Clearly, the results reported in this issue of the Journal ... · Biocon/Mylan MYL-1401O August...

October 25th 2005

"Clearly, the results reported in this issue of the Journal are not evolutionary…

but revolutionary."

G Hortobagyi

Trastuzumab biosimilars are currently undergoing regulatory review

EMA, European Medicines Agency; FDA, Food and Drug AdministrationEMA and FDA submission information available from company press releases (see notes page for citation details)

Company Biosimilar Submitted to EMA Submitted to FDA

Amgen ABP 980 March 2017 July 2017

Biocon/Mylan MYL-1401O August 2016 November 2016

Celltrion CT-P6 October 2016 July 2017

Samsung Bioepis SB3 August 2016*

Pfizer PF-05280014 July 2017 Submitted(date unknown)

*Positive CHMP opinion received September 15, 2017ABP 980 is an investigational product

X. Pivot et al. Clin Ther 2018

respectively. The number of subjects who experiencedAEs related to the study drug were 13 (36.1%), 16(44.4%), and 22 (61.1%) after SB3, EU trastuzumab,and US trastuzumab administration, respectively.

The most frequently reported AE related to the studydrug was infusion-related reactions (IRRs) (9 in theSB3 group, 8 in the EU trastuzumab group, and 16 inthe US trastuzumab group). All other AEs related to

0 500 1000 1500

Time (h)

0.1

1.0

10.0

100.0

1000.0

A SB3

Seru

m T

rast

uzum

ab C

once

ntra

tion

(mg/

mL)

US Trastuzumab

Seru

m T

rast

uzum

ab C

once

ntra

tion

(mg/

mL)

0.1

1.0

10.0

100.0

1000.0

0 500 1000 1500

Time (h)

C

Seru

m T

rast

uzum

ab C

once

ntra

tion

(mg/

mL)

1000.0

10.0

1.0

0.1

100.0

0 500 1000 1500

Time (h)

EU TrastuzumabB

Mean (SD)

Seru

m T

rast

uzum

ab C

once

ntra

tion

(mg/

mL)

0 500 1000 1500

Time (h)

0.1

1.0

10.0

100.0

1000.0

SB3EU Trastuzumab

US Trastuzumab

D

Figure. Serum concentration-time profiles after a single dose of 6 mg/kg in healthy male subjects of SB3 (1),trastuzumab sourced in the European Union (EU trastuzumab) (B), trastuzumab sourced in theUnited States (US trastuzumab) (C), and 3 mean serum concentration-time profiles of 3antibodies (D).

X. Pivot et al.

July 2016 1669

the study drug occurred in 3 or fewer subjects in eachgroup. There were no serious AEs related to the studydrug, death, or discontinuations attributable to AEsduring the study.

Of the subjects receiving SB3, EU trastuzumab, orUS trastuzumab, 33 experienced IRRs. Most IRRswere grade 1 (n¼ 18; 5, 4 and 9 subjects in the SB3, EUtrastuzumab, and US trastuzumab groups, respectively)

Table II. Summary statistics of pharmacokinetic parameters after a single dose of 6 mg/kg in healthy malesubjects.*

Statistic SB3 (n ¼ 36) EU Trastuzumab (n ¼ 36) US Trastuzumab (n ¼ 36)

AUC0–1, mg " h/mL 34,783 (5614) 35,890 (5761) 37,370 (5620)AUC0–last, mg " h/mL 34,321 (5349) 35,368 (5524) 36,690 (5342)Cmax, mg/mL 154 (28) 153 (25) 156 (26)Tmax, median (range), h 1.58 (1.52–95.95) 1.61 (1.53–48.07) 1.57 (1.53–24.03)t1/2, h 196 (45) 198 (42) 215 (53)CL, mL/h 13.83 (2.10) 13.52 (2.43) 12.82 (2.24)Cday21, mg/mL† 23.4 (4.6) 25.0 (5.7) 25.0 (6.4)

Cday21 ¼ concentration at day 21; EU trastuzumab ¼ trastuzumab sourced in the European Union; US trastuzumab ¼trastuzumab sourced in the United States.*Data are expressed as mean (SD) unless otherwise indicated.†Estimated by using a 2-compartment model.

Table III. Statistical comparison of primary pharmacokinetic parameters between test and referenceproducts.*

Comparison

Geometric Least Square Means

Test-Reference Ratio (90% CI)Test Reference

SB3 vs EU trastuzumabAUC0–1, mg " h/mL 34,331 35,427 0.969 (0.908–1.034)AUC0–last, mg " h/mL 33,903 34,933 0.971 (0.911–1.034)Cmax, mg/mL 152 152 1.001 (0.935–1.072)

SB3 vs US trastuzumabAUC0–1, mg " h/mL) 34,331 36,924 0.930 (0.872–0.991)AUC0–last, mg " h/mL 33,903 36,279 0.934 (0.878–0.994)Cmax, mg/mL 152 154 0.988 (0.924–1.057)

EU trastuzumab vs US trastuzumabAUC0–1, mg " h/mL 35,427 36,924 0.959 (0.900–1.023)AUC0–last, mg " h/mL 34,933 36,279 0.963 (0.905–1.025)Cmax, mg/mL 152 154 0.987 (0.926–1.051)

EU trastuzumab ¼ trastuzumab sourced in the European Union; US trastuzumab ¼ trastuzumab sourced in the UnitedStates.*Pharmacokinetic equivalence was indicated if the 90% CI for the ratio of geometric least square means of pairwisecomparison was within the predefined equivalence margin of 0.8 to 1.25.

Clinical Therapeutics

1670 Volume 38 Number 7

TRAEs were reported by 20, 21 and 19 subjects from thePF-05280014, trastuzumab-EU and trastuzumab-US treat-ment arms, respectively. A total of 19 subjects reportedgrade 2 TEAEs (eight, six and five subjects from thePF-05280014, trastuzumab-EU and trastuzumab-US treat-ment arms, respectively) and 11 subjects reported grade 2TRAEs (five, two and four subjects from the PF-05280014,trastuzumab-EU and trastuzumab-US treatment arms,respectively). There were only two subjects with grade 3laboratory abnormality AEs, both in the trastuzumab-EUarm. One of these subjects experienced treatment-relatedelevated transaminase and the other experienced unre-lated creatine kinase increase. Both events resolved

without sequelae or intervention. There were no AEs ofgrade 4 or higher grade severity.

Common TEAEs were IRR (30 subjects, 28.6%), head-ache (30 subjects, 28.6%), chills (21 subjects, 20.0%),pyrexia (15 subjects, 14.3%) and nausea (13 subjects,12.4%). The majority of all-causality TEAEs were evenly dis-tributed among the three treatment arms (Table 5). Withthe small study size and low occurrence of individual AEs,numerical imbalances were observed across the threetreatment arms. There was a higher incidence of the AEterm ‘pyrexia’ in the PF-05280014 arm (n = 10) comparedwith trastuzumab-EU (n = 3) and trastuzumab-US (n = 2).However, the severity of pyrexia in the PF-05280014 arm

PF-05280014

Time (h)

Seru

m d

rug

conc

entr

atio

n (µ

g m

l–1)

0 500 1000 1500

0.1

1.0

10.0

100.0

1000.0

0.1

1.0

10.0

100.0

1000.0

0.1

1.0

10.0

100.0

1000.0

0.1

1.0

10.0

100.0

1000.0

Trastuzumab-EUBA Trastuzumab-USC Mean (SD)D

Time (h)0 500 1000 1500

Time (h)0 500 1000 1500

Time (h)0 500 1000 1500

Figure 3Individual (A–C) and mean ± SD (D) serum concentration–time profiles of PF-05280014, trastuzumab-EU and trastuzumab-US following a single doseof 6 mg kg−1 in healthy subjects. SD, standard deviation. A, B and C: , median; , individual; D: ●, PF-02580014; ■, trastuzumab-EU; ▲,trastuzumab-US

Table 2Mean ± SD pharmacokinetic parameter estimates

PF-05280014 Trastuzumab-EU Trastuzumab-US

Subjects (n) 34 35 32Cmax (μg ml−1) 159 ± 26 174 ± 31 164 ± 31

AUC(0, )lastt (μg ml−1 h)* 35700 ± 6287 38510 ± 6569 35870 ± 6878AUC(0,∞) (μg ml−1 h) 37130 ± 6305 40330 ± 6994 37310 ± 6728

CL (ml h−1 kg−1) 0.166 ± 0.026 0.153 ± 0.025 0.166 ± 0.032Vss (ml kg−1) 56.1 ± 8.2 51.7 ± 6.9 55.7 ± 8.8

t1/2 (h) 213 ± 42 220 ± 42 212 ± 47

* AUC last( , )0 t was ≥80% of corresponding AUC(0,∞) in all PK eligible subjects. AUC last( , )0 t , area under the concentration–time curve from time 0 to last time point of measurableconcentration; AUC(0,∞), area under the concentration–time curve from time 0 extrapolated to infinite time; CL, clearance; Cmax, maximum drug concentration; SD, standarddeviation; t1/2, terminal half-life; Vss, volume of distribution at steady-state.

PF-05280014, a potential trastuzumab biosimilar

Br J Clin Pharmacol / 78:6 / 1285

TRAEs were reported by 20, 21 and 19 subjects from thePF-05280014, trastuzumab-EU and trastuzumab-US treat-ment arms, respectively. A total of 19 subjects reportedgrade 2 TEAEs (eight, six and five subjects from thePF-05280014, trastuzumab-EU and trastuzumab-US treat-ment arms, respectively) and 11 subjects reported grade 2TRAEs (five, two and four subjects from the PF-05280014,trastuzumab-EU and trastuzumab-US treatment arms,respectively). There were only two subjects with grade 3laboratory abnormality AEs, both in the trastuzumab-EUarm. One of these subjects experienced treatment-relatedelevated transaminase and the other experienced unre-lated creatine kinase increase. Both events resolved

without sequelae or intervention. There were no AEs ofgrade 4 or higher grade severity.

