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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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European Journal of Cancer 93 (2018) 19e27
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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: [email protected] (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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