36·4) 458 (33·5)

Western Europe, Australia and South Africa 48 (37·8) 438 (33·9) 21 (47·7) 510 (37·3)

Asia Pacific, East Europe and South

America

30 (23·6) 384 (29·7) 7 (15·9) 399 (29·2)

Race – no· (%)

White 104 (81·9) 1059 (82·0) 31 (70·5) 1098 (80·3)

Black 6 (4·7) 21 (1·6) 4 (9·1) 43 (3·1)

Asian 14 (11·0) 174 (13·5) 7 (15·9) 187 (13·7)

Other 3 (2·4) 37 (2·9) 2 (4·5) 39 (2·9)

Age at randomization – no. (%)

<35 yr 2 (1·6) 44 (3·4) 6 (13·6) 49 (3·6)

35–49 yr 46 (36·2) 476 (36·9) 15 (34·1) 495 (36·2)

50–59 yr 40 (31·5) 456 (35·3) 8 (18·2) 479 (35·0)

≥60 yr 39 (30·7) 315 (24·4) 15 (34·1) 344 (25·2)

Age – yr

Median 54·0 52·0 50·5 53·0

Menopausal status at diagnosis – no· (%)

Premenopausal 52 (40·9) 610 (47·3) 20 (45·5) 640 (46·8)

Postmenopausal 75 (59·1) 681 (52·7) 24 (54·5) 727 (53·2)

Nodal status – no. (%)†

Negative 41 (32·3) 294 (22·8) 8 (18·2) 328 (24·0)

1–3 Positive nodes 54 (42·5) 609 (47·2) 22 (50·0) 635 (46·5)

≥4 Positive nodes 32 (25·2) 388 (30·1) 14 (31·8) 404 (29·6)

HR status – no. (%)

Positive (ER and/or PR positive) 78 (61·4) 737 (57·1) 27 (61·4) 784 (57·4)

Negative (ER and/or PR negative) 49 (38·6) 554 (42·9) 17 (38·6) 583 (42·6)

Prior trastuzumab regimen – no. (%)

Concurrent 75 (59·1) 807 (62·5) 21 (47·7) 861 (63·0)

Sequential 52 (40·9) 484 (37·5) 23 (52·3) 506 (37·0)

T-stage – no. (%)

T1 51 (40·2) 389 (30·1) 15 (34·1) 443 (32·4)

T2 49 (38·6) 535 (41·4) 16 (36·4) 534 (39·1)

T3 and above 8 (6·3) 135 (10·5) 4 (9·1) 112 (8·2)

Unknown 19 (15·0) 231 (17·9) 9 (20·5) 277 (20·3)

Missing – 1 (0·1) – 1 (0·1)

Histologic grade of tumor – no. (%)

Undifferentiated 1 (0·8) 6 (0·5) 1 (2·3) 17 (1·2)

Poorly differentiated 62 (48·8) 600 (46·5) 16 (36·4) 660 (48·3)

Moderately differentiated 40 (31·5) 421 (32·6) 16 (36·4) 399 (29·2)

Well differentiated 7 (5·5) 69 (5·3) 4 (9·1) 61 (4·5)

Unknown 17 (13·4) 195 (15·1) 7 (15·9) 230 (16·8)

Prior surgery – no. (%)

Lumpectomy only 49 (38·6) 419 (32·5) 12 (27·3) 498 (36·4)

Mastectomy 78 (61·4) 871 (67·5) 32 (72·7) 868 (63·5)

Missing – 1 (0·1) – 1 (0·1)

Prior radiotherapy – no. (%)

Yes 96 (75·6) 1033 (80·0) 37 (84·1) 1107 (81·0)

No 31 (24·4) 258 (20·0) 7 (15·9) 260 (19·0)

Prior neoadjuvant therapy – no. (%)

No 101 (79·5) 976 (75·6) 32 (72·7) 1003 (73·4)

Yes 26 (20·5) 315 (24·4) 12 (27·3) 364 (26·6)

16

Trastuzumab 16 (12·6) 215 (16·7) 7 (15·9) 250 (18·3)

Anthracycline only 2 (1·6) 38 (2·9) 0 34 (2·5)

Anthracycline plus taxane 13 (10·2) 201 (15·6) 10 (22·7) 246 (18·0)

Taxane only 11 (8·7) 72 (5·6) 2 (4·5) 82 (6·0)

Non-anthracycline or taxane – 4 (0·3) – 2 (0·1)

Prior adjuvant therapy – no. (%)

No 1 (0·8) 4 (0·3) 0 1 (0·1)

Yes 126 (99·2) 1287 (99·7) 44 (100) 1366 (99·9)

Trastuzumab 125 (98·4) 1287 (99·7) 44 (100) 1364 (99·8)

Anthracycline only 18 (14·2) 128 (9·9) 6 (13·6) 140 (10·2)

Anthracycline plus taxane 60 (47·2) 662 (51·3) 21 (47·7) 652 (47·7)

Taxane only 28 (22·0) 253 (19·6) 6 (13·6) 281 (20·6)

Non-anthracycline or taxane 20 (15·7) 244 (18·9) 11 (25·0) 293 (21·4)

Duration of prior adjuvant trastuzumab therapy –

months

n=125 n=1286 n=44 n=1363

Median (IQR) 11·4 (10·9-12·0) 11·5 (10·9-

11·9)

11·5 (11·1-

12·1)

11·4 (10·8-

11·9)

Time since last dose of trastuzumab to randomization –

months

Median (IQR) 6·2 (2·0-11·0) 4·3 (1·6-10·3) 5·9 (1·6-10·7) 4·6 (1·5-10·8)

17

Table S4. Treatment-Emergent Adverse Events of Grade 3 or Greater in Descending Order of Frequency

(Safety Population).

Preferred Term

Neratinib (N =1408) Placebo (N =1408)