Common TEAEs were IRR (30 subjects, 28.6%), head-ache (30 subjects, 28.6%), chills (21 subjects, 20.0%),pyrexia (15 subjects, 14.3%) and nausea (13 subjects,12.4%). The majority of all-causality TEAEs were evenly dis-tributed among the three treatment arms (Table 5). Withthe small study size and low occurrence of individual AEs,numerical imbalances were observed across the threetreatment arms. There was a higher incidence of the AEterm ‘pyrexia’ in the PF-05280014 arm (n = 10) comparedwith trastuzumab-EU (n = 3) and trastuzumab-US (n = 2).However, the severity of pyrexia in the PF-05280014 arm

PF-05280014

Time (h)

Seru

m d

rug c

on

cen

trati

on

(µ

g m

l–1)

0 500 1000 1500

0.1

1.0

10.0

100.0

1000.0

0.1

1.0

10.0

100.0

1000.0

0.1

1.0

10.0

100.0

1000.0

0.1

1.0

10.0

100.0

1000.0

Trastuzumab-EUBA Trastuzumab-USC Mean (SD)D

Time (h)0 500 1000 1500

Time (h)0 500 1000 1500

Time (h)0 500 1000 1500

Figure 3Individual (A–C) and mean ± SD (D) serum concentration–time profiles of PF-05280014, trastuzumab-EU and trastuzumab-US following a single doseof 6 mg kg−1 in healthy subjects. SD, standard deviation. A, B and C: , median; , individual; D: ●, PF-02580014; ■, trastuzumab-EU; ▲,trastuzumab-US

Table 2Mean ± SD pharmacokinetic parameter estimates

PF-05280014 Trastuzumab-EU Trastuzumab-US

Subjects (n) 34 35 32Cmax (μg ml−1) 159 ± 26 174 ± 31 164 ± 31

AUC(0, )lastt (μg ml−1 h)* 35700 ± 6287 38510 ± 6569 35870 ± 6878AUC(0,∞) (μg ml−1 h) 37130 ± 6305 40330 ± 6994 37310 ± 6728

CL (ml h−1 kg−1) 0.166 ± 0.026 0.153 ± 0.025 0.166 ± 0.032Vss (ml kg−1) 56.1 ± 8.2 51.7 ± 6.9 55.7 ± 8.8

t1/2 (h) 213 ± 42 220 ± 42 212 ± 47

* AUC last( , )0 t was ≥80% of corresponding AUC(0,∞) in all PK eligible subjects. AUC last( , )0 t , area under the concentration–time curve from time 0 to last time point of measurableconcentration; AUC(0,∞), area under the concentration–time curve from time 0 extrapolated to infinite time; CL, clearance; Cmax, maximum drug concentration; SD, standarddeviation; t1/2, terminal half-life; Vss, volume of distribution at steady-state.

PF-05280014, a potential trastuzumab biosimilar

Br J Clin Pharmacol / 78:6 / 1285

Yin D, et al. Br J Clin Pharmacol 2014;78:1281–9;Pivot X, et al. Clin Ther 2016;38:1665–1673.e3

Phase 1 PK studies of trastuzumab biosimilars in healthy volunteers

Randomised Phase 1 PK trial comparing potential biosimilar PF-05280014 with

trastuzumab in healthy volunteers (REFLECTIONS B327-01)1

Randomised Phase 1 PK study comparing biosimilar candidate SB3 and trastuzumab in

healthy male subjects2

Challenges in the implementation of trastuzumab biosimilars: an expert panel’s recommendations

1. Choosing a valid clinical endpoint is critical and challenging for the assessment of trastuzumab biosimilars

2. What should the comparison criterion be between trastuzumab biosimilars and their reference medicinal products?

3. Are safety events of particular importance during follow-up of trastuzumab biosimilars?

Pivot, X. Aulagner, G. Blay, J. Y. Fumoleau, P. Kaliski, A. Sarkozy, F. Limat, S.. Anticancer Drugs 2015;26:1009–1016

1. Choosing a valid clinical endpoint is critical and challenging for the assessment of trastuzumab biosimilars

Patient criteria1,2

• Overall survival (OS)

Disease criteria1–3

• Objective response rate (ORR)• Disease-free survival (DFS) • Disease-free progression (PFS)• Pathological complete response (pCR)

1. Gourgou-Bourgade S, et al. Ann Oncol 2015;26:873–879; 2. Fiteni F, et al. J Visc Surg 2014;151:17–22; 3. Pivot X, et al. Cancer J 2009;15:361–365; 4. WHO. Guidelines on evaluation of monoclonal antibodies as similar biotherapeutic products (SBPs), 2016; 5. EMA. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues, 2014; 6. He K, et al. Clin Cancer Res 2016;22:5167–5170

– Clinically relevant, objective measure, able to detect differences

– Continuous endpoints may be preferred over binary endpoints

– Length of study should be sufficient to allow for adequate safety and immunogenicity assessment

Sensitive endpoints are recommended for biosimilar

clinical trials4–6

pCR and long-term survival in clinical trials of neoadjuvant treatment of early breast cancer

EFS, event-free survival; pCR, pathological complete responseCortazar P, et al. Lancet 2014;384:164–172

Relationship between pCR and EFS by breast cancer subtypeCTNeoBC pooled analysis

Articles

www.thelancet.com Published online February 14, 2014 http://dx.doi.org/10.1016/S0140-6736(13)62422-8 5

anthracycline-based and taxane-based regimens were done, with the exception of the NOAH16 and TECHNO22 trials, which were limited to patients with HER2-positive locally advanced or infl ammatory breast cancer. Patients in the NOAH16 trial were randomly assigned to preoperative chemotherapy with or without trastuzumab, and those in the TECHNO22 trial received trastuzumab and chemo therapy followed by 1 year of adjuvant trastuzumab. In the GeparQuattro trial,11,12 patients with HER2-positive tumours received trastu-zumab con comitantly with chemotherapy. Overall, 1087 (55%) of 1989 patients with HER2-positive tumours included in the pooled analysis did not receive 1 year of adjuvant trastuzumab because they were treated before adjuvant trastuzumab trials were reported. All

patients with hormone-receptor-positive tumours were supposed to receive at least 5 years of endocrine therapy. Breast cancer subtype was established by clinic-opathological criteria, such as hormone-receptor status, HER2 overexpression, and histological grade as assessed by local pathologists. The Ki-67 labelling index had not been routinely assessed in the included studies.

11 955 patients were included in our pooled responder analysis (fi gure 1). Baseline characteristics are shown in the appendix. Median age was 49 years (IQR 43–57). 7328 patients (61%) had T2 tumours, 482 (4%) had infl ammatory breast cancer (ie, T4d tumours), and 5487 (46%) had clinically involved lymph nodes. 3572 (30%) patients had hormone-receptor-negative breast cancer, and 1989 (17%) had HER2-positive

Figure 5: Association between pCR and event-free survival, by breast cancer subtypepCR=pathological complete response. HR=hazard ratio.

Number at riskpCR

No pCR

0

20

40

60

80

100

Even

t-fre

e sur

viva

l (%

)

0 1 2 3 4 5 6 7 8 9

2702491

2442226

2241978

1841616

1131017

69658

21247

684

220

21

0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9

0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9

Hormone-receptor-positive, HER2-negative

1481838

1341653

1231493

1021236

55790

33517

10198

568

215

21

Hormone-receptor-positive, HER2-negative, grade 1/2

102528

92458

83376

71290

49173

30111

938

114

05

Hormone-receptor-positive, HER2-negative, grade 3

Number at riskpCR

No pCR

0

20

40

60

80

100

Even

t-fre

e sur

viva

l (%

)

5861403

5271157

454918

371713

212436

120269

37106

433

23

11

HER2-positive

HR 0·49 (95% CI 0·33–0·71) HR 0·63 (95% CI 0·38–1·04) HR 0·27 (95% CI 0·14–0·50)

HR 0·39 (95% CI 0·31–0·50) HR 0·58 (95% CI 0·42–0·82) HR 0·25 (95% CI 0·18–0·34)

HR 0·24 (95% CI 0·18–0·33)

Number at riskpCR

No pCR

0

20

40

60

80

100

Even

t-fre

e sur

viva

l (%

)

0 1 2 3 4 5 6 7 8 9

389768

349604

310429

250317

166198

88125

2950

1113

11

Time since randomisation (years)

Triple negative

247839

224723

194617

157484

91306

50198

1779

224

11

23


HER2-positive, hormone-receptor-positive

325510

293392

250269

205200

115111

6559

1922

26


HER2-positive, hormone-receptor-negative

pCR No pCR

HannaH: Phase 3 trial to demonstrate non-inferiority of trastuzumab SC vs IV in terms of PK and efficacy

FEC, fluorouracil, epirubicin and cyclophosphamide; IV, intravenous; Q3W, once every 3 weeks; R, randomisation; SC, subcutaneousIsmael G, et al. Lancet Oncol 2012;13:869–878

1 year (18 cycles) of trastuzumab

FEC 500/75/500 mg/m2 Q3W

HER2+ EBC (N=596)

Safety, tumour response, immunogenicity pCR Safety, EFS, OS,

immunogenicity

PK

Trastuzumab IV

Surg

ery

Trastuzumab SC Q3WFixed dose of 600 mg(5 mL over 5 minutes)

Trastuzumab IV Q3W8 mg/kg loading dose;6 mg/kg maintenance dose

Docetaxel 75 mg/m2

Trastuzumab SC

Follow-up: 2 years

Primary endpoints• Non-inferiority of trastuzumab SC vs IV based on co-primary endpoints:

– PK: observed trastuzumab Ctrough pre-dose at Cycle 8 (presurgery)– Efficacy: pCR (breast only)

R1:1

n=299

n=297

Neo-adjuvant setting has become the first choicefor the assessment of new strategies

X. Pivot, DG Cox. A new era for early development in HER2-positive breast cancer Lancet Oncology 2018

“It allows for evaluation of innovative therapies an

evaluation in a homogeneous population with rare

confounding factors, and the relationship between

pathological complete response (pCR) and survival

outcomes is an early indicator of efficacy.”

