9408-9590NSSIVolume 93, April 2018

EJCEUROPEAN JOURNAL OF CANCER

Reprinted from Eur J Cancer. 2018;93:19‐27

A phase III study comparing SB3 (a proposed trastuzumab biosimilar) and trastuzumab reference product in HER2-positive early breast cancer treated with neoadjuvant-adjuvant treatment: Final safety, immunogenicity and survival resultsX. Pivot, I. Bondarenko, Z. Nowecki, M. Dvorkin, E. Trishkina,J.-H. Ahn, S.-A. Im, T. Sarosiek, S. Chatterjee, M.Z. Wojtukiewicz,Y. Shparyk, V. Moiseyenko, M. Bello III, V. Semiglazov, Y. Leeand J. Lim

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Original Research

A phase III study comparing SB3 (a proposedtrastuzumab biosimilar) and trastuzumab referenceproduct in HER2-positive early breast cancer treated withneoadjuvant-adjuvant treatment: Final safety,immunogenicity and survival results

X. Pivot a,*,1, I. Bondarenko b, Z. Nowecki c, M. Dvorkin d, E. Trishkina e,J.-H. Ahn f, S.-A. Im g, T. Sarosiek h, S. Chatterjee i, M.Z. Wojtukiewicz j,Y. Shparyk k, V. Moiseyenko l, M. Bello III m, V. Semiglazov n, Y. Lee o,J. Lim o

a Administrateur de l’Institut Regional du Cancer, 3 rue de la porte de l’hopital, BP 30042, 67065, Strasbourg Cedex, Franceb Oncology and Medical Radiology Department, Dnipropetrovsk Medical Academy, Dnipropetrovsk, Ukrainec Department of Oncology, M Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Polandd Department of Oncology, Clinical Oncology Dispensary, Omsk, Russiae Department of Oncology, Leningrad Regional Oncology Centre, St. Petersburg, Russiaf Department of Oncology, Asan Medical Center, Seoul, Republic of Koreag Department of Oncology, Seoul National University Hospital, Seoul, Republic of Koreah Department of Clinical Oncology, Centrum Medyczne Ostrobramska NZOZ MAGODENT, Warsaw, Polandi Department of Oncology, Tata Medical Centre, Kolkata, Indiaj Department of Oncology, Medical University of Bialystok, Bialystok, Polandk Chemotherapy Department, Lviv State Oncological Regional Treatment and Diagnostic Center, Lviv, Ukrainel Department of Oncology, N.N. Petrov Cancer Center, St. Petersburg, Russiam Department of Oncology, Saint Luke’s Medical Center, Quezon City, Philippinesn Department of Oncology, N.N. Petrov Research Institute of Oncology, St. Petersburg, Russiao Biometrics Group (Y. Lee) and Clinical Development Group (J. Lim), Samsung Bioepis Co., Ltd., Incheon, Republic of

Korea

Received 31 October 2017; received in revised form 11 January 2018; accepted 15 January 2018

Available online 12 February 2018

* Corresponding author: Administrateur de l’Institut Regional du Cancer, 3 rue de la porte de l’hopital, BP 30042, 67065, Strasbourg Cedex,

France.

E-mail address: xpivot@strasbourg.unicancer.fr (X. Pivot).1 URL: http://www.centre-paul-strauss.fr.

https://doi.org/10.1016/j.ejca.2018.01.072

0959-8049/ª 2018 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://

creativecommons.org/licenses/by-nc-nd/4.0/).

X. Pivot et al. / European Journal of Cancer 93 (2018) 19e2720

KEYWORDS

Biosimilar;

Trastuzumab;

HER2;

Early breast cancer;

Event-free survival;

Safety

Abstract Background: The equivalent efficacy between SB3, a proposed trastuzumab bio-

similar, and the trastuzumab reference product (TRZ) in terms of the breast pathologic com-

plete response rate after neoadjuvant therapy in patients with early or locally advanced human

epidermal growth factor receptor 2-positive breast cancer was demonstrated in the previous

report. Here, we report the final safety, immunogenicity and survival results after

neoadjuvant-adjuvant treatment.