Grade 3 Grade 4 Grade 5 Grade 3 Grade 4 Grade 5

Diarrhoea 561 (39·8) 1 (0·1) 0 23 (1·6) 0 0

Vomiting 47 (3·3) 0 0 5 (0·4) 0 0

Nausea 26 (1·8) 0 0 2 (0·1) 0 0

Abdominal pain 24 (1·7) 0 0 3 (0·2) 0 0

Fatigue 23 (1·6) 0 0 6 (0·4) 0 0

Alanine aminotransferase increased 15 (1·1) 3 (0·2) 0 3 (0·2) 0 0

Dehydration 12 (0·9) 1 (0·1) 0 1 (0·1) 0 0

Abdominal pain upper 11 (0·8) 0 0 3 (0·2) 0 0

Syncope 10 (0·7) 0 0 4 (0·3) 0 0

Headache 8 (0·6) 0 0 6 (0·4) 0 0

Aspartate aminotransferase increased 7 (0·5) 3 (0·2) 0 4 (0·3) 0 0

Asthenia 6 (0·4) 0 0 1 (0·1) 0 0

Cellulitis 6 (0·4) 0 0 3 (0·2) 0 0

Dyspepsia 6 (0·4) 0 0 0 0 0

Electrocardiogram QT prolonged 5 (0·4) 0 0 7 (0·5) 0 0

Erysipelas 5 (0·4) 0 0 0 0 0

Hyponatraemia 5 (0·4) 0 0 5 (0·4) 2 (0·1) 0

Rash 5 (0·4) 0 0 0 0 0

Abdominal distension 4 (0·3) 0 0 0 0 0

Ejection fraction decreased 4 (0·3) 0 0 2 (0·1) 0 0

Hypermagnesaemia 4 (0·3) 0 0 0 0 0

Hypokalaemia 4 (0·3) 1 (0·1) 0 5 (0·4) 0 0

Hypophosphataemia 4 (0·3) 0 0 4 (0·3) 0 0

Lymphopenia 4 (0·3) 0 0 3 (0·2) 0 0

Stomatitis 4 (0·3) 0 0 1 (0·1) 0 0

Decreased appetite 3 (0·2) 0 0 0 0 0

Dizziness 3 (0·2) 0 0 3 (0·2) 0 0

Herpes zoster 3 (0·2) 0 0 1 (0·1) 0 0

Malaise 3 (0·2) 0 0 1 (0·1) 0 0

Mucosal inflammation 3 (0·2) 0 0 0 0 0

Paronychia 3 (0·2) 0 0 0 0 0

Renal failure 3 (0·2) 0 0 0 0 0

Renal failure acute 3 (0·2) 0 0 0 0 0

Anaemia 2 (0·1) 1 (0·1) 0 0 1 (0·1) 0

Arthralgia 2 (0·1) 0 0 4 (0·3) 0 0

Bronchitis 2 (0·1) 0 0 1 (0·1) 0 0

Cholelithiasis 2 (0·1) 0 0 0 0 0

Depression 2 (0·1) 0 0 5 (0·4) 1 (0·1) 0

Dermatitis acneiform 2 (0·1) 0 0 0 0 0

Gamma-glutamyltransferase increased 2 (0·1) 0 0 2 (0·1) 0 0

Gastroenteritis 2 (0·1) 0 0 1 (0·1) 0 0

Hyperglycaemia 2 (0·1) 0 0 4 (0·3) 0 0

Hyperkalaemia 2 (0·1) 0 0 1 (0·1) 0 0

Hypertension 2 (0·1) 0 0 6 (0·4) 0 0

Hypotension 2 (0·1) 0 0 0 0 0

Migraine 2 (0·1) 0 0 0 0 0

Non-cardiac chest pain 2 (0·1) 0 0 0 0 0

Pain 2 (0·1) 0 0 0 0 0

Pulmonary embolism 2 (0·1) 1 (0·1) 0 3 (0·2) 0 0

Skin fissures 2 (0·1) 0 0 0 0 0

Vertigo 2 (0·1) 0 0 1 (0·1) 1 (0·1) 0

Abdominal abscess 1 (0·1) 0 0 0 0 0

Abdominal strangulated hernia 1 (0·1) 0 0 0 0 0

18

Preferred Term



Amylase increased 1 (0·1) 0 0 0 1 (0·1) 0

Angina pectoris 1 (0·1) 0 0 0 0 0

Ankle fracture 1 (0·1) 0 0 1 (0·1) 0 0

Anorectal cellulitis 1 (0·1) 0 0 0 0 0

Anorectal discomfort 1 (0·1) 0 0 0 0 0

Anosmia 1 (0·1) 0 0 0 0 0

Appendicitis 1 (0·1) 0 0 1 (0·1) 0 0

Appendicitis perforated 1 (0·1) 0 0 0 0 0

Basal cell carcinoma 1 (0·1) 0 0 1 (0·1) 0 0

Benign female reproductive tract

neoplasm 1 (0·1) 0 0 0 0 0

Blood alkaline phosphatase increased 1 (0·1) 0 0 0 0 0

Blood creatine phosphokinase increased 1 (0·1) 0 0 0 0 0

Blood creatinine increased 1 (0·1) 1 (0·1) 0 0 0 0

Blood lactate dehydrogenase increased 1 (0·1) 0 0 1 (0·1) 0 0

Blood urea increased 1 (0·1) 0 0 0 0 0

Breast cellulitis 1 (0·1) 0 0 1 (0·1) 0 0

Cancer pain 1 (0·1) 0 0 0 0 0

Carbohydrate antigen 27·29 increased 1 (0·1) 0 0 0 0 0

Cholecystitis 1 (0·1) 0 0 0 0 0

Dermatitis 1 (0·1) 0 0 0 0 0

Dermatitis contact 1 (0·1) 0 0 0 0 0

Device related infection 1 (0·1) 0 0 3 (0·2) 0 0

Dry mouth 1 (0·1) 0 0 0 0 0

Dysgeusia 1 (0·1) 0 0 0 0 0

Dyspnoea 1 (0·1) 0 0 2 (0·1) 0 0

Dysuria 1 (0·1) 0 0 0 0 0

Enterocele 1 (0·1) 0 0 0 0 0

Escherichia urinary tract infection 1 (0·1) 0 0 0 0 0

Facial neuralgia 1 (0·1) 0 0 0 0 0

Faecal incontinence 1 (0·1) 0 0 0 0 0

Flatulence 1 (0·1) 0 0 1 (0·1) 0 0

Flushing 1 (0·1) 0 0 0 0 0

Food poisoning 1 (0·1) 0 0 0 0 0

Fracture 1 (0·1) 0 0 0 0 0

Fungal infection 1 (0·1) 0 0 0 0 0

Furuncle 1 (0·1) 0 0 0 0 0

Gastric disorder 1 (0·1) 0 0 0 0 0

Gastroenteritis salmonella 1 (0·1) 0 0 0 0 0

Gastrointestinal inflammation 1 (0·1) 0 0 0 0 0

Gastrointestinal pain 1 (0·1) 0 0 0 0 0

Gastrointestinal viral infection 1 (0·1) 0 0 0 0 0

Glioblastoma 1 (0·1) 0 0 0 0 0

Glossodynia 1 (0·1) 0 0 0 0 0

Haemoglobin decreased 1 (0·1) 0 0 0 0 0

Hepatic enzyme increased 1 (0·1) 0 0 0 0 0

Hepatotoxicity 1 (0·1) 0 0 0 0 0

Hot flush 1 (0·1) 0 0 1 (0·1) 0 0

Hypertriglyceridaemia 1 (0·1) 0 0 1 (0·1) 0 0

Hypoglycaemia 1 (0·1) 0 0 1 (0·1) 1 (0·1) 0

Inflammation 1 (0·1) 0 0 0 0 0

Influenza 1 (0·1) 0 0 1 (0·1) 0 0

International normalised ratio increased 1 (0·1) 0 0 0 0 0

Joint effusion 1 (0·1) 0 0 0 0 0

Laryngitis 1 (0·1) 0 0 0 0 0

Left ventricular dysfunction 1 (0·1) 0 0 0 0 0

19

Preferred Term



Lethargy 1 (0·1) 0 0 0 0 0

Lipase increased 1 (0·1) 0 0 0 0 0

Liver function test abnormal 1 (0·1) 0 0 0 0 0

Malignant pleural effusion 1 (0·1) 0 0 0 0 0

Menstruation irregular 1 (0·1) 0 0 0 0 0

Mental status changes 1 (0·1) 0 0 0 0 0

Mouth ulceration 1 (0·1) 0 0 0 0 0

Muscle spasms 1 (0·1) 0 0 1 (0·1) 0 0

Musculoskeletal pain 1 (0·1) 0 0 3 (0·2) 0 0

Myocardial infarction 1 (0·1) 1 (0·1) 0 0 0 0

Myocardial ischaemia 1 (0·1) 0 0 0 0 0

Nail disorder 1 (0·1) 0 0 0 0 0

Neuropathy peripheral 1 (0·1) 0 0 2 (0·1) 0 0

Oedema peripheral 1 (0·1) 0 0 0 0 0

Ophthalmic herpes zoster 1 (0·1) 0 0 0 0 0

Osteoarthritis 1 (0·1) 0 0 1 (0·1) 0 0

Osteoporosis 1 (0·1) 0 0 0 0 0

Palpitations 1 (0·1) 0 0 0 0 0

Pancreatitis 1 (0·1) 0 0 0 0 0

Panniculitis 1 (0·1) 0 0 0 0 0

Paresis 1 (0·1) 0 0 0 0 0

Periodontal disease 1 (0·1) 0 0 0 0 0

Peripheral ischaemia 1 (0·1) 0 0 0 0 0

Pleural effusion 1 (0·1) 0 0 1 (0·1) 0 0

Pneumothorax 1 (0·1) 0 0 0 0 0

Pollakiuria 1 (0·1) 0 0 0 0 0

Procedural complication 1 (0·1) 0 0 0 0 0

Procedural pain 1 (0·1) 0 0 1 (0·1) 0 0

Pruritus 1 (0·1) 0 0 1 (0·1) 0 0

Rectal abscess 1 (0·1) 0 0 0 0 0

Renal colic 1 (0·1) 0 0 0 0 0

Skin necrosis 1 (0·1) 0 0 1 (0·1) 0 0

Staphylococcal infection 1 (0·1) 0 0 0 0 0

Staphylococcus test positive 1 (0·1) 0 0 0 0 0

Streptococcal sepsis 1 (0·1) 0 0 0 0 0

Tattoo 1 (0·1) 0 0 0 0 0

Thrombocytopenia 1 (0·1) 0 0 0 0 0

Tooth disorder 1 (0·1) 0 0 0 0 0

Urinary tract infection 1 (0·1) 0 0 0 0 0

Urticaria 1 (0·1) 0 0 0 0 0

Viral infection 1 (0·1) 0 0 0 0 0

Weight decreased 1 (0·1) 0 0 0 0 0

Wound dehiscence 1 (0·1) 0 0 1 (0·1) 0 0

Wrist fracture 1 (0·1) 0 0 0 0 0

Abdominal wall abscess 0 0 0 1 (0·1) 0 0

Acute myeloid leukaemia 0 0 1 (0·1) 0 0 0

Amnesia 0 0 0 1 (0·1) 0 0

Anxiety 0 0 0 3 (0·2) 0 0

Atrial fibrillation 0 0 0 1 (0·1) 0 0

Back pain 0 0 0 5 (0·4) 0 0

Benign breast neoplasm 0 0 0 1 (0·1) 0 0

Bladder prolapse 0 0 0 1 (0·1) 0 0

Blood creatine increased 0 1 (0·1) 0 0 0 0

Blood phosphorus decreased 0 0 0 1 (0·1) 0 0

Blood pressure increased 0 0 0 2 (0·1) 0 0

Bradyphrenia 0 0 0 1 (0·1) 0 0

20

Preferred Term



Brain oedema 0 0 0 0 1 (0·1) 0

Breast abscess 0 0 0 1 (0·1) 0 0

Breast cancer 0 0 0 0 2 (0·1) 0

Breast cancer metastatic 0 0 1 (0·1) 0 0 0

Breast neoplasm 0 0 0 1 (0·1) 0 0

Cardiac function test abnormal 0 0 0 1 (0·1) 0 0

Cardiac tamponade 0 0 0 1 (0·1) 0 0

Cartilage injury 0 0 0 1 (0·1) 0 0

Cerebrovascular accident 0 0 0 0 1 (0·1) 0

Colitis 0 0 0 1 (0·1) 0 0

Colitis ischaemic 0 0 0 1 (0·1) 0 0

Constipation 0 0 0 2 (0·1) 0 0

Cough 0 0 0 2 (0·1) 0 0

Cyst 0 0 0 1 (0·1) 0 0

Cystitis 0 0 0 1 (0·1) 0 0

Deep vein thrombosis 0 0 0 1 (0·1) 0 0

Dental caries 0 0 0 1 (0·1) 0 0

Diabetes mellitus 0 0 0 1 (0·1) 0 0

Disturbance in attention 0 0 0 1 (0·1) 0 0

Diverticulitis 0 0 0 1 (0·1) 0 0

Endometrial hyperplasia 0 0 0 1 (0·1) 0 0

Epistaxis 0 0 0 1 (0·1) 0 0

Erythema multiforme 0 0 0 1 (0·1) 0 0

Fall 0 0 0 1 (0·1) 0 0

Food allergy 0 0 0 0 1 (0·1) 0

Gastric cancer 0 0 0 0 0 1 (0·1)