2. Equivalence margins: how similar is similar enough?

• ‘Minimally Clinically Important Difference’ (MCID)

EMA. ICH Topic E 9 statistical principles for clinical trials, 1998. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002928.pdf; FDA. Guidance for industry statistical approaches to establishing bioequivalence, 2001. Available at: http://www.fda.gov/downloads/Drugs/Guidances/ucm070244.pdf. Accessed August 2017

Risk difference (RD)Confidence interval for the absolute difference in primary endpoint between biosimilar and reference product

% biosimilar – % reference product • If drugs have same efficacy, risk difference = 0

Risk ratio (RR)Confidence interval for the ratio of primary endpoint for biosimilar versus reference product

% biosimilar% reference product

• If drugs have same efficacy, risk ratio = 1

Lower bound Upper bound0

Lower bound Upper bound1

*Additional analysis of RD requested by the EMA. AE, adverse event; CR, complete response; ITT, intention-to-treat; LD, loading dose; LVEF, left ventricular ejection fraction; MD, maintenance dose; ORR, overall response rate; PR, partial response; TTP, time to progressionRugo HS, et al. JAMA 2017;317:37–47

HER2+MBC

(N=500)

MYL-1401O (LD 8 mg/kg IV, MD 6 mg/kg IV Q3W) + docetaxel or paclitaxel x

8 cycles (n=230)

Trastuzumab RP(LD 8 mg/kg IV, MD 6 mg/kg IV Q3W) + docetaxel or paclitaxel x

8 cycles (n=228)

24 weeks

Primary endpoints• ORR (CR or PR) at Week 24; ITT population• Pre-defined equivalence margins: 90% CI for RR 0.81–1.24; 95% CI for RD +/-15%*Secondary endpoints• TTP, PFS, OS at Week 48• AEs, LVEF, and immunogenicity at Weeks 24 and 48; PK

STUDY

END

MYL-1401O MD 6 mg/kg IV Q3W

until disease progression

Trastuzumab RPMD 6 mg/kg IV Q3W


Responding/ stable disease after 8 cycles

R1:1

Copyright 2016 American Medical Association. All rights reserved.

Effect of a Proposed Trastuzumab Biosimilar ComparedWith Trastuzumab onOverall Response Rate in PatientsWith ERBB2 (HER2)–PositiveMetastatic Breast CancerA Randomized Clinical TrialHope S. Rugo, MD; Abhijit Barve, MD, PhD, MBA; Cornelius F. Waller, MD; Miguel Hernandez-Bronchud, MD, PhD; Jay Herson, PhD; Jinyu Yuan, PhD;Rajiv Sharma, MBBS, MS; Mark Baczkowski, MS, RPh; Mudgal Kothekar, MD; Subramanian Loganathan, MD; AlexeyManikhas, MD; Igor Bondarenko, MD;Guzel Mukhametshina, MD; Gia Nemsadze, MD, PhD; Joseph D. Parra, MD; Maria Luisa T. Abesamis-Tiambeng, MD; Kakhaber Baramidze, MD, PhD;Charuwan Akewanlop, MD; Ihor Vynnychenko, MD; Virote Sriuranpong, MD; GopichandMamillapalli, MS, MCh; Sirshendu Ray, MS;Eduardo P. Yanez Ruiz, MD; Eduardo Pennella, MD, MBA; for the Heritage Study Investigators

IMPORTANCE Treatmentwith the anti-ERBB2 humanizedmonoclonal antibody trastuzumaband chemotherapy significantly improves outcome in patientswith ERBB2 (HER2)–positivemetastatic breast cancer; a clinically effective biosimilarmay help increase access to this therapy.

OBJECTIVE To compare the overall response rate and assess the safety of a proposedtrastuzumab biosimilar plus a taxane or trastuzumab plus a taxane in patients without priortreatment for ERBB2-positive metastatic breast cancer.

DESIGN, SETTING, AND PARTICIPANTS Multicenter, double-blind, randomized, parallel-group,phase 3 equivalence study in patients with metastatic breast cancer. FromDecember 2012 toAugust 2015, 500 patients were randomized 1:1 to receive a proposed biosimilar ortrastuzumab plus a taxane. Chemotherapy was administered for at least 24 weeks followedby antibody alone until unacceptable toxic effects or disease progression occurred.

INTERVENTIONS Proposed biosimilar (n = 230) or trastuzumab (n = 228) with a taxane.

MAIN OUTCOMES ANDMEASURES The primary outcomewasweek 24 overall response rate(ORR) defined as complete or partial response. Equivalence boundaries were 0.81 to 1.24with a 90%CI for ORR ratio (proposed biosimilar/trastuzumab) and −15% to 15%with a 95%CI for ORR difference. Secondary outcomemeasures included time to tumor progression,progression-free and overall survival at week 48, and adverse events.

RESULTS Among500women randomized, the intention-to-treat population included458women (mean [SD] age, 53.6 [11.11] years) and the safetypopulation included493women.TheORRwas69.6%(95%CI, 63.62%-75.51%) for theproposedbiosimilar vs64.0%(95%CI,57.81%-70.26%) for trastuzumab. TheORR ratio (1.09;90%CI,0.974-1.211) andORRdifference(5.53; 95%CI,−3.08 to 14.04)werewithin theequivalenceboundaries. Atweek48, therewasnostatistically significant differencewith theproposedbiosimilar vs trastuzumab for time to tumorprogression (41.3%vs43.0%;−1.7%;95%CI,−11.1% to6.9%), progression-free survival (44.3%vs44.7%;−0.4%;95%CI,−9.4%to8.7%), or overall survival (89.1%vs85.1%;4.0%;95%CI,−2.1% to 10.3%). In theproposedbiosimilar and trastuzumabgroups, 239 (98.6%)and233(94.7%)hadat least 1 adverse event, themost common includingneutropenia (57.5%vs53.3%),peripheral neuropathy (23.1%vs24.8%), anddiarrhea (20.6%vs20.7%).

CONCLUSIONS AND RELEVANCE Amongwomenwith ERBB2-positivemetastatic breast cancerreceiving taxanes, the use of a proposed trastuzumab biosimilar compared with trastuzumabresulted in an equivalent overall response rate at 24 weeks. Further study is needed to assesssafety and long-term clinical outcome.

TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT02472964; EudraCT Identifier:2011-001965-42

JAMA. doi:10.1001/jama.2016.18305Published online December 1, 2016.

Editorial

Supplemental content

Author Affiliations:Authoraffiliations are listed at the end of thisarticle.

Group Information: A complete listof the Heritage Study Investigatorsis provided in the eAppendixin Supplement 1.

Corresponding Author:Hope S.Rugo, MD, University of CaliforniaSan Francisco Helen Diller FamilyComprehensive Cancer Center, 1600Divisadero St, San Francisco, CA94127 ([email protected]).

Research

JAMA | Original Investigation

(Reprinted) E1


Downloaded From: http://jamanetwork.com/ on 12/01/2016

Mylan/Biocon (MYL-1401O) vs trastuzumab RP in HER2+ MBC: primary efficacy results

Rugo HS, et al. JAMA 2017;317:37–47

Efficacy at Week 24(ITT population)

MYL-1401O + taxane(n=230)

Trastuzumab RP + taxane(n=228)

ORR, % (95% CI) 69.6 (63.62, 75.51) 64.0 (57.81, 70.26)

Risk ratio (90% CI) 1.09 (0.974, 1.211)

Risk difference (95% CI) 5.53 (-3.08, 14.04)

1Favours trastuzumab RP Favours MYL-1401O

0.974 1.211

0.81 1.24

1.09

Primary analysis: RR (90% CI) for ORR

Pfizer (PF-05280014) vs trastuzumab RP in HER2+ MBC:Phase 3 equivalence study

*80 mg/m2 (with provision for dose reduction) D1, 8, 15 x ≥6 4-week cycles or until maximal benefit of response†Following completion of the paclitaxel administration period and beginning no earlier than Week 33 of the study, the PF-05280014 or

trastuzumab RP regimen may be changed at the discretion of the investigator to 6 mg/kg Q3W‡ Until death or 1 year from randomisation ≥6 months following last dose of study drug, whichever was longer. QW, once every weekPegram M, et al. ESMO 2017; Poster 238PD

HER2+MBC

(N=707)

PF-05280014(LD 4 mg/kg IV, MD 2 mg/kg IV QW)

for ≥33 weeks + paclitaxel*(n=352)

Trastuzumab RP(LD 4 mg/kg IV, then 2 mg/kg IV QW)

for ≥33 weeks + paclitaxel*(n=355)

Primary endpoint• ORR (CR or PR by Week 25, confirmed at Week 33); ITT population• Pre-defined equivalence margins: 95% CI for RR 0.8–1.25Secondary endpoints• DOR, PFS and OS rates at 1 year; PK; safety; immunogenicity