Patients and methods: Patients were randomised 1:1 to receive neoadjuvant SB3 or TRZ for 8

cycles concurrently with chemotherapy (4 cycles of docetaxel followed by 4 cycles of 5-

fluorouracil/epirubicin/cyclophosphamide). Patients then underwent surgery, followed by 10

cycles of adjuvant SB3 or TRZ as randomised. End-points included safety, immunogenicity,

event-free survival (EFS) and overall survival through the adjuvant period.

Results: Of 875 patients randomised, 764 (SB3, n Z 380; TRZ, n Z 384) completed the study.

The median follow-up duration was 437 days in the SB3 group and 438 days in the TRZ

group. The incidence of treatment-emergent adverse events was comparable between groups

(SB3, 97.5%; TRZ, 96.1%) during the overall study period. Up to the end of study, the overall

incidence of antidrug antibody was low in both treatment groups (3 patients each). EFS was

comparable between groups with a hazard ratio (SB3/TRZ) of 0.94 (95% confidence interval,

0.59e1.51) and EFS rates at 12 months of 93.7% for SB3 and 93.4% for TRZ.

Conclusions: Final safety, immunogenicity and survival results of this study further support

the biosimilarity established between SB3 and TRZ.

Trial registration: ClinicalTrials.gov (NCT02149524); EudraCT (2013-004172-35).

ª 2018 The Authors. Published by Elsevier Ltd. This is an open access article under the CC

BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction

Trastuzumab (Herceptin�; Roche Registration Limited,

Welwyn Garden City, UK and Genentech, Inc., South

San Francisco, CA, USA) provides benefits in terms of

tumour shrinkage, recurrence and survival when admin-

istered as neoadjuvant therapy with chemotherapy and

continued as adjuvant therapy [1], and when administered

as adjuvant therapy [2e7] for human epidermal growthfactor receptor 2 (HER2)-positive early breast cancer.

SB3 (Samsung Bioepis Co., Ltd., Incheon, Republic

of Korea) is a proposed trastuzumab biosimilar with

structural and physicochemical characteristics similar to

trastuzumab reference product (TRZ) [8]. A randomised

phase I pharmacokinetic study of healthy males

demonstrated similarity in terms of pharmacokinetic

equivalence [8]. We conducted a phase III trialcomparing SB3 and TRZ (EU-sourced) in patients with

early or locally advanced HER2-positive breast cancer

treated with neoadjuvant-adjuvant therapy. Equivalent

efficacy between SB3 and TRZ in terms of the primary

end-point, breast pathologic complete response (bpCR)

rate, was demonstrated after neoadjuvant therapy. The

bpCR rates in the per-protocol set were 51.7% for SB3

and 42.0% for TRZ, with an adjusted ratio (90% con-fidence interval [CI]) of 1.259 (1.112e1.426) and an

adjusted difference (95% CI) of 10.70% (4.13%e17.26%)

[9]. Biosimilarity of SB3 and TRZ has been assessed

based on the ‘totality of evidence’ approach, taking

structural, functional, nonclinical, pharmacokinetic,

clinical immunogenicity and comparative clinical study

data into consideration [10,11].

The objective of the current analysis was to compare

safety, immunogenicity, and survival with SB3 and TRZ

after neoadjuvant-adjuvant therapy in this phase IIItrial.

2. Materials and methods

The study and clinical protocols were reviewed and

approved by the Independent Ethics Committee (IEC)

or Institutional Review Board (IRB) for each study

center. This study was conducted in accordance with theethical principles that have their origin in the Declara-

tion of Helsinki and that are consistent with Interna-

tional Council for Harmonisation of Technical

Requirements for Registration of Pharmaceuticals for

Human Use (ICH) Good Clinical Practice (GCP)

guidelines and applicable local regulatory requirements

and laws.

2.1. Patients

Inclusion and exclusion criteria were previously

described [9], and the key elements follow. Eligible pa-

tients were women 18e65 years of age with an Eastern

Cooperative Oncology Group (ECOG) performance

status of 0e1; with non-metastatic, unilateral, newly

diagnosed, histologically confirmed, primary invasive

breast adenocarcinoma (clinical stages IIeIII) includinginflammatory breast cancer, with tumour size �2 cm

and confirmed HER2-positivity (immunohistochemistry

3þ or fluorescence in situ hybridisation þ); and with

known oestrogen receptor (ER) and progesterone

X. Pivot et al. / European Journal of Cancer 93 (2018) 19e27 21

receptor (PR) status. All patients provided written

informed consent before undergoing any study-related

procedures.