Glioma 0 1 (0·1) 0 0 0 0

Hepatic function abnormal 0 0 0 0 1 (0·1) 0

Hip fracture 0 0 0 1 (0·1) 0 0

Humerus fracture 0 0 0 1 (0·1) 0 0

Hyperbilirubinaemia 0 0 0 1 (0·1) 0 0

Hyperhidrosis 0 0 0 2 (0·1) 0 0

Hypernatraemia 0 1 (0·1) 0 0 0 0

Hyperuricosuria 0 1 (0·1) 0 0 0 0

Hypomagnesaemia 0 0 0 1 (0·1) 0 0

Hysterosalpingo-oophorectomy 0 0 0 1 (0·1) 0 0

Incision site cellulitis 0 0 0 1 (0·1) 0 0

Insomnia 0 0 0 2 (0·1) 0 0

Iritis 0 0 0 1 (0·1) 0 0

Jaundice cholestatic 0 0 0 0 1 (0·1) 0

Laceration 0 0 0 1 (0·1) 0 0

Lumbar spinal stenosis 0 0 0 1 (0·1) 0 0

Lung adenocarcinoma 0 0 0 1 (0·1) 0 0

Mastitis 0 0 0 1 (0·1) 0 0

Menorrhagia 0 0 0 1 (0·1) 0 0

Metastases to eye 0 0 0 0 1 (0·1) 0

Metastases to meninges 0 0 1 (0·1) 0 0 0

Metrorrhagia 0 0 0 1 (0·1) 0 0

Motor dysfunction 0 0 0 1 (0·1) 0 0

Multiple injuries 0 1 (0·1) 0 0 0 0

Muscular weakness 0 0 0 1 (0·1) 0 0

Myalgia 0 0 0 1 (0·1) 0 0

Neck pain 0 0 0 1 (0·1) 0 0

Neutropenia 0 1 (0·1) 0 2 (0·1) 0 0

Neutrophil count decreased 0 0 0 1 (0·1) 0 0

Pain in extremity 0 0 0 2 (0·1) 0 0

21

Preferred Term



Patella fracture 0 0 0 1 (0·1) 0 0

Pelvic pain 0 0 0 1 (0·1) 0 0

Peripheral sensory neuropathy 0 0 0 1 (0·1) 0 0

Pneumonia 0 0 0 3 (0·2) 0 0

Postoperative wound complication 0 0 0 1 (0·1) 0 0

Rectal cancer 0 1 (0·1) 0 0 0 0

Sarcoma uterus 0 0 0 0 1 (0·1) 0

Septic shock 0 0 0 0 1 (0·1) 0

Seroma 0 0 0 1 (0·1) 0 0

Tachycardia 0 0 0 1 (0·1) 0 0

Thermal burn 0 0 0 1 (0·1) 0 0

Tibia fracture 0 0 0 1 (0·1) 0 0

Tooth abscess 0 0 0 2 (0·1) 0 0

Tooth infection 0 0 0 1 (0·1) 0 0

Transient ischaemic attack 0 0 0 1 (0·1) 0 0

Tremor 0 0 0 1 (0·1) 0 0

Uterine leiomyoma 0 0 0 1 (0·1) 0 0

Vascular neoplasm 0 0 0 1 (0·1) 0 0

Weight increased 0 0 0 1 (0·1) 0 0

Wound complication 0 0 0 1 (0·1) 0 0

Data are n (%).

22

Table S5. Summary of Treatment-Emergent Diarrhea in the ExteNET Study (Safety Population) and

Study 5201.*

This table provides details of treatment-emergent diarrhea in the ExteNET study, which occurred without

implementation of an antidiarrheal prophylactic regimen. In ExteNET, no antidiarrheal prophylaxis was

stipulated in the study protocol, but rather treatment for diarrhea was recommended after symptoms had

developed. Since the ExteNET treatment phase was completed, an antidiarrheal prophylactic regimen has been

implemented in all subsequent studies of neratinib using high-dose loperamide given with the first dose of

neratinib and continuing for the entire first cycle of neratinib treatment.† For the purpose of illustrating how

loperamide prophylaxis reduces neratinib-related diarrhea (compared with ExteNET), this table also includes

the safety data from a study of neratinib monotherapy in patients with metastatic cancer (Study 5201) which

included this antidiarrheal prophylactic regimen.

Variable

ExteNET Study 5201†

Neratinib

(N = 1408)

Placebo

(N = 1408)

Neratinib

(N=97)

Patients ever experienced treatment-emergent diarrhea – no. (%) 1343 (95·4) 499 (35·4) 62 (63·9)

Maximum toxicity – no. (%)

Grade 1 323 (22·9) 382 (27·1) 24 (24·7)

Grade 2 458 (32·5) 94 (6·7) 23 (23·7)

Grade 3 561 (39·8) 23 (1·6) 15 (15·5)

Grade 4 1 (0·1) 0 0

Drug-related diarrhea – no. (%) 1330 (94·5) 411 (29·2) 59 (60·8)

Serious events – no. (%) 22 (1·6) 1 (0·1) 7 (7·2)

Actions taken due to diarrhea – no. (%)

Withdrawn from study 23 (1·6) 0 0

Discontinued study drug 237 (16·8) 3 (0·2) 2 (2·1)

Dose reduction 372 (26·4) 8 (0·6) 1 (1·0)

Hospitalized 20 (1·4) 1 (0·1) 0

Dose hold

Once 263 (18·7) 22 (1·6) 8 (8·2)

Twice 97 (6·9) 2 (0·1) 1 (1·0)

Three or more times 117 (8·3) 2 (0·1) 2 (2·1)

Median (IQR) time to onset of diarrhea – days

Any grade 2 (2–4) 18 (4–82) 7 (3-14)

Grade ≥2 5 (2–15) 90 (17–189) 10·5 (6-38)

Grade ≥3 8 (4–33) 124 (21–257) 8 (6-24)

Duration of grade ≥3 diarrhea per patient – days

Median (IQR) 5 (2–9) 2 (1–5) 5 (2-11)

Grade ≥3 events per patient – no.

Mean 2·7 1·3 1·8

Median (IQR) 2 (1–3) 1 (1–1) 1 (1-2)

Median (IQR) duration of diarrhea per event – days

Any grade 2 (1–3) 2 (1–3) 2 (1-3)

Grade ≥2 1 (1–2) 2 (1–2) 2 (1-4)

Grade ≥3 2 (1–3) 2 (1–4) 2 (1-7)

*A treatment-emergent adverse event is any adverse event that occurs or worsens on or after the first dose of investigational product and

up to 28 days after the last dose.

†Included mandatory prophylaxis for diarrhea using the following regimen: loperamide 4 mg with the first dose of neratinib, then 2 mg

every 4 hours for the first 3 days, then 2 mg every 6-8 hours for the remainder of cycle 1.