PF-05280014 (QW or Q3W)†


Trastuzumab RP(QW or Q3W)†


R1:1

Follow-up for survival‡

Pfizer (PF-05280014) vs trastuzumab RP in HER2+ MBC:primary efficacy results

*RR and associated 95% CI based on the Miettinen and Nurminen methodPegram M, et al. ESMO 2017; Poster 238PD

Efficacy by Week 25 (confirmed at Week 33)(ITT population)

PF-05280014(n=352)

Trastuzumab RP(n=355)

ORR (ITT), % patients (95% CI) 62.5 (57.2, 67.6) 66.5 (61.3, 71.4)Risk ratio* (95% CI) 0.940 (0.842, 1.049)

CR, % 2.8 3.7

PR, % 59.7 62.8

0.80 1.251

0.940 1.0490.842

Primary analysis: RR (95% CI) for ORR

Favours trastuzumab RP Favours PF-05280014

Biocad (BCD-022) vs trastuzumab RP in HER2+ MBC:Phase 3 non-inferiority study

*Or until progression or unbearable toxicity.PD, progressive disease; SD, stable disease

Shustova M, et al. ESMO 2016; Abstract 224 (and corresponding poster presented by Burdaeva et al.);NCT01764022. Available at: https://clinicaltrials.gov/ct2/show/NCT01764022?term=BCD-022&rank=1. Accessed August 2017

Primary endpoints• ORR at Day 127; pre-defined non-inferiority margin for RD of -20% (lower 95% CI)• AUC after the first test drug administration (PK substudy)Secondary endpoint• Rates of CR, PR, SD and PD

BCD-022(LD 8 mg/kg, MD 6 mg/kg) + paclitaxel (175 mg/m2)

Q3W x 6 cycles*(n=63)

Trastuzumab RP(LD 8 mg/kg, MD 6 mg/kg) + paclitaxel (175 mg/m2)

Q3W x 6 cycles*(n=61)

HER2+ MBC(N=126)

R1:1

STUDY

END

Biocad (BCD-022) vs trastuzumab RP in HER2+ MBC:primary efficacy results

*Yates-corrected Pearson’s testShustova M, et al. ESMO 2016; Abstract 224 (and corresponding poster presented by Burdaeva et al.);NCT01764022. Available at: https://clinicaltrials.gov/ct2/show/NCT01764022?term=BCD-022&rank=1. Accessed August 2017

0-20

Primary analysis: RD (lower 95% CI) for ORR

-0.13-19.83 18.35

Efficacy (Day 127)BCD-022

+ paclitaxel(n=54)

Trastuzumab RP+ paclitaxel

(n=56)P*

ORR, % patients (95% CI) 53.6 (40.7, 66.0) 53.7 (40.6, 66.3) 0.862

Difference in ORR, % (95% CI) -0.13 (-19.83, 18.35)

Favours trastuzumab RP Favours BCD-022

HER2+ EBC(N=549)

*Initial dose of 8 mg/kg IV, then 6 mg/kg for remaining cycles.**pCRinbreastandaxillarylymphnodes.†Fromthedateoflastpatientenrolment. DCIS,ductalcarcinoma insitu

StebbingJ,etal.LancetOncol2017;18:917–928;EstevaFJ,etal.ESMO2017;Poster152PD

Neoadjuvant AdjuvantCT-P6 Q3W*Trastuzumab RP Q3W*Docetaxel 75 mg/m2 Q3WFEC 500/75/500 mg/m2 Q3W

R1:1 Su

rger

y

tpCR

Primaryendpoint• tpCR**afterneoadjuvant therapyandsurgery(upto30weeks);per-protocolpopulation• Pre-definedequivalencemargins:95%CIforRR0.74–1.35;95%CIforRD+/-15%Secondaryendpoints

• Efficacy:pCR(breastonly), tpCR(withoutDCIS),ORR,breastconservation rate,DFS,PFS,OS• Other:PK,PD,biomarkersandsafety

24weeks Uptototalof1year(additional10cycles)

Upto3years†

n=271

n=278

Follo

w-u

p

www.thelancet.com/oncology Vol 18 July 2017 917

Articles

CT-P6 compared with reference trastuzumab for HER2-positive breast cancer: a randomised, double-blind, active-controlled, phase 3 equivalence trialJustin Stebbing, Yauheni Baranau, Valeriy Baryash, Alexey Manikhas, Vladimir Moiseyenko, Giorgi Dzagnidze, Edvard Zhavrid, Dmytro Boliukh, Daniil Stroyakovskii, Joanna Pikiel, Alexandru Eniu, Dmitry Komov, Gabriela Morar-Bolba, Rubi K Li, Andriy Rusyn, Sang Joon Lee, Sung Young Lee, Francisco J Esteva

SummaryBackground CT-P6 is a proposed biosimilar to reference trastuzumab. In this study, we aimed to establish equivalence of CT-P6 to reference trastuzumab in neoadjuvant treatment of HER2-positive early-stage breast cancer.

Methods In this randomised, double-blind, active-controlled, phase 3 equivalence trial, we recruited women aged 18 years or older with stage I–IIIa operable HER2-positive breast cancer from 112 centres in 23 countries. Inclusion criteria were an Eastern Cooperative Oncology Group performance status score of 0 or 1; a normal left ventricular ejection fraction of at least 55%; adequate bone marrow, hepatic, and renal function; at least one measureable lesion; and known oestrogen and progesterone receptor status. Exclusion criteria included bilateral breast cancer, previous breast cancer treatment, previous anthracycline treatment, and pregnancy or lactation. We randomly allocated patients 1:1 to receive neoadjuvant CT-P6 or reference trastuzumab intravenously (eight cycles, each lasting 3 weeks, for 24 weeks; 8 mg/kg on day 1 of cycle 1 and 6 mg/kg on day 1 of cycles 2–8) in conjunction with neoadjuvant docetaxel (75 mg/m² on day 1 of cycles 1–4) and FEC (fluorouracil [500 mg/m²], epirubicin [75 mg/m²], and cyclophosphamide [500 mg/m²]; day 1 of cycles 5–8) therapy. We stratified randomisation by clinical stage, receptor status, and country and used permuted blocks. We did surgery within 3–6 weeks of the final neoadjuvant study drug dose, followed by an adjuvant treatment period of up to 1 year. We monitored long-term safety and efficacy for 3 years after the last patient was enrolled. Participants and investigators were masked to treatment until study completion. The primary efficacy endpoint, analysed in the per-protocol population, was pathological complete response, assessed via specimens obtained during surgery, analysed by masked central review of local histopathology reports. The equivalence margin was –0·15 to 0·15. This trial is registered with ClinicalTrials.gov, number NCT02162667, and is ongoing, but no longer recruiting.

Findings Between Aug 7, 2014, and May 6, 2016, we randomly allocated 549 patients (271 [49%] to CT-P6 vs 278 [51%] to reference trastuzumab). A similar proportion of patients achieved pathological complete response with CT-P6 (116 [46·8%; 95% CI 40·4–53·2] of 248 patients) and reference trastuzumab (129 [50·4%; 44·1–56·7] of 256 patients). The 95% CI of the estimated treatment outcome difference (–0·04% [95% CI –0·12 to 0·05]) was within the equivalence margin. 19 (7%) of 271 patients in the CT-P6 group reported serious treatment-emergent adverse events versus 22 (8%) of 278 in the reference trastuzumab group; frequent (occurring in more than one patient) serious adverse events were febrile neutropenia (four [1%] vs one [<1%]) and neutropenia (one [<1%] vs two [1%]). Grade 3 or worse treatment-related adverse events occurred in 17 (6%) of 271 patients in the CT-P6 group versus 23 (8%) of 278 in the reference trastuzumab group; the most frequently reported adverse event was neutropenia in ten (4%) versus 14 (5%).

Interpretation CT-P6 showed equivalent efficacy to reference trastuzumab and adverse events were similar. Availability of trastuzumab biosimilars could increase access to this targeted therapy for HER2-positive early-stage cancer.

Funding Celltrion Inc.

IntroductionApproximately 25% of invasive breast cancers amplify the HER2 oncogene, resulting in constitutive activation of the type I transmembrane HER2 protein.1–3 Development of trastuzumab, a humanised monoclonal antibody that binds to the extracellular domain of HER2, was a major advance in treatment of HER2-overexpressing (HER2-positive) cancers. The first clinical trial4,5 of trastuzumab in the neoadjuvant setting was discontinued

prematurely when addition of the antibody to chemo-therapy doubled the proportion of patients achieving a pathological complete response (pCR) com pared with chemotherapy alone in patients with HER2-positive, early-stage, operable breast cancer. Sub sequent studies6,7 have substantiated the efficacy of trastuzumab with respect to increasing pCR and shown that pCR is associated with favourable long-term survival outcomes.8 European (European Society for Medical Oncology)9 and