2.2. Study design

This phase III, randomised, double-blind, parallel-

group, multicentre, study contained a neoadjuvant

therapy period, a surgical intervention, and an adjuvant

therapy period. Patients were randomised 1:1 to receiveneoadjuvant SB3 or TRZ every 3 weeks for 8 cycles

concurrently with chemotherapy (4 cycles of docetaxel

75 mg/m2 followed by 4 cycles of 5-fluorouracil 500 mg/

m2, epirubicin 75 mg/m2, and cyclophosphamide

500 mg/m2). Randomisation was stratified by hormone

receptor status (ER and/or PR positive versus ER and

PR negative) and breast cancer stage (operable versus

locally advanced).After neoadjuvant therapy and assessment of clinical

response, patients underwent surgery within 6 weeks of

the last dose of neoadjuvant therapy, followed by 10

cycles of adjuvant SB3 or TRZ as randomised to com-

plete neoadjuvant-adjuvant therapy. Adjuvant radiation

therapy and/or hormone therapy were allowed accord-

ing to local practice. The present analysis was carried

out to assess the safety, immunogenicity, and event-freeand overall survival results following the complete 1

year of neoadjuvant-adjuvant therapy.

2.3. Study end-points

The primary end-point, bpCR, and secondary end-

points related to primary tumour responses, were ana-

lysed previously after completion of the neoadjuvant

therapy period [9]. Secondary end-points reported in this

manuscript include event-free survival (EFS), defined astime from the date of randomisation to the date when an

event occurs. An event is a disease recurrence or pro-

gression (distant, local, or regional) or death due to any

cause. A post hoc search to investigate factors influ-

encing EFS was performed. As an exploratory analysis,

the relationship between EFS and pCR was analysed.

Other secondary end-points were overall survival (OS),

defined as time from the date of randomisation to thedate of death, regardless of the cause of death; safety,

graded according to the National Cancer Institute-

Common Terminology Criteria for Adverse Events

(NCI-CTCAE) v4.0 with several exceptions; and

immunogenicity, determined by the incidence of anti-

drug antibodies (ADAs) and neutralising antibodies

(NAbs) pre-dose at cycles 1, 5, 9, and 14, and 30 days

after the last dose. ADA results were defined as positivefor patients with a negative ADA at pre-dose cycle 1

who had �1 positive result after dosing at cycle 1 and

for patients with a positive ADA at pre-dose cycle 1 who

had �1 positive result after the dose at cycle 1 with a

higher titre level compared with baseline.

2.4. Statistical analysis

The target sample size and power calculations for theprimary analysis were reported previously [9]. The full

analysis set (FAS) was defined as all patients who were

randomised at the randomisation visit and was used in

the current analysis of survival. The safety set was

defined as all patients who received �1 dose of double-

blind study drug during the study phase and was used in

the current analyses of safety and immunogenicity.

Treatment-emergent adverse events (TEAEs) weresummarised by study periods: the neoadjuvant period

(from cycle 1 to before surgery), the adjuvant period

(from surgery date to end of study) and the overall study

period (neoadjuvant þ adjuvant period).

The survival curves (EFS and OS) were estimated

using the KaplaneMeier method. Estimated hazard

ratios (HRs, SB3/TRZ) with 95% CIs were calculated

from a stratified Cox proportional hazard model withhormone receptor status, disease stage and region as

factors. As exploratory analyses, the EFS HRs were

calculated within subgroups dependent on the presence

or absence of bpCR and total pathologic complete

response (tpCR). In addition, the Cox proportional

hazard regression model was estimated to investigate the

clinical factors influencing EFS. The clinical factors used

for estimation were: bpCR/tpCR (yes versus no); age(<45 versus � 45 years); hormone receptor status (ER

and/or PR positive versus ER and PR negative); breast

cancer type (operable versus locally advanced); race

(Asian versus other); menopausal status (yes versus no);

clinical T stage (T1/2 versus T3/4); and clinical N stage

(N0 versus N1/2/3). All analyses were performed with

the FAS without imputation, and patients who did not

have an event at the time of analysis were censored atthe date of the last available visit.