23

Table S6. Summary of Study Sites, Principle Investigators Responsible for Each Site and the Number

of Patients Enrolled from Each Site

Principle investigator(s) Investigational site Country Patients

randomized, n

Arlene Chan Mount Hospital, Perth Australia 46

Vernon Harvey Auckland Hospital, Auckland New Zealand 31

Tajana Silovski; Robert Separovic;

Rudolf Tomek Klinika Za Tumore, Zagreb Croatia 29

Erhan Gokmen Ege University, Izmir Turkey 29

Nicholas J. Robert Virginia Cancer Specialists, Fairfax USA 29

Ira Gore Jr. Alabama Oncology, Birmingham USA 26

Suzette Delaloge Institut Gustave Roussy, Villejuif France 25

John W. Smith II Northwest Cancer Specialists, PC, Vancouver USA 25

Norikazu Masuda National Hospital Organization Osaka National Hospital, Osaka

Japan 23

S. Di Sean Kendall; William Graydon

Harker Utah Cancer Specialists, Utah USA 23

Katarina Petrakova Masarykuv Onkologicky ustav, Brno Czech Republic 22

Amparo Ruiz Simon; Angel Guerrero Zotano

Instituto Valenciano de Oncologia, Valencia Spain 22

Zorica Tomasevic; Zora Neskovic

Konstantinovic

Institute of Oncology and Radiology of Serbia,

Belgrade Serbia 22

Nicholas O. Iannotti Hematology Oncology Associates of Treasure Coast,

Port Saint Lucie USA 21

Erik Hugger Jakobsen Vejle Sygehus, Velje Denmark 20

Pierfrancesco Tassone Tommaso Campanella Cancer Center, Catanzaro Italy 20

Gladys I. Rodriguez South Texas Oncology and Hematology, San Antonio USA 20

Anil Abrahma Joy Cross Cancer Institute, Edmonton Canada 19

Noelia Martinez; Carmen Crespo Hospital Universitario Ramon y Cajal, Madrid Spain 19

Sung-Bae Kim Asan Medical Center, Seoul Korea 19

Snezana Smickoska University Clinic for Radiotherapy and Oncology,

Skopje Macedonia 19

Isil Somali; Ugur Yilmaz Dokuz Eylul Universitesi Tip Fakultesi, Izmir Turkey 19

Friedrich Overkamp Oncologianova GmbH, Recklinghausen Germany 18

Mirta Garcia Alonso; Adolfo Murias Rosales

Compejo Hospitalario Materno Insular de Las Palmas Spain 18

Audrone Ciceniene Oncology Institute of Vilnius University, Vilnius Lithuania 18

Soeren Cold; Ann Soegaard Knoop Odense University Hospital, Odense Denmark 17

Beth A. Hellerstedt Texas Oncology, PA, Austin USA 17

Serafin Morales Murillo Hospital Universitari Arnau de Vilanova de Lleida, Lleida

Spain 16

John S. Link Breastlink Medical Group Inc, Long Beach USA 16

Ingrid A. Mayer; Julie Ann Means-Powell

Vanderbilt-Ingram Cancer Center, Nashville USA 16

Rina Hui Sydney West Cancer Trials Centre, Westmead Australia 15

Manuel Ruiz Borrego Hospital Universitario Virgen del Rocio, Sevilla Spain 15

Miguel Martin Jimenez Hospital General Universitario Gregorio Maranon,

Madrid Spain 15

Kenichi Inoue Saitama Cancer Center, Saitama Japan 15

Francis M. Senecal Northwest Medical Specialties PLLC, Tacoma USA 15

Richard Hendry De Boer Royal Melbourne Hospital, Melbourne Australia 14

Zhenzhou Shen Fudan University Cancer Hospital, Shanghai China 14

Adam Andrzej Luczak Aalborg Sygehus, Aalborg Denmark 14

Anne Armstrong Christie Hospital, Manchester UK 14

Janice Wing-hang Tsang Queen Mary Hospital, Hong Kong Hong Kong 14

Istvan Lang Orszagos Onkologiai Intezet "B" Belgyogyaszati osztaly, Budapest

Hungary 14

Yoshiaki Rai Hakuaikai Medical Corporation Sagara Hospital,

Kagoshima Japan 14

Yasuo Hozumi Jichi Medical University Hospital, Tochigi Japan 14

Albert J. Ten Tije Amphia Ziekenhuis, Breda Netherlands 14

24


randomized, n

Manish Bhandari Christ Hospital of Cincinnati, Cincinnati USA 14

Cynthia R.C. Osborne Texas Oncology, PA, Dallas USA 14

Shoichiro Ohtani; Kenji Higaki Hiroshima City Hospital, Hiroshima Japan 13

Kenichi Watanabe; Kazunori Taguchi;

Masato Takahashi

National Hospital Organization Hokkaido Cancer

Center, Hokkaido Japan 13

Sladjana Filipovic Clinical Centre Nis, Nis Serbia 13

Vincent L. Hansen North Utah Associates, Ogden USA 13

Beverly Moy Dana Farber Cancer Institute, Boston USA 13

Vijayarama Phooshkooru Rao Mid Dakota Clinic PC, Bismarck USA 13

Manish Gupta Texas Oncology, PA, Garland USA 13

Petar Petrov District Dispensary for Oncology Diseases Internal

Unit, Plovdiv Bulgaria 12

Bruno Coudert Centre Georges Francois Leclerc, Dijon France 12

Zeljko Vojnovic General Hospital Varazdin, Varazdin Croatia 12

Zsofia Polya Jósa András Oktatókórház Egészségügyi Szolgáltató,

Nyiregyhaza Hungary 12

Naohito Yamamoto Chiba Cancer Center, Chiba Japan 12

Stephen Brincat Sir Paul Boffa Hospital, Floriana Malta 12

Krzysztof Lesniewski-Kmak Samodzielny Publiczny Zaklad Opieki Zdrowotnej

Szpital Uniwersytecki w Krakowie, Krakow Poland 12

Ewa Chmielowska Centrum Onkologii im. Prof. Franciszka, Bydgoszcz Poland 12

Ruemu E. Birhiray Hematology Oncology of Indiana, Indianapolis USA 12

Marc L. Citron ProHealth Care Associates, Lake Success USA 12

Steven William Papish Hematology and Oncology Associates of Northern New Jersey, Morristown

USA 12

William R. Berry Raleigh Hematology Oncology Associates, PC,

Raleigh USA 12

Sven Tyge Langkjer Aarhus University Hospital, Aarhus Denmark 11

Jose Angel Garcia Saenz Hospital Clinico San Carlos, Madrid Spain 11

Ana Maria Arance Hospital Clinic i Provincial de Barcelona, Barcelona Spain 11

Noa Efrat Kaplan Medical Center, Rehovot Israel 11

Tomasz Sarosiek Centrum Medyczne Ostrobramska Niepubliczny,

Warsaw Poland 11

Yvonne Manalo Coastal Bend Cancer Center, Corpus Christi USA 11

Julie C. Smith Wenatchee Valley Medical Center, Wenatchee USA 11

Irfan Vaziri Great Plains Regional Medical Center, North Platte USA 11

Beverly Moy Massachusetts General Hospital, Boston USA 11

Tabitha Healey North Adelaide Oncology, North Adelaide Australia 10

Yasmin Rahim; Cynthia Luk Southlake Regional Health Centre, Newmarket Canada 10

Brian Dingle London Regional Cancer Program, London Canada 10

Sandra Franco Administradora Country SA, Bogota Colombia 10

Peter Grundtvig Sorensen Herlev Hospital, Herlev Denmark 10

Anjana Anand; Sarah Khan Nottingham City Hospital, Nottingham UK 10

George Fountzilas Papageorgiou General Peripheral Hospital of Thessaloniki, Thessaloniki

Greece 10

Kenjiro Aogi National Hospital Organization Shikoku Cancer

Center, Ehime Japan 10

Satoru Shimizu Kanagawa Cancer Center, Kanagawa Japan 10

Stanislav Spanik Interna onkologicka klinika, Bratislava Slovakia 10

Robert A. Somer Cooper University Hospital, Voorhees USA 10

Patrick J. Flynn Minnesota Oncology Hematology, PA, Minneapolis USA 10

Paul Mainwaring Mater Adult Hospital, South Brisbane Australia 9

Guy Jerusalem Centre Hospitalier Universitaire de Liege, Liege Belgium 9

Bent Ejlertsen Rigshospitalet, Copenhagen Denmark 9

Carine Segura-Djezzar; Christelle Levy;

Thierry Delozier Centre Francois Baclesse, Caen France 9

David Khayat Hopital Pitie-Salpetriere, Paris France 9

Robert E. Coleman Weston Park Hospital, Sheffield UK 9

Martin J. Rolles Singleton Hospital, Swansea UK 9

25


randomized, n

Janine Mansi Guy's Hospital, London UK 9

Robert Maisano; Mario Nardi Azienda Opsedaliera Bianchi Melacrino Morelli,

Reggio Calabria Italy 9

Yoshinori Ito Cancer Institute Hospital of Japanese Foundation for

Cancer Research, Tokyo Japan 9

Perran Fulden Yumuk; Gul Basaran; Nazim Serdar Turhal

Marmara University, Istanbul Turkey 9

Mary J. Wilkinson Medical Oncology & Hematology Associates of

Northern Virginia, Fairfax USA 9

Nathan B. Green Southeast Nebraska Hematology & Oncology

Consultants, PC, Lincoln USA 9

Algis P. Sidrys Cookeville Regional Cancer Center, Cookeville USA 9

Sigrun Hallmeyer Oncology Specialists, SC, Park Ridge USA 9

Douglas J. Testori Hanover Medical Specialists, PA, Wilmington USA 9

Srikala Sridhar Princess Margaret Hospital, Toronto Canada 8

Jose Chang Lakeridge Health Oshawa, Oshawa Canada 8

Qiang Sun Peking Union Medical College Hospital, Beijing China 8

Carlos Jara Sanchez; Xabier Rubio Hospital Universitario Fundacion de Alcorcon,

Madrid Spain 8

Maria Lomas Garrido Complejo Hospitalario de Jaen, Jaan Spain 8

Juan Rafael De La Haba Rodriguez Hospital Universitario Reina Sofia, Cordoba Spain 8

Antoni Avelia Mestre; Julio Rifa Ferrer Hospital Universitario Son Espases, Palma de Mallorca

Spain 8

Sonia del Barco Berron ICO de Girona - Hospital Universitario de Girona Dr.