Lancet Oncol 2017; 18: 917–28

Published Online June 4, 2017 http://dx.doi.org/10.1016/ S1470-2045(17)30434-5

Imperial College Healthcare NHS Trust, Charing Cross Hospital, London, UK, and Division of Cancer, Imperial Centre for Translational and Experimental Medicine, London, UK (Prof J Stebbing MD); Chemotherapy Department #1, Minsk City Clinical Oncological Dispensary, Minsk, Belarus (Y Baranau MD); Department of Oncology, Belarusian State Medical University, Minsk, Belarus (V Baryash MD); Breast Cancer Department, City Clinical Oncology Dispensary, Saint Petersburg, Russia (A Manikhas MD); St Petersburg Clinical Scientific and Practical Centre of Specialized Kinds of Medical Care (Oncologic), Saint Petersburg, Russia (Prof V Moiseyenko MD); Breast Unit, Khechinashvili University Hospital, Tbilisi, Georgia (G Dzagnidze MD); Chemotherapy Department, NN Alexandrov Republican Scientific and Practical Centre of Oncology and Medical Radiology, Minsk, Belarus (Prof E Zhavrid MD); Surgical Department, Vinnytsya Regional Clinical Oncologic Dispensary, Vinnytsya, Ukraine (D Boliukh MD); Moscow City Oncology Hospital #62 of Moscow Healthcare Department, Moscow Oblast, Russia (D Stroyakovskii MD); Copernicus Wojewódzkie Centrum Onkologii Gdańsk, Gdańsk, Poland (J Pikiel MD); Department of Breast Tumors, Cancer Institute Ion Chiricuta, Cluj-Napoca, Romania (A Eniu MD, G Morar-Bolba MD); Russian Cancer Research Center, Moscow, Russia (D Komov MD); St Luke’s Medical Center, Quezon City,

www.thelancet.com/oncology Vol 18 July 2017 917

Articles

CT-P6 compared with reference trastuzumab for HER2-positive breast cancer: a randomised, double-blind, active-controlled, phase 3 equivalence trialJustin Stebbing, Yauheni Baranau, Valeriy Baryash, Alexey Manikhas, Vladimir Moiseyenko, Giorgi Dzagnidze, Edvard Zhavrid, Dmytro Boliukh, Daniil Stroyakovskii, Joanna Pikiel, Alexandru Eniu, Dmitry Komov, Gabriela Morar-Bolba, Rubi K Li, Andriy Rusyn, Sang Joon Lee, Sung Young Lee, Francisco J Esteva

SummaryBackground CT-P6 is a proposed biosimilar to reference trastuzumab. In this study, we aimed to establish equivalence of CT-P6 to reference trastuzumab in neoadjuvant treatment of HER2-positive early-stage breast cancer.

Methods In this randomised, double-blind, active-controlled, phase 3 equivalence trial, we recruited women aged 18 years or older with stage I–IIIa operable HER2-positive breast cancer from 112 centres in 23 countries. Inclusion criteria were an Eastern Cooperative Oncology Group performance status score of 0 or 1; a normal left ventricular ejection fraction of at least 55%; adequate bone marrow, hepatic, and renal function; at least one measureable lesion; and known oestrogen and progesterone receptor status. Exclusion criteria included bilateral breast cancer, previous breast cancer treatment, previous anthracycline treatment, and pregnancy or lactation. We randomly allocated patients 1:1 to receive neoadjuvant CT-P6 or reference trastuzumab intravenously (eight cycles, each lasting 3 weeks, for 24 weeks; 8 mg/kg on day 1 of cycle 1 and 6 mg/kg on day 1 of cycles 2–8) in conjunction with neoadjuvant docetaxel (75 mg/m² on day 1 of cycles 1–4) and FEC (fluorouracil [500 mg/m²], epirubicin [75 mg/m²], and cyclophosphamide [500 mg/m²]; day 1 of cycles 5–8) therapy. We stratified randomisation by clinical stage, receptor status, and country and used permuted blocks. We did surgery within 3–6 weeks of the final neoadjuvant study drug dose, followed by an adjuvant treatment period of up to 1 year. We monitored long-term safety and efficacy for 3 years after the last patient was enrolled. Participants and investigators were masked to treatment until study completion. The primary efficacy endpoint, analysed in the per-protocol population, was pathological complete response, assessed via specimens obtained during surgery, analysed by masked central review of local histopathology reports. The equivalence margin was –0·15 to 0·15. This trial is registered with ClinicalTrials.gov, number NCT02162667, and is ongoing, but no longer recruiting.

Findings Between Aug 7, 2014, and May 6, 2016, we randomly allocated 549 patients (271 [49%] to CT-P6 vs 278 [51%] to reference trastuzumab). A similar proportion of patients achieved pathological complete response with CT-P6 (116 [46·8%; 95% CI 40·4–53·2] of 248 patients) and reference trastuzumab (129 [50·4%; 44·1–56·7] of 256 patients). The 95% CI of the estimated treatment outcome difference (–0·04% [95% CI –0·12 to 0·05]) was within the equivalence margin. 19 (7%) of 271 patients in the CT-P6 group reported serious treatment-emergent adverse events versus 22 (8%) of 278 in the reference trastuzumab group; frequent (occurring in more than one patient) serious adverse events were febrile neutropenia (four [1%] vs one [<1%]) and neutropenia (one [<1%] vs two [1%]). Grade 3 or worse treatment-related adverse events occurred in 17 (6%) of 271 patients in the CT-P6 group versus 23 (8%) of 278 in the reference trastuzumab group; the most frequently reported adverse event was neutropenia in ten (4%) versus 14 (5%).

Interpretation CT-P6 showed equivalent efficacy to reference trastuzumab and adverse events were similar. Availability of trastuzumab biosimilars could increase access to this targeted therapy for HER2-positive early-stage cancer.

Funding Celltrion Inc.

IntroductionApproximately 25% of invasive breast cancers amplify the HER2 oncogene, resulting in constitutive activation of the type I transmembrane HER2 protein.1–3 Development of trastuzumab, a humanised monoclonal antibody that binds to the extracellular domain of HER2, was a major advance in treatment of HER2-overexpressing (HER2-positive) cancers. The first clinical trial4,5 of trastuzumab in the neoadjuvant setting was discontinued

prematurely when addition of the antibody to chemo-therapy doubled the proportion of patients achieving a pathological complete response (pCR) com pared with chemotherapy alone in patients with HER2-positive, early-stage, operable breast cancer. Sub sequent studies6,7 have substantiated the efficacy of trastuzumab with respect to increasing pCR and shown that pCR is associated with favourable long-term survival outcomes.8 European (European Society for Medical Oncology)9 and

Lancet Oncol 2017; 18: 917–28

Published Online June 4, 2017 http://dx.doi.org/10.1016/ S1470-2045(17)30434-5

Imperial College Healthcare NHS Trust, Charing Cross Hospital, London, UK, and Division of Cancer, Imperial Centre for Translational and Experimental Medicine, London, UK (Prof J Stebbing MD); Chemotherapy Department #1, Minsk City Clinical Oncological Dispensary, Minsk, Belarus (Y Baranau MD); Department of Oncology, Belarusian State Medical University, Minsk, Belarus (V Baryash MD); Breast Cancer Department, City Clinical Oncology Dispensary, Saint Petersburg, Russia (A Manikhas MD); St Petersburg Clinical Scientific and Practical Centre of Specialized Kinds of Medical Care (Oncologic), Saint Petersburg, Russia (Prof V Moiseyenko MD); Breast Unit, Khechinashvili University Hospital, Tbilisi, Georgia (G Dzagnidze MD); Chemotherapy Department, NN Alexandrov Republican Scientific and Practical Centre of Oncology and Medical Radiology, Minsk, Belarus (Prof E Zhavrid MD); Surgical Department, Vinnytsya Regional Clinical Oncologic Dispensary, Vinnytsya, Ukraine (D Boliukh MD); Moscow City Oncology Hospital #62 of Moscow Healthcare Department, Moscow Oblast, Russia (D Stroyakovskii MD); Copernicus Wojewódzkie Centrum Onkologii Gdańsk, Gdańsk, Poland (J Pikiel MD); Department of Breast Tumors, Cancer Institute Ion Chiricuta, Cluj-Napoca, Romania (A Eniu MD, G Morar-Bolba MD); Russian Cancer Research Center, Moscow, Russia (D Komov MD); St Luke’s Medical Center, Quezon City,

Celltrion (CT-P6) vs trastuzumab RP in HER2+ EBC:primary efficacy results

*After neoadjuvant therapy and surgery (up to 30 weeks)Stebbing J, et al. Lancet Oncol 2017;18:917–928

Efficacy up to 30 weeks(Per-protocol population)

CT-P6(n=248)


tpCR rate,* % (95% CI) 46.8 (40.4, 53.2) 50.4 (44.1, 56.7)

Risk difference (95% CI) -4 (-12, 5)

Risk ratio (95% CI) 0.93 (0.78, 1.11)

Co-primary analysis: RD (95% CI) for tpCR

-4 -12 5 0.93 0.78 1.11

Co-primary analysis: RR (95% CI) for tpCR

-15 +15 0.74Favourstrastuzumab RP

1.35Favours CT-P6

Favourstrastuzumab RP

Favours CT-P6

0 1

Amgen (ABP 980) vs trastuzumab RP in HER2+ EBC:Phase 3 equivalence study (LILAC)

von Minckwitz G, et al. ESMO 2017; Poster 151PD; Kolberg H-C, et al. SABCS 2017; Poster PD3-10; von Minckwitz, G et al. SABCS 2017; Poster P5-20-13

RANDOMISATION

END

OF

STUDY

SURGERY

SURGERY

ABP 980Q3W for up to 1 year‡

(n=349)

ABP 980Q3W for up to 1 year‡

(n=171)

Trastuzumab RP Q3W for up to 1 year‡

(n=171)

ABP 980 Q3W for 4 cycles†

+ paclitaxel (n=364)

Trastuzumab RPQ3W for 4 cycles†

+ paclitaxel (n=361)

Epirubicin + cyclophosphamide

Q3W for 4 cycles

End of study

Neoadjuvant phase Surgery Adjuvant phase

tpCR assessment;

primary analysis

Study population• HER2+ invasive

breast cancer• Histologically confirmed,

measurable disease (≥2.0 cm)

• No prior treatment• Planning for surgical resection of

breast tumour and sentinel node or axillary lymph node resection

• Planning neoadjuvant chemotherapy

• No distant metastases

Single switch

SCREENING

ENROLLMENT

†Initial dose of 8 mg/kg IV then 6 mg/kg for remaining cycles; ‡Total of up to 1 year from the first day of ABP 980/trastuzumab RP administered in the neoadjuvant phase

tpCR, total pathological complete response absence of invasive tumour cellsin the breast tissue and axillary lymph node[s] regardless of residual ductal carcinoma in situ).