3. Results

3.1. Patients

Of 875 patients randomised, 764 (87.3%) completed the

study (SB3, n Z 380; TRZ, n Z 384; Fig. 1). Baseline

demographics and disease characteristics were compa-

rable between groups as previously reported, with nostatistically significant differences. The majority of pa-

tients were ER and/or PR positive (SB3, 60.9%; TRZ,

57.3%), and the most frequent disease stages were IIB

(SB3, 34.3%; TRZ, 33.3%), IIIB (SB3, 23.6%; TRZ,

19.6%), and IIIA (SB3, 19.5%; TRZ, 22.6%). The rela-

tive dose intensity was comparable between groups

during the overall study period (SB3, 98.65%; TRZ,

98.37%).Surgery completion rate was comparable between

two groups (SB3, n Z 419 (95.9%); TRZ, n Z 416

(95.0%)). During the adjuvant phase, 227 (51.9%) pa-

tients and 219 (50.0%) patients received at least 1 dose of

Fig. 1. Consort. *Multiple screening failures were possible. yPPS defined as all patients randomised who completed 8 cycles of neoadjuvant

therapy and surgery without pre-specified major protocol deviations. zOne patient in the SB3 treatment group was lost to follow-up after

completion of adjuvant therapy. N, number of patients in the randomised set; n, number of patients; PPS, per-protocol set; TRZ,

trastuzumab reference product; SB3, trastuzumab biosimilar.

X. Pivot et al. / European Journal of Cancer 93 (2018) 19e2722

radiation therapy in SB3 and TRZ, respectively. A total

of 517 patients (SB3, n Z 266; TRZ, n Z 251) were

hormone receptor-positive; of these, 185 (69.5%) in the

SB3 group and 169 (67.3%) in the TRZ group received

endocrine therapy. The most frequently given hormonal

treatment was tamoxifen (SB3, 130 patients; TRZ, 126patients).

3.2. Efficacy

Data cut-off was at the end of the study,whichwas 30 days

after adjuvant therapy completion. With the median

follow-up duration of 438 days, EFS (SB3, 92.2%; TRZ,

91.6%) and OS (SB3, 99.8%; TRZ, 98.9%) rates were

similar between groups (Table 1; Fig. 2), with a total of 71

patients experiencing events (SB3, nZ 34; TRZ, nZ 37).At 12 months, EFS (SB3, 93.7%; TRZ, 93.4%) and OS

(SB3, 99.8%; TRZ, 98.8%) rates were also comparable.

Within each treatment group, bpCR achievement was

related to tendency of favourable EFS outcome (Fig. 3A

and B) and tpCR achievement was significantly related to

favourable EFS outcome (Fig. 3D and E). In the com-

bined analysis of both treatment groups, the EFS differ-

ence by attainment or no attainment of bpCR/tpCR wasrather significant: EFS by bpCR (HR 0.43; 95% CI,

0.24e0.77) and EFS by tpCR (HR 0.27; 95% CI,

0.13e0.55; Fig. 3C andF). In theCoxproportional hazard

regression model, bpCR or tpCR were the only

independent clinical factors influencing EFS. Age, hor-

mone receptor status, breast cancer type, race, clinical T

stage, and clinical N stage did not affect EFS. Regardless

of treatment group, bpCR (HR 0.46, 95% CI 0.26e0.83;

Supplementary Table A) and tpCR (HR 0.29, 95% CI

0.14e0.60; Supplementary Table B) were associated witha reduced risk of an event (disease recurrence/progression

and death). OS subgroup analyses were not done because

of the short follow-up period, as well as the small number

of patients experiencing events. Efficacy results in the per-

protocol set are summarised on Supplementary Table C.