Josep Trueta, Girona Spain 8

Zsuzsanna Nagy Fovarosi Onkormanyzat Szent Imre Korhaz,

Budapest Hungary 8

Maki Tanaka Kurume Daiichi Social Insurance Hospital, Fukuoka Japan 8

Young-Hyuck Im Samsung Medical Center, Seoul Korea 8

Robert R. Carroll; Laura C. Dickerson Florida Cancer Specialists & Research Institute, Gainesville

USA 8

Joseph R. Mace Gulfcoast Oncology Associates, St Petersburg USA 8

Ragene Rivera El Paso Cancer Treatment Center - West, El Paso USA 8

Leonard M. Klein Cancer Care & Hematology Specialists of

Chicagoland, Niles USA 8

Robert Ruxer Texas Oncology PA, Fort Worth USA 8

Sharon T. Wilks Cancer Care Centers of South Texas, San Antonio USA 8

Dusan Kotasek Adelaide Cancer Centre Research, Adelaide Australia 7

Violina Taskova Interdistrict Dispensary for Oncology Diseases,

Varna Bulgaria 7

Constanta Timcheva Specialised Hospital of Active Treatment in Oncology, Sofia

Bulgaria 7

Christine Desbiens Centre Hospitalier Affilie Universitaire de Quebec,

Qubec Canada 7

Jean-Pierre Ayoub CHUM Hôpital Notre-Dame, Montreal Canada 7

Debjani Grenier CancerCare Manitoba, Winnipeg Canada 7

Norbert Marschner Praxis für interdisziplinaere Onkologie &

Haematologie GbR, Freiburg Germany 7

Hans Tesch Onkologische Gemeinschaftspraxis Frankfurt, Frankfurt am Main

Germany 7

Hans-Joachim Lueck Fachpraxis fuer Frauenheilkunde, Hannover Germany 7

Jan Janssen Gemeinschaftspraxis fuer Haematologie und Onkologie, Westerstede

Germany 7

Ingo Schwaner Onkologische Schwerpunktpraxis, Berlin Germany 7

Eva Harder Brix Hillerod Hospital, Hillerod Denmark 7

Susanne Vallentin; Dan Kristensen;

Anna Andreeva; Vesna Glavicic Næstved Sygehus, Onkologisk Afdeling, Næstved Denmark 7

Isabel Calvo Plaza Hospital de Madrid Norte-Sanchinarro, Madrid Spain 7

Antonio Anton Torres Hospital Universitario Miguel Servet, Zaragoza Spain 7

Corinne Veyret Centre Henri Becquerel, Rouen France 7

Jean-Pierre Bergerat Centre Hospitalier Universitaire Strasbourg,

Strasbourg France 7

26


randomized, n

Emmanuelle Bourbouloux Centre Rene Gauducheau, Saint-Herblain France 7

Wendy Ann Ella; Hafiz Algurafi; Anne

Robinson Southend University Hospital, Westcliffe-on-Sea UK 7

Hiroji Iwata Aichi Cancer Center, Nagoya Japan 7

Seung Jin Kim; Tetsuya Taguchi Osaka University Hospital, Osaka Japan 7

Elona Juozaityte Kaunas University of Medicine Hospital, Kaunas Lithuania 7

Stanley Madretsma; Sandra Radema Gelre ZH, Apeldoorn Netherlands 7

Wojciech Rogowski Zaklad Opieki Zdrowotnej MSWiA z Warminsko, Olsztyn

Poland 7

Maria Wagnerova Oddelenie radioterapie a onkologie, Kosice Slovakia 7

Donald A. Richards Texas Oncology, PA, Tyler USA 7

Elizabeth Tan-Chiu Florida Cancer Research Institute, Plantation USA 7

Charles Arthur Henderson Peachtree Hematology Oncology Consultants, PC, Atlanta

USA 7

Viran Roger Holden St. John's Medical Research Institute Inc, Springfield USA 7

Xiaojia Wang Zhejiang Cancer Hospital, Hangzhou China 6

Zhongsheng Tong Tianjin Cancer Hospital, Tianjin China 6

Junlan Yang Chinese People's Liberation Army General Hospital,

Beijing China 6

Manuel Enrique Gonzalez Oncomedica SA IMAT, Cordoba Colombia 6

Gunter von Minckwitz Luisenkrankenhaus, Duesseldorf Germany 6

John Hackmann Marienhospital Witten, Witten Germany 6

Eduardo Martinez de Dueñas Consorcio Hospitalario Provincial de Castellon,

Castellon Spain 6

Begoña Bermejo de las Heras Hospital Clinico Universitario de Valencia, Valencia Spain 6

Louis Marie Dourthe Clinique Sainte Anne, Strasbourg France 6

Philippe Bougnoux Centre Hospitalier Universitaire Bretonneau, Tours France 6

Stylianos Kakolyris University Hospital of Alexandroupoli,

Alexandroupoli Greece 6

Haralabos Kalofonos University General Hospital of Patras, Patras Greece 6

Dimitrios Pectasidis University General Hospital "ATTIKON", Athens Greece 6

Ting Ying Ng Tuen Mun Hospital, Hong Kong Hong Kong 6

Gabor Pajkos Bacs-Kiskun Megyei Korhaz, Onkoradiologiai

kozpont, Kecskemet Hungary 6

Eva Ezer Somogyine Kaposi Mor Oktato Korhaz, Kaposvar Hungary 6

Giuseppe Tonini Universita Campus Bio-Medico, Rome Italy 6

Dario Giuffrida Istituto Oncologico del Mediterraneo, Viagrande Italy 6

Shintaro Takao Hyogo Cancer Center, Hyogo Japan 6

Makoto Ishitobi; Hideo Inaji Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka

Japan 6

Yutaka Tokuda Tokai University Hospital, Kanagawa Japan 6

Katarzyna Wozniak Samodzielny Publiczny Zaklad Opieki Zdrowotnej Szpital Wojewodzki Oddzial, Jelenia Gora

Poland 6

Dan Lungulescu SC Oncolab SRL, Dolj Romania 6

Yen-Shen Lu; King-Jen Chang National Taiwan University Hospital, Taipei Taiwan 6

Christopher Charles Croot North Mississippi Hematology and Oncology

Associates, Ltd, Tupelo USA 6

Albert Dekker Facey Medical Foundation, Mission Hills USA 6

Neil D. Belman Oncology-Hematology of Lehigh Valley, PC,

Bethlehem USA 6

Richard A. Michaelson Saint Barnabas Medical Center, Livingston USA 6

Kathleen Kemmer; Stephen Chui;

Shiuh-Wen Luoh

Oregon Health and Science University, Cancer

Institute, Portland USA 6

Kenneth Nahum Jersey Shore University Medical Center, Neptune USA 6

Frankie Ann Holmes Texas Oncology, PA, Houston USA 6

Andrew R. Greenspan Central Indiana Cancer Centers, Indianapolis USA 6

Joni C. Nichols Cancer Care Northwest-North, Spokane USA 6

Carlos A. Encarnacion Texas Oncology, PA, Waco USA 6

Thomas M.J. Niederman University Cancer Institute, LLC USA 6

27


randomized, n

Roland Alexander; Robert Gordon PinnacleHealth Hematology Oncology Associates,

Harrisburg USA 6

Antoanet Tomova District Dispensary for Oncology Diseases Internal Unit, Plovdiv

Bulgaria 5

Daniel Rauch Spital STS AG, Thun Switzerland 5

Razvan Andrei Popescu Hirslanden Medical Center, Aarau Switzerland 5

Gustavo Adolfo Rojas Oncologos del Occidente, Pereira Colombia 5

Jaroslav Vanasek Pardubicka Krajska Nemocnice, Pardubice Czech Republic 5

Tanja Neunhoeffer; Jana Barinoff Dr. Horst Schmidt Klinik GmbH, Wiesbaden Germany 5