ABP 980 is an investigational product

Amgen (ABP 980) vs trastuzumab RP in HER2+ EBC:primary efficacy results

*pCR in breast and axillary lymph nodes.ABP 980 is an investigational productvon Minckwitz G, et al. ESMO 2017; Poster 151PD

Efficacy Co-primary analysis (local pathology assessment)

Sensitivity analysis(central pathology assessment)

tpCR* evaluable population ABP 980(n=358)


ABP 980(n=339)


tpCR rate, % 48.0 40.5 47.8 41.8Risk ratio (90% CI) 1.19 (1.03, 1.37) 1.14 (0.99, 1.31)Risk difference (90% CI) 7.3 (1.2, 13.4) 5.8 (-0.5, 12.0)


7.3 1.2 13.4 5.8-0.5 12.0

Sensitivity analysis: RD (90% CI) for tpCR

-13 +13 -13Favourstrastuzumab RP

13Favours ABP 980


Favours ABP 980

0 0

LABC, locally-advancedbreastcancerPivotX,etal.JCO2018

HER2+ EBC/LABC

(N=875)

Neoadjuvant AdjuvantSB3 Q3WTrastuzumab RP Q3WDocetaxel 75 mg/m2 Q3WFEC 500/75/500 mg/m2 Q3W

R1:1

Surg

ery

pCR

n=437

n=438

Primaryendpoint• pCR(breastonly)afterneoadjuvanttherapyandsurgery;per-protocolpopulation• Pre-definedequivalencemargins:90%CIforRR0.785–1.546;95%CIforRD+/-13%Secondaryendpoints

• Efficacy:tpCR,ORR,EFS• Other:PK, immunogenicityandsafety

24weeks Uptototalof1year(additional10cycles)

JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T

Phase III, Randomized, Double-Blind Study Comparing theEfficacy, Safety, and Immunogenicity of SB3 (TrastuzumabBiosimilar) and Reference Trastuzumab in Patients TreatedWith Neoadjuvant Therapy for Human Epidermal GrowthFactor Receptor 2–Positive Early Breast Cancer Q:1; 2; 3

Xavier Pivot, Igor Bondarenko, Zbigniew Nowecki, Mikhail Dvorkin, Ekaterina Trishkina, Jin-Hee Ahn, YuriyVinnyk, Seock-Ah Im, Tomasz Sarosiek, Sanjoy Chatterjee, Marek Z. Wojtukiewicz, Vladimir Moiseyenko,Yaroslav Shparyk, Maximino Bello III, Vladimir Semiglazov, Sujeong Song, and Jaeyun Lim

A B S T R A C T

PurposeThis Q:4phase III study compared SB3, a trastuzumab (TRZ) biosimilar, with reference TRZ in patientswith human epidermal growth factor receptor 2–positive early breast cancer in the neoadjuvantsetting (ClinicalTrials.gov identifier: NCT02149524).

Patients and MethodsPatients were randomly assigned to receive neoadjuvant SB3 or TRZ for eight cycles concurrently withchemotherapy (four cycles of docetaxel followed by four cycles of fluorouracil, epirubicin, and cyclo-phosphamide) followed by surgery, and then 10 cycles of adjuvant SB3 or TRZ. The primary objectivewas comparison of breast pathologic complete response (bpCR) rate in the per-protocol set; equivalencewas declared if the 95% CI of the ratio was within 0.785 to 1.546 or the 95% CI of the difference waswithin6 13%. Secondary end points included comparisons of total pathologic complete response rate,overall response rate, event-free survival, overall survival, safety, pharmacokinetics, and immunogenicity.

ResultsEight hundred patients were included in the per-protocol set (SB3, n = 402; TRZ, n = 398). The bpCRrates were 51.7% and 42.0% with SB3 and TRZ, respectively. The adjusted ratio of bpCR was 1.259(95%CI, 1.085 to 1.460),whichwaswithin the predefined equivalencemargins. The adjusted differencewas 10.70% (95% CI, 4.13% to 17.26%), with the lower limit contained within and the upper limitoutside the equivalence margin. The total pathologic complete response rates were 45.8% and 35.8%and the overall response rates were 96.3% and 91.2%with SB3 and TRZ, respectively. Overall, 96.6%and 95.2%of patients experienced one ormore adverse event, 10.5%and 10.7%had a serious adverseevent, and 0.7% and 0.0% had antidrug antibodies (up to cycle 9) with SB3 and TRZ, respectively.

ConclusionEquivalence for efficacy was demonstrated between SB3 and TRZ on the basis of the ratio of bpCRrates. Safety and immunogenicity were comparable.

J Clin Oncol 35. © 2017 by American Society of Clinical Oncology

INTRODUCTION

The introduction of trastuzumab (TRZ; Herceptin;Genentech, South San Francisco, CA) into thetherapeutic armamentarium for human epidermalgrowth factor receptor 2 (HER2)–positive breastcancer has dramatically changed the natural his-tory of this disease.1-8 However, biotherapies areexpensive and not readily available in somecountries. As a result, economical biosimilars may

increase patient access to critical therapies in someareas and save costs, thereby facilitating theavailability of resources for innovative biotherapiesin other countries.9

SB3 (Samsung Bioepis, Incheon, Republic ofKorea), a proposed TRZ biosimilar, has been ex-tensively characterized and compared with refer-ence TRZ.10 These investigations demonstratedthat SB3 and TRZhave highly similar structural andphysicochemical characteristics, similarly inhibitingHER2-expressing human tumor cell proliferation

Author affiliations and support information(if applicable) appear at the end of thisarticle.

Published at jco.org on XXXX, 2017.

Clinical trial information: NCT02149524,2013-004172-35.

Corresponding author: Xavier Pivot, MD,PhD, Centre Hospitalier Universitaire JeanMinjoz, 1 Boulevard Fleming, 25030Besançon Cedex 03, France; e-mail:[email protected].

© 2017 by American Society of ClinicalOncology

0732-183X/17/3599-1/$20.00

ASSOCIATED CONTENT

AppendixDOI: https://doi.org/10.1200/JCO.2017.74.0126

Data SupplementDOI: https://doi.org/10.1200/JCO.2017.74.0126

DOI: https://doi.org/10.1200/JCO.2017.74.0126

© 2017 by American Society of Clinical Oncology 1

SB3 (Trastuzumab Biosimilar) Versus Reference Trastuzumab

DOI: 10.1200/JCO.2017.74.0126

Samsung Bioepis (SB3) vs trastuzumab RP in HER2+ EBC: primary efficacy analysis

Pivot X, et al. JCO 2018



Efficacy (Per-protocol population) SB3(n=402)


Breast pCR rate, % patients 51.7 42.0

Risk difference (95% CI) 10.70 (4.13, 17.26)

Risk ratio (90% CI) 1.259 (1.112, 1.426)

Co-primary analysis: RD (95% CI) for breast pCR Co-primary analysis: RR (90% CI) for breast pCR

Favours SB3

Favours SB3

10.70

130-13

4.13 17.26 1.259

1.54610.785

1.112 1.426

Although equivalence of efficacy was demonstrated based on the RR of breast pCR rates, the upper limit of the 95% CI for the RD was outside the pre-defined equivalence margin

• Downward drift in %afucose (G0±G1±G2) observed (EU + US reference product)

Kim S, et al. mAbs 2017 [epub ahead of print]

02015 2016

2

2017 2018 2019 2020

468

1012

Expiry date

Rel

ativ

e ar

ea (%

)% afucose (G0 + G1 + G2)

1st drift 2nd driftEU HerceptinUS Herceptin

0~ July 2018

2

1st drift 2nd drift

4

6

8

10

12

Rel

ativ

e ar

ea (%

) * *

*p≤0.05

REPORT

Drifts in ADCC-related quality attributes of Herceptin!: Impact on developmentof a trastuzumab biosimilar

Seokkyun Kim*, Jinsu Song*, Seungkyu Park, Sunyoung Ham, Kyungyeol Paek, Minjung Kang, Yunjung Chae,Heewon Seo, Hyung-Chan Kim, and Michael Flores

Quality Evaluation Team, Samsung Bioepis, Incheon, South Korea

ARTICLE HISTORYReceived 16 December 2016Revised 6 March 2017Accepted 7 March 2017

ABSTRACTA biosimilar product needs to demonstrate biosimilarity to the originator reference product, and thequality profile of the latter should be monitored throughout the period of the biosimilar’s development tomatch the quality attributes of the 2 products that relate to efficacy and safety. For the development of abiosimilar version of trastuzumab, the reference product, Herceptin! , was extensively characterized forthe main physicochemical and biologic properties by standard or state-of-the-art analytical methods,using multiple lots expiring between March 2015 and December 2019. For lots with expiry dates up to July2018, a high degree of consistency was observed for all the tested properties. However, among the lotsexpiring in August 2018 or later, a downward drift was observed in %afucose (G0CG1CG2). Furthermore,the upward drift of %high mannose (M5CM6) was observed in the lots with expiry dates from June 2019to December 2019. As a result, the combination of %afucose and %high mannose showed 2 marked driftsin the lots with expiry dates from August 2018 to December 2019, which was supported by the similartrend of biologic data, such as FcgRIIIa binding and antibody-dependent cell-mediated cytotoxicity(ADCC) activity. Considering that ADCC is one of the clinically relevant mechanisms of action fortrastuzumab, the levels of %afucose and %high mannose should be tightly monitored as critical qualityattributes for biosimilar development of trastuzumab.