3.3. Safety

Safety was comparable between groups throughout the

overall treatment period; at least 1 TEAE was reportedby 426 (97.5%) patients in the SB3 group and by 421

(96.1%) patients in the TRZ group (Table 2). The most

common TEAEs were alopecia and neutropenia. TEAEs

of grade 1 severity occurred most oftend2844 (52.3%)

events in the SB3 group and 2805 (53.5%) events in the

TRZ group. Safety was also comparable between groups

during the adjuvant treatment period; at least 1 TEAE

was reported by 246 (56.3%) patients in the SB3 groupand by 241 (55.0%) patients in the TRZ group (Table 3).

Again, TEAEs of grade 1 severity occurred most

oftend664 (63.7%) events with SB3 and 644 (65.9%)

events with TRZ. Common TEAEs were radiation skin

Table 1Summary of efficacy results during neoadjuvant-adjuvant treatment (full analysis set).

Efficacy parameters SB3 (N Z 437)

%

TRZ (N Z 438)

%

Adjusted % difference

(SB3-TRZ; 95% CI)

Adjusted ratio

(SB3/TRZ; 90% CI)

Breast pathologic complete

response (bpCR)

49.0 39.7 9.59 (3.26, 15.91) 1.243 (1.096, 1.410)

Total pathologic complete

response (tpCR)

41.2 32.4 9.32 (3.19, 15.46) 1.291 (1.114, 1.495)

Overall response rate (ORR) 93.6 87.0 5.94 (2.17, 9.71) 1.068 (1.029, 1.108)

Event-free survival (EFS) 92.2 91.6 eOverall survival (OS) 99.8 98.9 e

Patients with an event 7.8 8.4 e

Recurrence after surgery 4.3 4.3 eDistant 0.9 1.6 e

Local 0.5 0.5 e

Regional 0.2 0.5 e

Unknown 2.7 1.8 eProgression before surgery 3.2 3.0 e

Death 0.2 1.1 e

Abbreviations: SB3, trastuzumab biosimilar; TRZ, trastuzumab reference product.

Fig. 2. EFS by treatment group (SB3 versus TRZ). EFS, event-free survival; TRZ, trastuzumab reference product; SB3, trastuzumab

biosimilar.

X. Pivot et al. / European Journal of Cancer 93 (2018) 19e27 23

injury, procedural pain, and lymphorrhea, which were

mostly due to surgery or adjuvant radiation therapy

rather than trastuzumab (SB3 or TRZ) administration.

The TEAEs of special interest (AESI) were infusion-related reaction, asymptomatic left ventricular systolic

dysfunction (LVSD) and congestive heart failure

(CHF), for which incidence was comparable between

groups during the overall treatment period and during

the adjuvant monotherapy period (Tables 2 and 3).

The analysis focused on cardiac dysfunction,

asymptomatic left ventricular dysfunction events were

reported as LVSD. In the SB3 group, 14 LVSD events

were reported in 11 (2.5%) patients and, in the TRZ

group, 9 LVSD events were reported in 8 (1.8%) pa-

tients. A total of 4 patients (SB3, n Z 3; TRZ, n Z 1)reported CHF. The incidence of CHF observed in this

study was within the expected ranges as reported in

previous literature (0%e0.7%) with neoadjuvant tras-

tuzumab given concurrently with taxanes and anthra-

cyclines [1,12,13]. All 4 patients had a history of

hypertension or diabetes/glucose intolerance, and no

CHF cases were fatal. Three CHF cases in the SB3

Fig. 3. EFS by bpCR and tpCR. (A) EFS by bpCR in SB3 group; (B) EFS by bpCR in TRZ group; (C) EFS by bpCR in combined SB3

and TRZ groups; (D) EFS by tpCR in SB3 group; 3 (E) EFS by tpCR in TRZ group; (F) EFS by tpCR in combined SB3 and TRZ groups.

bpCR, breast pathologic complete response; tpCR, total pathologic complete response; EFS, event-free survival; TRZ, trastuzumab

reference product.

X. Pivot et al. / European Journal of Cancer 93 (2018) 19e2724

group resolved or improved and 1 CHF case in the TRZgroup did not resolve. The overall incidence of a sig-

nificant decrease in LVEF �10% points from baseline

and resulting in LVEF <50% was comparable between

treatment groups (SB3, n Z 16 [3.7%]; TRZ, n Z 12

[2.8%]). The mean LVEF was slightly decreased from

baseline (65.3% in the SB3 group and 65.2% in the TRZ

group) to cycle 14 and maintained until the end of the

study (62.9% in the SB3 group and 63.0% in the TRZgroup) in both treatment groups (Fig. 4).