Gerd Graffunder Frauenarzt-Zentrum-Zehlendorf, Berlin Germany 5

Peter Bojko Fachpraxis fuer Innere Medizin Elisenhof, Muenchen

Germany 5

Bernhard Heinrich Onkologische Praxis, Augsburg Germany 5

Albert von der Assen Niels-Stensen-Kliniken, Georgsmarienhuette Germany 5

Lene Adrian Onkologisk Ambulatorium, Sonerborg Denmark 5

Manuel Ramos Vazquez Centro Oncologico de Galicia, A Coruna Spain 5

Santiago Gonzalez Santiago Hospital San Pedro de Alcantara, Caceres Spain 5

Veronique Dieras Institut Curie, Paris France 5

Jill Mercia Bishop North West Cancer Treatment Centre, Bodelwydan UK 5

Timothy John Perren St James's University Hospital, Leeds UK 5

Ioannis Varthalitis General Hospital of Chania Ag. Georgios, Chania Greece 5

Vassilis Georgoulias University Hospital of Heraklion, Heraklion Greece 5

Louis W. C. Chow UNIMED Medical Institute, Hong Kong Hong Kong 5

Chung Cheung Thomas Yau; Raymond

Hin-Suen Liang Queen Mary Hospital, Hong Kong Hong Kong 5

Bela Piko Bekes Megyei Pandy Kalman Korhaz, Gyula Hungary 5

Agnes Weber Borsod-Abaúj-Zemplén Megyei Kórház és Egyetemi,

Miskolc Hungary 5

Bella Kaufman Sheba Medical Center, Tel Hashomer Israel 5

Karen Drumea Rambam Health Care Campus, Haifa Israel 5

Andrea De Matteis; Francesco Nuzzo Fondazione Giovanni Pascale Istituto Nazionale per lo Studio e la Cura dei Tumori, Napoli

Italy 5

Giacomo Carteni Azienda Ospedaliera Cardarelli, Napoli Italy 5

Shinji Ohno National Hospital Organization Kyushu Cancer Center, Kukouka

Japan 5

Nobuaki Sato Niigata Cancer Center Hospital, Niigata Japan 5

Katsumasa Kuroi Tokyo Metropolitan Cancer & Infectious Disease Center, Tokyo

Japan 5

Reiki Nishimura Kumamoto Municipal Hospital, Kumamoto Japan 5

Junichiro Watanabe Shizuoka Cancer Center, Shizuoka Japan 5

Yoon Ji Choi; Kyong Hwa Park Korea University Medical Center, Seoul Korea 5

Marek Wojtukiewicz Bialostockie Centrum Onkologii im. M. Sklodowskiej-Curie w Bialymstoku, Bialystok

Poland 5

Jacek Jassem Uniwersyteckie Centrum Kliniczne, Gdansk Poland 5

Niklas Loman Skånes Universitetssjukhus Malmö, Lund Sweden 5

Mustafa Kadri Altundag Hacettepe University, Sihhiye/Ankara Turkey 5

Pinar Saip Istanbul University, Instanbul Turkey 5

Muhammad Amjad Ali Quincy Medical Group, Quincy USA 5

James Lloyd Wade III Decatur Memorial Hospital, Decatur USA 5

(Amy) Jo Chien University of California San Francisco, San Francisco USA 5

Debra Brandt Northwestern Connecticut Oncology and Hematology

Associates, Torrington USA 5

Yelena Novik NYU Clinical Cancer Center, New York USA 5

Chirag Jani Phoebe Cancer Center, Albany USA 5

Robert L. Rice; Yousuf A. Gaffar Alliance Hematology Oncology PA, Westminster USA 5

Mark R. Keaton Augusta Oncology Associates PC, Augusta USA 5

Rajesh Bajaj McLeod Oncology and Hematology Associates, Florence

USA 5

Gretchen Kimmick Duke University Medical Center, Durham USA 5

28


randomized, n

David Campbell; Richard Hendry De

Boer Western Hospital, Melbourne Australia 4

Theodore Turnquest Affinity Research Limited, Nassau Bahamas 4

Pierre Dube Hopital Maisonneuve – Rosemont, Montreal Canada 4

Stephen Chia British Columbia Cancer Agency, Vancouver Canada 4

Binghe Xu Cancer Hospital, Beijing China 4

Joerg Schilling Onkologische Schwerpunktpraxis, Berlin Germany 4

Klaus Apel Facharzt fuer Frauenheilkunde und Geburtshilfe, Erfurt

Germany 4

Peter Grundtvig Sorensen; Peter

Michael Vestlev Roskilde Sygehus, Roskilde Denmark 4

Erik Hugger Jakobsen; Brita

Bjerregaard Jensen Sydvestjysk Sygehus Esbjerg, Esbjerg Denmark 4

Vera Haahr Regionshospital Viborg, Viborg Denmark 4

Alvaro Rodriguez Lescure Hospital General Universitario de Elche, Elche Spain 4

Begona Grana Suarez; Cristina Saura

Manich Hospital Universitario Vall d´Hebron, Barcelona Spain 4

Jean-Philippe Jacquin Institut de Cancerologie de la Loire (ICL) France 4

Ion Boiangiu University Hospitals of Leicester, Leicester UK 4

Magdolna Dank Semmelweis Egyetem Radiologiai es Onkoterapias

Klinika, Budapest Hungary 4

Cristina Falci; Antonio Jirillo Universita degli Studi di Padova, Padova Italy 4

Saverio Cinieri Presidio Ospedaliero di Summa Antonio Perrino,

Brindisi Italy 4

Takayuki Ueno; Fumiaki Sato; Hiroyasu Yamashiro; Tomoharu Sugie

Kyoto University Hospital, Kyoto Japan 4

Keun Seok Lee; Jung Sil Ro; In Hae

Park National Cancer Center, Gyeonggi-do Korea 4

Anita Zarina Bustam University Malaya Medical Centre, Kuala Lumpur Malaysia 4

MalgorzataSuszko-Kazarnowicz; Artur Piktel

Olsztynski Osrodek Onkologiczny, Olsztyn Poland 4

Krzysztof Krzemieniecki Samodzielny Publiczny Zaklad Opieki Zdrowotnej

Szpital Uniwersytecki w Krakowie, Krakow Poland 4

Polizenia Georgeta Iorga Spitalul Universitar de Urgenta, Bururesti Romania 4

Yap Yoon Sim National Cancer Centre Singapore, Singapore Singapore 4

Marian Kakalejcik Poliklinika ADUS, Poprad Slovakia 4

Alper Sevinc Gaziantep University, Sehitkamil/Gaziantep Turkey 4

Mustafa Ozguroglu Istanbul University, Cerrahpasa Turkey 4

Shin-Cheh Chen Chang Gung Medical Foundation, Taipei Branch Taiwan 4

Richard H. Greenberg The Center for Cancer and Hematologic Disease,

Cherry Hill USA 4

Allan D. Eisemann Rutland Regional Medical Center, Rutland USA 4

Robert Droder East Texas Medical Center Cancer Institute, Tyler USA 4

M. Rashid Abbasi Oncology and Hematology Specialist, Danville USA 4

Marina Vaysburd Cedar-Sinai Medical Group, Beverly Hills USA 4

Humberto Jose Caldera Hematology Oncology Associates, Loxahatchee USA 4

Barbara Bacsik Haley University of Texas Southwestern Medical Center,

Dallas USA 4

Erwin Robin Munster Community Hospital, Munster USA 4

Roger C. Inhorn Mercy Hospital, Portland USA 4

David Hufnagel; Peter D. Kenyon Samaritan Hematology & Oncology Consultants, Corvallis

USA 4

Ellen Spremulli Anniston Oncology, Anniston USA 4

Paula Silverman University Hospitals Case Medical Center (UHCMC), Cleveland

USA 4

Sharad Jain Texas Oncology, PA, Denton USA 4

Robert Weigand St. Joseph Oncology Inc, St Joseph USA 4

Jeroen Mebis VZW Jesseziekenhuis - campus Virga Jesse, Hasselt Belgium 3

Tatyana Koynova District Dispensary for Oncology Diseases Internal Unit – Sofia EOOD, Sofia

Bulgaria 3

Bernard Lesperance Hopital du Sacre-Coeur de Montreal, Montreal Canada 3

29


randomized, n

Jana Prausova Fakultni Nemocnice v Motole, Praha Czech Republic 3

Claus-Henning Kohne Klinikum Oldenburg gGmbH, Oldenburg Germany 3

Andreas Schneeweiss Universitaetsfrauenklinik, Heidelberg Germany 3

Christian Jackisch Klinik für Gynaekologie und Geburtshilfe, Offenbach Germany 3

Stefan Fuxius Onkologische Schwerpunktpraxis, Heidelberg Germany 3

Ricardo Cubedo Cervera Hospital Puerta de Hierro-Majadahonda,

Majadahonda Spain 3

Ander Urruticoechea Ribate; Sonia Pernas Simon

ICO de Barcelona - Hospital Duran i Reynals, Barcelona

Spain 3

Jose Valero Gallego Hospital Provincial de Zamora, Zamora Spain 3

Angels Arcusa Lanza Consorci Sanitari de Terrassa, Terrassa Spain 3

Maria del Pilar Alvarez Hospital Universitario Nuestra Señora de Candelaria,

Santa Cruz de Tenerife Spain 3

Jesus Florian Gerico Hospital de Barbastro, Barbastro Spain 3

Laurent Cany Polyclinique Francheville, Perigueux France 3

Justin Stebbing Charing Cross Hospital, London UK 3

Damir Gugic University Hospital Centre Osijek, Osijek Croatia 3

Damir Vrbanec University Hospital Zagreb, Zagreb Croatia 3

Fausto Roila Azienda Ospedaliera S. Maria, Terni Italy 3

Sandro Barni Ospedali Treviglio Caravaggio, Treviglio Italy 3

Paolo Bidoli Azienda Ospedaliera San Gerardo, Monza Italy 3

Hirofumi Mukai National Cancer Center Hospital East, Chiba Japan 3

Vanessa Bermudez Clínica Vista Alegre / Unidad de Investigacion, Surco Peru 3

Alexandru Eniu Institutul Oncologic "Prof. Dr. Ion Chiricuta", Cluj-

Napoca Romania 3

Barry C. Mirtsching Center for Research and Treatment PA, Dallas USA 3

Emad Ibrahim Beaver Medical Group, LP, Highland USA 3

Joan Trey; Paul Francis Hergenroeder MetroHealth Medical Center, Cleveland USA 3

Aftab Mahmood; Anneliese Gonzalez Cancer Specialists of South Texas PA, Corpus Christi USA 3