Abbreviations: 2-AB, 2-aminobenzamide; ADCC, antibody-dependent cell-mediated cytotoxicity; BSA, bovine serumalbumin; CDC, complement-dependent cytotoxicity; CE-SDS, capillary electrophoresis-sodium dodecyl sulfate;DMEM/F12, Dulbecco’s Modified Eagle Medium: Nutrient Mixture F-12; EMA, European Medicines Agency; EU, Euro-pean Union; FBS, fetal bovine serum; GSH, glutathione; GST, glutathione-S-transferase; HMW, high molecularweight; HPLC, high-performance liquid chromatography; icIEF, imaged capillary isoelectric focusing; HRP, horserad-ish peroxidase; LC-MS, liquid chromatography-mass spectrometry; Max, maximum; Min, minimum; PLA, parallel lineanalysis; SEC, size exclusion chromatography; US, United States

KEYWORDSADCC; biosimilar; FcgRIIIa;Herceptin! ; N-glycan;trastuzumab; quality drift

Introduction

A biosimilar is a medicinal product that is highly similar toan authorized, original biologic drug (called the referenceproduct in this context) in terms of structural and func-tional properties and the clinical outcome. Similarity instructural and functional properties is expected to translateinto no clinical meaningful difference. To demonstrate thesimilarity to reference product, the cornerstone of biosimilardevelopment is the extensive analytical characterization ofboth biosimilar product and reference product. The guide-lines regarding biosimilar development recommend a step-wise approach, starting with extensive physicochemical andbiologic characterization against reference products beforeinitiating clinical studies.1–4 Characterization studies againstreference products lay the groundwork for identifying andfocusing efficacy, safety, pharmacokinetic, and immunoge-nicity comparisons in clinical studies. Therefore, extensive

physicochemical and biologic characterization of referenceproducts and establishment of a quality target profile arecritical steps in the biosimilar development.

Considering inherent properties of biologic therapeutics,biologics are highly sensitive to changes in manufacturingconditions and therefore robust quality management sys-tems ensure process and product consistency.1 Because ofthe high structural complexity compared with small mole-cules, even minor alterations (e.g., pH, temperature andmanufacturing site) may reduce product consistency andcause drifts in target attributes.5 For example, Schiestl et al.analyzed multiple batches of Aranesp!, Rituxan/Mabthera!

and Enbrel! to study the variability in the glycan profiles.6

Different lots of Aranesp! showed different charges result-ing from varying numbers of sialic acids per molecule.Different lots of Rituxan/Mabthera! and Enbrel! showedchanges of the N- and C-terminal heterogeneity, and the

CONTACT Seokkyun Kim [email protected] Samsung Bioepis Co., Ltd., 107, Cheomdan-daero, Yeonsu-gu, Incheon 21987, Republic of Korea.*Co-first authors and contributed equally to this work.

Supplemental data for this article can be accessed on the publisher’s website.Published with license by Taylor & Francis Group, LLC © 2017 Samsung BioepisThis is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/),which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.

MABS2017, VOL. 9, NO. 4, 704–714http://dx.doi.org/10.1080/19420862.2017.1305530

Impact of drifts on anti-proliferative potency and HER2 binding activity

Kim S, et al. mAbs 2017

02015 2016

25

2017 2018 2019 2020

5075

100125

150

Expiry date

Rel

ativ

e po

tenc

y (%

) Relative anti-proliferation potency

1st drift2nd drift

0~ July 2018

20

1st drift 2nd drift

406080

100120

Rel

ativ

e po

tenc

y (%

) 140

02015 2016

25

2017 2018 2019 2020

5075

100125

150

Expiry date

Rel

ativ

e ac

tivity

(%)

Relative HER2 binding activity

1st drift2nd drift

0~ July 2018

20

1st drift 2nd drift

406080

100120

Rel

ativ

e ac

tivity

(%) 140

EU HerceptinUS Herceptin


Impact of drifts on ADCC and FcγRIIIa binding

Kim S, et al. mAbs 2017

Levels of %afucose and %high mannose should be tightly monitored as critical quality attributes for biosimilar development of trastuzumab

02015 2016

25

2017 2018 2019 2020

5075

100125

150

Expiry date

Rel

ativ

e ac

tivity

(%)

Relative ADCC activity

1st drift2nd drift

0~ July 2018

20

1st drift 2nd drift

406080

100120

Rel

ativ

e ac

tivity

(%) 140

02015 2016

25

2017 2018 2019 2020

5075

100125

150

Expiry date

Rel

ativ

e ac

tivity

(%)

Relative FcγRIIIa binding activity

1st drift2nd drift

0~ July 2018

20

1st drift 2nd drift

406080

100120

Rel

ativ

e ac

tivity

(%) 140



**

***p≤0.05

Summary: results of equivalence analyses of biosimilar vs trastuzumab in studies of HER2+ EBC

NOTE: results cannot be directly compared due to differences in study design. *In per-protocol population. †In tpCR evaluable population. ABP 980 is an investigational product

1. Stebbing J, et al. Lancet Oncol 2017;18:917–928; 2. von Mickwitz G, et al. ESMO 2017; Poster 151PD; 3. Pivot X, et al. JCO 2018


Co-primary analysis: RD (95% CI) for tpCR-4 -12 5 0.930.78 1.11


-15 +15 0.74 1.350 1

Celltrion (CT-P6)1

(N=504)*

Co-primary analysis: RD (95% CI) for bpCR Co-primary analysis: RR (90% CI) for bpCR

10.7

130-13

4.13 17.26 1.259

1.54610.785

1.112 1.426Samsung Bioepis (SB3)3

(N=800)*

1.191.03

0.76 1 1.32

1.37

–13 0

7.3 1.2 13.4

13


Amgen (ABP 980)2

(N=696)†

Favours trastuzumab RP Favours biosimilar Favours biosimilarFavours trastuzumab RP

3. Are safety events of particular importance during follow-up of trastuzumab biosimilars?

• Adverse events • Serious adverse events• Adverse events of special interest• Anti-drug antibodies• Safety following a switch from reference product


variation of response to attribute variation to random effect,controlling for everything else in themodel. In addition, typeIII test results showed that all fixed effects in themodel werenot significant, with P > .11.

Population Pharmacokinetic AnalysisIn the pharmacokinetic population, the mean concentrationsof trastuzumab from the 2 treatments were similar (eFigurein Supplement 1). Trough (minimum) drug concentrationswere comparable between the treatment groups at cycle 6(week 15). In the proposed biosimilar and trastuzumabgroups, geometric least squares means were 34.011 and32.740 μg/mL, respectively, with a ratio of 103.88% (90% CI,

93.7%-115.11%). Dose-normalized mean maximum drug con-centrations were 0.4321 and 0.4196 μg/mL/mg, respectively,while dose-normalized mean areas under the curve were98.350 and 94.391 μg · d/mL/mg, respectively, with a coeffi-cient of variation ranging from 21.87% to 31.06%; both ofthese parameters were comparable.

Safety EvaluationExtent of ExposureThe extent of exposure was similar between the 2 treatmentgroups in terms of dose and duration of exposure. The mean(SD) loading dose was 8.0 (0) mg/kg in both treatment groupswith similar subsequent dose intensity (2.011 mg/kg/wk for

Table 4. Treatment-Emergent Adverse Events and Serious Adverse Events byWeek 24 in the Overall SafetyPopulation

Event

Participants, No. (%)ProposedBiosimilar + Taxane(n = 247)

Trastuzumab + Taxane(n = 246)

Overall(n = 493)

Treatment-Emergent Adverse Eventsa

≥1 Treatment-emergent adverse event 239 (96.8) 233 (94.7) 472 (95.7)

CTCAE preferred term

Alopecia 142 (57.5) 135 (54.9) 277 (56.2)

Neutropenia 142 (57.5) 131 (53.3) 273 (55.4)

Peripheral neuropathy 57 (23.1) 61 (24.8) 56 (23.9)

Diarrhea 51 (20.6) 51 (20.7) 102 (20.7)

Asthenia 54 (21.9) 40 (16.3) 94 (19.1)

Leukopenia 42 (17.0) 51 (20.7) 93 (18.9)

Nausea 49 (19.8) 34 (13.8) 83 (16.8)

Anemia 40 (16.2) 40 (16.3) 80 (16.2)

Peripheral edema 35 (14.2) 28 (11.4) 63 (12.8)

Fatigue 28 (11.3) 33 (13.4) 61 (12.4)

Pyrexia 21 (8.5) 30 (12.2) 51 (10.3)

Myalgia 23 (9.3) 23 (9.3) 46 (9.3)

Vomiting 26 (10.5) 19 (7.7) 45 (9.1)

Decreased appetite 21 (8.5) 24 (9.8) 45 (9.1)

Rash 21 (8.5) 23 (9.3) 44 (8.9)

Arthralgia 30 (12.1) 11 (4.5) 41 (8.3)

Alanine aminotransferase increased 18 (7.3) 21 (8.5) 39 (7.9)

Urinary tract infection 21 (8.5) 16 (6.5) 37 (7.5)

Nail disorder 17 (6.9) 20 (8.1) 37 (7.5)

Aspartate aminotransferaseincreased

13 (5.3) 22 (8.9) 35 (7.1)

Hyperglycemia 13 (5.3) 17 (6.9) 30 (6.1)

Bone pain 17 (6.9) 13 (5.3) 30 (6.1)

Headache 15 (6.1) 15 (6.1) 30 (6.1)

Cough 14 (5.7) 16 (6.5) 30 (6.1)

Dyspnea 13 (5.3) 16 (6.5) 29 (5.9)

Infusion-related reaction 17 (6.9) 11 (4.5) 28 (5.7)

Serious Adverse Eventsb

≥1 Serious adverse event 94 (38.1) 89 (36.2) 183 (37.1)

CTCAE preferred term

Neutropenia 68 (27.5) 62 (25.2) 130 (26.4)

Neutropenia with fever 11 (4.5) 10 (4.1) 21 (4.3)

Leukopenia 4 (1.6) 12 (4.9) 16 (3.2)

Pneumonia 4 (1.6) 5 (2.0) 9 (1.8)

Abbreviation: CTCAE, CommonTerminology Criteria for AdverseEvents.a Treatment-emergent adverseevents by week 24 in more than 5%of patients in either treatmentgroup, in descending order offrequency in the overall safetypopulation.

b Serious adverse events, defined bythe investigator as grade 4 orrequiring hospitalization, by week24 in at least 2% of patients in eithertreatment group, in descendingorder of frequency in the overallsafety population.