Serious adverse events occurred in 12.8% and 13.2%of patients in the SB3 and TRZ groups, respectively.

Most common events were due to neutrophil count

decrease. Six deaths were reported during study. One

patient (0.2%) in the SB3 group died from suicide, and 5

patients (1.1%) in the TRZ group died from myocardial

infarction, sudden death, haemorrhagic stroke,

pneumonitis and pulmonary embolism (1 patient each).

No death was related to progressive disease/diseaserecurrence.

Table 2Summary of TEAEs during the overall treatment period.

Safety parameters SB3 (N Z 437) TRZ (N Z 438)

Patients with �1 TEAE, n (%) 426 (97.5) 421 (96.1)

Grade 1 19 (4.3) 25 (5.7)

Grade 2 82 (18.8) 81 (18.5)

Grade 3 119 (27.2) 129 (29.5)

Grade 4 205 (46.9) 181 (41.3)

Grade 5 1 (0.2) 5 (1.1)

Frequently reported TEAEs �20% in either group, n (%)

Alopecia 299 (68.4) 283 (64.6)

Neutropenia 294 (67.3) 282 (64.4)

Nausea 144 (33.0) 135 (30.8)

Leukopenia 125 (28.6) 114 (26.0)

Anaemia 96 (22.0) 95 (21.7)

Diarrhoea 92 (21.1) 67 (15.3)

Fatigue 88 (20.1) 80 (18.3)

TEAEs of special interest, n (%) 48 (11.0) 53 (12.1)

Infusion-related reaction 37 (8.5) 44 (10.0)

Asymptomatic LVSD 11 (2.5) 8 (1.8)

Congestive heart failure 3 (0.7) 1 (0.2)

Serious TEAEs, n (%) 56 (12.8) 58 (13.2)

Deaths, n (%) 1 (0.2) 5 (1.1)

Abbreviations: LVSD, left ventricular systolic dysfunction; N, number

of patients in the randomised set; n, number of patients; TEAE,

treatment-emergent adverse event; TRZ, trastuzumab reference prod-

uct; SB3, trastuzumab biosimilar.

Table 3Summary of TEAEs during the adjuvant period.

Safety parameters SB3

(N Z 437)

TRZ

(N Z 438)

Patients with �1 TEAE, n (%) 246 (56.3) 241 (55.0)

Grade 1 93 (21.3) 80 (18.3)

Grade 2 126 (28.8) 125 (28.5)

Grade 3 24 (5.5) 32 (7.3)

Grade 4 3 (0.7) 2 (0.5)

Grade 5 0 2 (0.5)

Frequently reported TEAEs �5% in either group, n (%)

Radiation skin injury 48 (11.0) 36 (8.2)

Procedural pain 38 (8.7) 53 (12.1)

Fatigue 37 (8.5) 31 (7.1)

Lymphorrhea 32 (7.3) 30 (6.8)

Anaemia 28 (6.4) 20 (4.6)

Joint range of motion decreased 26 (5.9) 20 (4.6)

Postoperative wound complication 26 (5.9) 21 (4.8)

Upper respiratory tract infection 25 (5.7) 21 (4.8)

TEAEs of special interest, n (%) 11 (2.5) 6 (1.4)

Infusion-related reaction 2 (0.5) 0

Asymptomatic LVSD 8 (1.8) 5 (1.1)

Congestive heart failure 1 (0.2) 1 (0.2)

Serious TEAEs, n (%) 15 (3.4) 14 (3.2)

Deaths, n (%) 0 2 (0.5)

Abbreviations: LVSD, left ventricular systolic dysfunction; N, number

of patients in the randomised set; n, number of patients; TEAE,

treatment-emergent adverse event; TRZ, trastuzumab reference prod-

uct; SB3, trastuzumab biosimilar.

Fig. 4. Mean � SD LVEF change during overall study.