Edward H. Kaplan; Stacy Ban North Shore Cancer Research Association, Skokie USA 3

Dhimant Patel Aurora Health Care Medical Center, Green Bay USA 3

Billy Clowney Santee Hematology Oncology, Sumter USA 3

Karen Hoelzer Springfield Clinic LLP, Springfield USA 3

Garry H. Schwartz Carolinas Medical Center NorthEast, Concord USA 3

Jame Abraham West Virginia University - Mary Babb Randolph

Cancer Center, Morgantown USA 3

Sunil Narula Midwest Center for Hematology Oncology, Joliet USA 3

Khaled Jabboury Jabboury Foundation for Cancer Research Inc,

Houston USA 3

Robert Scott Mocharnuk Simmons Cancer Institute at Southern Illinois

University School of Medicine, Springfield USA 3

Richard F. McDonough; David H. Sikes; Ronald H. Kawanchi

Florida Medical Clinic, PA, Zephyrhillis USA 3

Larry Schlabach Erlanger Health System, Chattanooga USA 3

Samuel Spence McCachren, Jr. Thompson Cancer Survival Center, Knoxville USA 3

Thomas M. Cosgriff Hematology Oncology Specialties LLC, New Orleans USA 3

Luke Dreisbach Desert Hematology Oncology Medical Group, Inc, Rancho Mirage

USA 3

Angela DeMichele University of Pennsylvania, Philadelphia USA 3

Lawrence Pawl Medical Specialty Associates, Grand Rapids USA 3

Jennifer Lucas California Cancer Care Inc, Greenbrae USA 3

Lowell C. Shinn; Nabiel Alkhouri; Manish Monga

Wheeling Hospital, Wheeling USA 3

Deborah L. Lindquist Arizona Oncology Associates, Sedona USA 3

Thomas C. Anderson Texas Oncology, PA, Bedford USA 3

Humera Khurshid; Sabrina Witherby Memorial Hospital of Rhode Island, Pawtucket USA 3

Nicholette Erickson; Ann Traynor Central Maine Medical Center, Lewiston USA 3

Ron Bose; Timothy J. Pluard Washington University School of Medicine, St Louis USA 3

Clyde Michael Jones The Jones Clinic, PC, Germantown USA 3

30


randomized, n

Sucharu Prakash Texas Oncology, PA, Paris USA 3

Fabio Volterra Eastchester Center for Cancer Care, Bronx USA 3

Gerardo Capo Trinitas Comprehensive Cancer Center, Elizabeth USA 3

Lawrence E. Flaherty; Elaina Gartner Barbara Ann Karmanos Cancer Institute, Detroit USA 3

Said Baidas MD Anderson Cancer Center, Orlando USA 3

Ian Okazaki Straub Clinic and Hospital, Honolulu USA 3

Bichlien Nguyen Long Beach Memorial Medical Center, Long Beach USA 3

Thomas Rakowski The Valley Hospital, Paramus USA 3

Ira Oliff Orchard Healthcare Research Inc, Skokie USA 3

Joseph W. Leach; Kendra Kubiak; Michaela Tsai

Park Nicollet Institute, St Louis Park USA 3

Philippe Vroman OL Vrouw Ziekenhuis, Aalst Belgium 2

Ines Deleu; Willem Lybaert AZ Nikolaas, St Nikolaas Belgium 2

Marleen Borms AZ Groeninge, Kortrijk Belgium 2

Felix Couture Hotel Dieu de Levis Hospital, Quebec Canada 2

Jonathan J. Wilson Humber River Regional Hospital, Weston Canada 2

Gordon Hunt; David R. Holland Jack Ady Cancer Centre, Lethbridge Canada 2

Walter Mingrone Kantonsspital Olten, Olten Switzerland 2

Donggeng Liu Sun Yat-Sen University Cancer Center, Guangzhou China 2

Zefei Jiang The Hospital Affiliated Academy Military Medical Science, Beijing

China 2

Vera Benesova Nemocnice Jihlava, Jihlava Czech Republic 2

Martin Smakal; Petra Garnolova Institut Onkologie a reahabilitace na Plesi, Nova Ves pod Plesi

Czech Republic 2

Monika Neumann; Wolfgang Janni Universitaetsklinikum Duesseldorf, Duesseldorf Germany 2

Dorothea Fischer Universitaetsklinikum Schleswig-Holstein Brustzentrum, Leubeck

Germany 2

Eva-Maria Grischke Universitaetsfrauenklinik Tuebingen, Tuebingen Germany 2

Dietmar Seeger St. Marienhospital Vechta, Vechta Germany 2

Volker Moebus Staedtische Kliniken Frankfurt am Main-Hoechst

Frauenklinik, Frankfurt am Main Germany 2

Anita Prechtl Praxis Gynaekologie Arabella Muenchen, Muenchen Germany 2

Juan Carlos Camara Toral Hospital de Torrevieja, Alicante Spain 2

Alfonso Sanchez Munoz Hospital Clinico Universitario Virgen de la Victoria, Malaga

Spain 2

Sonia Gonzalez Jimenez Hospital Mutua de Terrassa, Terrassa Spain 2

Javier Cassinello Espinosa Hospital Universitario de Guadalajara, Guadalajara Spain 2

Beatriz Cirauqui; Mireia Margeli Vila Hospital Universitari Germans Trias i Pujol,

Barcelona Spain 2

Norberto Batista Lopez Hospital Universitario de Canarias, Tenerife Spain 2

JoseIgnacio Chacon Lopez-Muniz;

Miguel Angel de la Cruz Mora Hospital Virgen de la Salud, Toledo Spain 2

Audrey Mailliez; Laurence Vanlemmens Centre Oscar Lambret, Lille France 2

Damien Pouessel; Marc Espie Hopital Henri Mondor, Paris France 2

Marc Espie Hopital Saint-Louis, Paris France 2

Rebecca Roylance St. Bartholomew's Hospital, London UK 2

Adrian Harnett Norfolk & Norwich University Hospitals, Norwich UK 2

David Geffen Soroka University MC, Beer-Sheva Israel 2

Enzo Maria Ruggeri Ospedale Belcolle Viterbo, Viterbo Italy 2

Teresa Gamucci Ospedale SS Trinita, Sora Italy 2

Cees J. Van Groeningen Ziekenhuis Amstelland, Amstelveen Netherlands 2

Renata Banas Szpital Wojewodzki im. Sw. Lukasza Samodzielny,

Tarnow Poland 2

Niklas Loman Skånes Universitetssjukhus, Malmo Sweden 2

Necati Alkis Dr. Abdurrahman Yurtarslan Ankara Oncology

Hospital, Demetevler/Ankara Turkey 2

Ming-Feng Hou Kaohsiung Medical University Chung-Ho Memorial Hospital, Kaohsiung

Taiwan 2

Amy K. Krie Avera Cancer Institute, Sioux Falls USA 2

31


randomized, n

Nandagopal S. Vrindavanam Signal Point Clinical Research Center, LLC,

Middletown USA 2

Orion M. Howard Southwestern Vermont Health Care, Bennington USA 2

Dennis Citrin Midwestern Regional Medical Center, Zion USA 2

Mark S. Morginstin; Ajit Desai Albert Einstein Cancer Center, Philadelphia USA 2

Ines J. Sanchez Center for Integrative Cancer Medicine, PA, El Paso USA 2

David Allen Nixon, Jr. Northeast Arkansas Clinic, Jonesboro USA 2

Patrick G. Beatty Montana Cancer Specialists, Missoula USA 2

Kathryn Edmiston University of Massachusetts Memorial Medical

Center, Worcester USA 2

Jonathan D. Eneman York Hospital Oncology Treatment Center, York USA 2

Cynthia A. Lynch; Edward O'Brien Guthrie Clinic Ltd, Sayre USA 2

Justin A. Call Northern Michigan Regional Hospital, Petoskey USA 2

Keith S. Lanier; Alison Conlin Providence Cancer Center, Portland USA 2

Donald J. Brooks Arizona Oncology Associates, Tuscon USA 2

Kristi McIntyre Texas Oncology, PA, Dallas USA 2

Marc A. Saltzman Innovative Medical Research of South Florida Inc,

Aventura USA 2

Michael J. Castine III Hematology-Oncology Clinic, Baton Rouge USA 2

Gregory L. Ortega Mid Florida Hematology & Oncology Centers, PA,

Orange City USA 2

Young M. Choi Wheaton Franciscan Cancer Care-All Saints, Racine USA 2

Craig H. Reynolds Ocala Oncology Center, Ocala USA 2

Frank Brescia; Rita Kramer Medical University of South Carolina, Charleston USA 2

Aimee D. Kohn Cascade Cancer Center, Kirkland USA 2

John P. Micha; Jessica M. Rhee Gynecologic Oncology Associates, Newport Beach USA 2

Satish Shah Gettysburg Cancer Center, Gettysburg USA 2

David A. Riseberg Mercy Medical Center, Baltimore USA 2

William Kevin Patterson The Queen Elizabeth Hospital, Adelaide Australia 1

Jean-Paul Salmon; Chantal Andre Centre Hospitalier Regional de la Citadelle, Liege Belgium 1

Alain Bols AZ St Jan Ruddershove, Brugge Belgium 1

Randal D'hondt AZ Damiaan - Site Sint-Jozef, Oostende Belgium 1

Sylvie Luce; Claire Nouwynck Cliniques Universitaires de Bruxelles, Bruxelles Belgium 1

Gino Pelgrims Sint-Elisabeth Ziekenhuis, Turnhout Belgium 1

Vincent Richard Centre Hospitalier Universitaire Ambroise Paré,

Mons Belgium 1

Johan Verschuere AZ Zusters van Barmhartigheid, Ronse Belgium 1

Kurt Geldhof Jan Yperman Ziekenhuis, Leper Belgium 1

Clemens Caspar Kantonsspital Baden, Baden Switzerland 1

Rongcheng Luo Southern Medical University Nanfang Hospital,

Guangzhou China 1

Otakar Bednarik Fakultni Nemocnice Brno, Brno Czech Republic 1

Kathrin Schwedler Frauenklinik der J.W. Goethe-Universitat, Frankfurt

am Main Germany 1

Marcus Schmidt Klinikum der Johannes Gutenberg-Universitaet,

Mainz Germany 1

Joachim Bischoff Universitaetsklinikum Magdeburg, Magdeburg Germany 1

Brigitte Rack Klinikum Innenstadt der Universitaet Muenchen,

Muenchen Germany 1

Roland Repp; Stefan Fries; Ralf Adrion Sozialstiftung Bamberg Klinik fuer Haematologie

und internistische Onkologie, Bamberg Germany 1

Volker Schulz MVZ Abtrs & Partner Kiel, Kiel Germany 1

Peter Klare Praxisklinik Krebsheilkunde fuer

Frauen/Brustzentrum, Berlin Germany 1

Dirk Ossenbuhl; Jakob Manfred Kusche Marienhospital Aachen, Aachen Germany 1

Frank Griesinger Pius-Hospital Oldenburg, Oldenburg Germany 1

Jose Manuel Baena Hospital Universitario Puerta del Mar, Cadiz Spain 1

Purificacion Martinez del Prado Hospital de Basurto, Vizcaya Spain 1

David Machover Hopital Paul Brousse, Villejuif France 1

32


randomized, n

Didier Mayeur Hopital de Versailles, Le Chesnay France 1

Nathalie Trufflandier Centre Hospitalier Universitaire De Bordeaux Saint

Andre, Bordeaux France 1

Valerie Delecroix Pôle Hospitalier Mutualiste, Saint-Nazaire France 1

Mireille Mousseau Hopital Albert Michalon, Grenoble France 1

Marie-Ange Mouret-Reynier; Jean-Marc Nabholtz

Centre Jean Perrin, Clermont-Ferran France 1

Anula D. Chetiyawardana Queens Hospital, Burton-on-Trent UK 1

Christos Papandreou University General Hospital of Larissa, Larissa Greece 1

Lajos Hornyak; Zsolt Faluhelyi;

Erzsebet Simo

Veszprem Megyei Csolnoky Ferenc Korhaz,

Veszprem Hungary 1

Mario Di Palma Ospedale San Pietro Fatebenefratelli, Roma Italy 1

Francesco Cognetti Medica Istituti Fisioterapici Ospitalieri - Istituto

Regina Elena, Roma Italy 1

Gabriella Gorzegno; Luigi Dogliotti Azienda Ospedaliera San Luigi Gonzaga, Orbassano Italy 1

Cesare Gridelli Ospedale San Giuseppe Moscati, Avellino Italy 1

Alfredo Falcone Riuniti Azienda Ospedaliero-Universitaria Pisana,

Pisa Italy 1

Hector Soto Parra; Calogero Buscarino AOU Policlinico - Vittorio Emanuele, Catania Italy 1

Seock-Ah Im Seoul National University Hospital, Seoul Korea 1

Benito Sanchez Llamas Nucleo De Especialidades Oncologicas, Guadalajara Mexico 1

Wouter Dercksen Maxima Medisch Centrum, Noord Brabant Netherlands 1

Franciscus Erdkamp Orbis Medisch Centrum, Sittard-Geleen Netherlands 1

J.B. Ruit; Hans Braun Vlietland Ziekenhuis, Schiedam Netherlands 1

Joanneke E.A. Portielje Haga Ziekenhuis, Den Haag Netherlands 1

Suleyman Buyukberber; Mustafa

Benekli Gazi Universitesi Tip Fakultesi, Besevler/Ankara Turkey 1

Andrew J. Zahalsky Andrew J. Zahalsky, MD, PC, Monongahela USA 1

Rebecca Jaslow Thomas Jefferson University, Philadelphia USA 1

Gary W. Thomas South Carolina Cancer Specialists, Hilton Head

Island USA 1

Archana Maini; Israel Wiznitzer Broward General Medical Center, Fort Lauderdale USA 1

Ali Khojasteh Columbia-Capitol Comprehensive Cancer Care

Clinic, Jefferson City USA 1

Manuel Francisco Gonzalez Francisco Gonzalez MD PA, Columbia USA 1

Lynn R. Kong Ventura County Hematology-Oncology Specialists,

Oxnard USA 1

Aruna Padmanabhan Temple University Hospital, Philadelphia USA 1

William A. Conkright Purchase Cancer Group, Paducah USA 1

Sandra M. Swain Washington Hospital Center, Washington USA 1

Douglas E. Faig North Broward Medical Center, Deerfield Beach USA 1

Kirti Jain Ashland-Bellefonte Cancer Center, Ashland USA 1

Ronald H. Yanagihara Ronald H. Yanagihara, Gilroy USA 1

Yvonne Ottaviano Harry and Jeanette Weinberg Cancer Center,

Baltimore USA 1

Beverly Moy Beth Israel Deaconess Medical Center, Boston USA 1

Heather A. Steele; Gordon K. Rainey;

Penelope J. Harris; Jason K. Burris; Erik J. Rupard; Esther Tan

Dwight David Eisenhower Army Medical Center,

Fort Gordon USA 1

Pat W. Whitworth Nashville Breast Cancer, Nashville USA 1

Abby R. Bova Mercy Clinic Oncology and Hematology – McAuley,

Oklahoma City USA 1

Ian C. Anderson Redwood Regional Medical Group, Santa Rosa USA 1

Mihran Shirinian Glendale Adventist Medical Center Cancer Services,

Glendale USA 1

Caesar Tin-u Texas Oncology, PA, Sugar Land USA 1

Timothy J. O'Rourke Cancer & Hematology Centers of Western Michigan,

Grand Rapids USA 1

Michael S. Roberts Arizona Oncology Associates, PC, Phoenix USA 1

Michael Francisco; A. Scott Pierson Portneuf Medical Center, Pocatello USA 1

33


randomized, n

Peter D. Byeff Cancer Center of Central Connecticut, Southington USA 1

Peter A. Kovach; John R. Caton, Jr. Willamette Valley Cancer Institute and Research

Center, Springfield USA 1

Mark Urban Rarick Kaiser Permanente Northwest Region Oncology

Hematology, Portland USA 1

William G. Schimidt, Jr. Bend Memorial Clinic, Bend USA 1

Alison T. Stopeck; Rachel Swart Arizona Cancer Center, Tuscon USA 1

Maria Regina Carrillo Flores; Carlos A.

Alemany; Brennely Lozada Cancer Centers of Florida, Orlando USA 1

Paul L. Weinstein Hematology Oncology, PC, Stanford USA 1

Wei Wang San Francisco Oncology Associates, San Francisco USA 1

Michael Porubcin Medical Arts Association, Ltd, Moline USA 1

David M. Ellison; George F. Geils Charleston Hematology Oncology Associates, PA,

Charleston USA 1

Edgardo Rivera The Methodist Hospital, Houston USA 1

Mahmoud Charif University of Cincinnati Cancer Center, Cincinnati USA 1

34

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chemotherapy for breast cancer. J Clin Oncol 2011; 29: 4491-7.

2. Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J

Med 2011; 365: 1273-83.

3. Eton DT, Cella D, Yost KJ, et al. A combination of distribution- and anchor-based approaches determined

minimally important differences (MIDs) for four endpoints in a breast cancer scale. J Clin Epidemiol 2004; 57:

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4. Pickard AS, Neary MP, Cella D. Estimation of minimally important differences in EQ-5D utility and VAS

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