X. Pivot et al. / European Journal of Cancer 93 (2018) 19e27 25

3.4. Immunogenicity

Up to end of study, immunogenicity was low and

comparable between groups. The overall incidence of

ADAs and NAbs was 0.7% (n Z 3) and 0.5% (n Z 2),

respectively, in each treatment group.

4. Discussion

In our previous report, equivalence of efficacy was

demonstrated between SB3 and TRZ based on the ratio

of bpCR rates in primary breast tumour in the neo-

adjuvant setting [9].

Current analysis shows results with data cut-off 30

days post adjuvant therapy completion. EFS (SB3,

92.2%; TRZ, 91.6%) and OS (SB3, 99.8%; TRZ, 98.9%)

rates were comparable, supporting the similarity of SB3and TRZ in addition to pCR results. The survival rates

are consistent with those of previous randomised

controlled trials of trastuzumab therapy for HER2-

positive breast cancer [14,15]. As exploratory analyses,

EFS rates were analysed by subgroups with and without

bpCR or tpCR. Within each treatment group, bpCR

achievement was related to tendency of favourable EFS,

and tpCR achievement was significantly related tofavourable EFS. In the combined analysis, the clinical

benefit of bpCR/tpCR attainment was magnified. A Cox

proportional hazard regression model that estimated the

HR with the clinical factors of treatment group, bpCR

or tpCR, region, hormone receptor status, age group,

breast cancer type, race, menopausal status, and clinical

T, N stage showed that bpCR (HR 0.46, 95% CI

0.26e0.83, P Z 0.0099) and tpCR (HR 0.29, 95% CI0.14e0.60, P Z 0.0009) were the only statistically sig-

nificant factors related to EFS. This result suggests that

bpCR and tpCR are surrogate markers for survival and

are consistent with historical results showing that pCR

achievement is associated with improved long-term

survival in HER2-positive breast cancer [13,16e19].

The overall safety data are reassuring, in that TEAEs

were as expected for this population and treatment

X. Pivot et al. / European Journal of Cancer 93 (2018) 19e2726

including combined chemotherapeutic agents. All safety

parameters did not show any unexpected safety issues

regarding SB3 administration. For AESI, there was no

serious infusion-related reaction to SB3. LVEF change

during the overall study period was not substantial

(about 2e3% points decrease) and was similar in degree

between treatment groups, and the incidence of symp-

tomatic LVSD (CHF) in the SB3 group was low (0.7%)and comparable to the TRZ group. In addition, safety

data collected during the adjuvant monotherapy period

appeared to show comparability between SB3 and TRZ.

In the development of therapeutic protein products,

immunogenicity assessment is important as generation

of an immune response to the drug might induce adverse

events and decrease efficacy [20]. However, the clinical

relevance of ADAs to trastuzumab is not fully under-stood in cancer patients. In this study, the overall inci-

dence of ADAs was low (0.7%), consistent with

published studies of intravenous trastuzumab (0e3.4%)

[12,21,22].

Even though the sample size of this study is the

largest ever among neoadjuvant clinical trials, a limita-

tion of this study is a relatively short follow-up. How-

ever, an extension of the present study is ongoing, whichis a 5-year follow-up study (NCT02771795) observing

the incidence of symptomatic CHF and significant

LVEF decrease and EFS/OS.

5. Conclusion

Using the totality of evidence approach, the final safety,

immunogenicity and survival results of this study further

support the biosimilarity established between SB3 and

TRZ.

Conflict of interest statement

Z. Nowecki has received honoraria from Samsung

Bioepis. S.-A. Im has received consulting or advisory

payments from Novartis, Hanmi, and Spectrum. Y. Lee

and J. Lim are employees of Samsung Bioepis and

stockowners of Samsung Biologics. All other authorsdeclare no conflict of interest.

Acknowledgements

This study was funded by Samsung Bioepis Co., Ltd.Medical writing assistance was provided by Stephanie

Leinbach, PhD, of C4 MedSolutions, LLC (Yardley,

PA), a CHC Group company, and funded by Samsung

Bioepis Co., Ltd.

Appendix A. Supplementary data

Supplementary data related to this article can be found

at https://doi.org/10.1016/j.ejca.2018.01.072.

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