Research Original Investigation Proposed Biosimilar vs Trastuzumab for HER2-Positive Metastatic Breast Cancer

E8 JAMA Published online December 1, 2016 (Reprinted) jama.com




the proposed biosimilar and 2.028 mg/kg/wk for trastu-zumab). For part 1, the mean (SD) total exposure was 21.038(6.4383) weeks for the proposed biosimilar and 20.327(6.8221) weeks for trastuzumab. The mean (SD) number ofcycles received was 7.8 (2.13) for the proposed biosimilargroup and 7.5 (2.27) for the trastuzumab group.

Treatment-Emergent Adverse EventsThe overall incidence of patients with at least 1 treatment-emergent adverse event was 96.8% (n = 239) in the proposedbiosimilargroupand94.7%(n = 233) in the trastuzumabgroup.The majority of events were mild or moderate in severity inboth treatment groups. In the safety population, a total of 14participants (7 patients [2.8%] in each group) reported an ad-verse event leading to discontinuation of treatment.

The incidence ratesof treatment-emergent adverseeventsof neutropenia, leukopenia, andanemiawere 57.5%(n = 142),17.0% (n = 42), and 16.2% (n = 40), respectively, in the pro-posedbiosimilar groupand53.3%(n = 131),20.7%(n = 51), and16.3% (n = 40), respectively, in the trastuzumab group. Ad-verse events with Common Terminology Criteria for AdverseEvents grade 3 or higher were reported for 312 (63.3%) of allparticipants,withneutropenia (221patients [44.8%]) and leu-kopenia (69 patients [14.0%]) the most frequently reported.The most frequent nonhematologic treatment-emergent ad-verse events inpatients in theproposedbiosimilar and trastu-zumab groups, respectively, included peripheral neuropathy(57 [23.1%] and 61 [24.8%]), diarrhea (51 [20.6%] and 51[20.7%]), asthenia (54 [21.9%]and40 [16.3%]), andnausea (49[19.8%]and34 [13.8%]).CommonTerminologyCriteria forAd-verse Events grade 3 events were reported for less than 2%ofall participantswith thesenonhematologic events.Treatment-emergent adverse events are summarized in Table 4.

Serious Adverse EventsThe overall incidence of patients with at least 1 serious ad-verse event (SAE)was 38.1%(n = 94) in the proposedbiosimi-lar group and 36.2% (n = 89) in the trastuzumab group(Table 4).

Only 4 SAE preferred terms were reported in at least 2%in either treatment group (Table 4). Overall, the most fre-quently reported SAE terms were neutropenia (130 patients

[26.4%]), febrile neutropenia (21 patients [4.3%]), and leuko-penia (16 [3.2%]). No other SAEs were reported in at least 2%of participants.

Eight participants (4 in each group) had SAEs that re-sulted in death. One death due to respiratory failure in eachgroupwas considered “possibly related” to studydrug. Otheradverse eventswith fatal outcomewere considered related totaxane therapy, related to underlying or progressive disease,or of unknown etiology.

Left Ventricular Ejection FractionThe LVEF values at baseline in the proposed biosimilar group(median, 64.0%; range, 51%-82%) and in the trastuzumabgroup (median, 63.0%; range, 51%-84%) did not change ap-preciably at week 24 (proposed biosimilar group: median,−1.0%;range,−13%to21%;trastuzumabgroup:median,−1.0%;range, −19% to 13%) (Table 5).

ImmunogenicityFourteenparticipants (5.9%) in theproposedbiosimilar groupand21participants (8.9%) in the trastuzumabgroupwereposi-tive for antidrug antibody prior to exposure to study treat-ment. The number of patients with detectable antibody de-clined over time.

Using a conservative approach that considers all patientswho tested positive for antidrug antibody at least once at anytimepointafterbaseline regardlessof theantidrugantibody re-sult at baseline, the overall antidrug antibody rate was 2.4%(6 of 245 patients) in the proposed biosimilar group and 2.8%(7of246patients) in the trastuzumabgroup.Themeanandme-dian titers forpatientswithpositive resultswere low(proposedbiosimilar group: mean, 3.2; median, 2.5; trastuzumab group:mean, 2.0; median, 2.3). The highest titers reported at base-line or any time after baseline (7.1 and 8.1, respectively, in theproposed biosimilar group and 5.2 and 5.5, respectively, inthe trastuzumab group) confirmed low immunogenicity.

DiscussionAmong women with ERBB2-positive metastatic breast can-cer, the use of a proposed trastuzumab biosimilar compared

Table 5. Descriptive Statistics for Cardiac Function (LVEF Values) by Visit in the Safety Population

Visit and Statistic

LVEF, %Proposed Biosimilar + Taxane(n = 247)

Trastuzumab + Taxane(n = 246)

Observed Change From Baseline Observed Change From BaselineBaselinea,b (n = 246) (n = 244)

Mean (95% CI) 64.0 (63.3 to 64.7) 64.1 (63.4 to 64.8)

Median (range) 64.0 (51 to 82) 63.0 (51 to 84)

Week 12b (n = 212) (n = 212) (n = 209) (n = 207)

Mean (95% CI) 63.3 (62.4 to 64.1) −1.0 (−1.7 to −0.2) 63.4 (62.6 to 64.2) −0.8 (−1.5 to −0.2)

Median (range) 63.0 (28 to 79) −1.0 (−29 to 14) 63.0 (52 to 82) 0.0 (−16 to 14)

Week 24b (n = 148) (n = 148) (n = 140) (n = 138)

Mean (95% CI) 63.6 (62.8 to 64.4) −0.6 (−1.5 to 0.2) 63.2 (62.2 to 64.2) −0.9 (−1.8 to −0.1)

Median (range) 63.5 (50 to 81) −1.0 (−13 to 21) 63.0 (41 to 82) −1.0 (−19 to 13)

Abbreviation: LVEF, left ventricularejection fraction.a Screening visit, prior to the firstdose of study drug.

b Sample sizes are the numbers ofpatients with available data withinthe treatment group.

Proposed Biosimilar vs Trastuzumab for HER2-Positive Metastatic Breast Cancer Original Investigation Research

jama.com (Reprinted) JAMA Published online December 1, 2016 E9



Rugo HS, et al. JAMA 2017;317:37–47

HERITAGE study: safety

Example safety findings: anti-drug antibodies (ADAs)

Neoadjuvant phase1

(+ paclitaxel) Adjuvant phase2

ABP 980(N=364)

n (%)

Trastuzumab RP (N=361)

n (%)

Continued ABP 980(N=349)

n (%)

ContinuedTrastuzumab RP

(N=171)n (%)

Trastuzumab RP/ ABP 980(N=171)

n (%)

Development of binding ADAs during the study,* n (%)

2 (0.6) 2 (0.6) 0 (0.0) 0 (0.0) 1 (0.6)

Development of neutralizing ADAs, n (%) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

ABP 980 is an investigational product*Patients with a negative or no result at baseline.1. von Minckwitz G, et al. ESMO 2017; Poster 151 PD; 2. Kolberg H-C, et al. SABCS 2017; Poster PD3-10

ABP 980 vs trastuzumab RP: development of anti-drug antibodies – by phase

Trastuzumab biosimilar clinical development: Summary of Phase 3 designs

E, epirubicin; C, cyclophosphamide; Ca, carboplatin; D, docetaxel; FEC, fluorouracil, epirubicin, cyclophosphamide; P paclitaxel; T, trastuzumab (reference product or proposed biosimilar)1. von Minckwitz G, et al. ESMO 2017; ; 2. Pivot X, et al. J Clin Oncol 2018:; 3. Stebbing J, et al. Lancet Oncol 2017; 4. Im YH, et al. ASCO 2013; 5. Lammers PE, et al. ESMO 2017,; 6. Pegram M, et al. ESMO 2017; 7. Rugo HS, et al. JAMA 2017;317:37–47.

AmgenABP9801

Samsung BioepisSB32

CelltrionCT-P63,4

PfizerPF-052800145,6

Biocon/MylanMYL-1401O7

Neoadjuvant/adjuvant ü ü ü (ü) -

Neoadjuvant regimenN

EC→T + P

725

T+ D→T + FEC

875

T+ D→T + FEC

549

T + DCa

226

Metastastic - - ü ü ü

RegimenN - - T + P

475T + P707

T + (D or P)458

Primary endpoint tpCR pCR breast only EBC: tpCRMBC: ORR

(EBC: PK endpoint)MBC: ORR ORR

Equivalence margin for efficacy (risk difference)

90% CI ±13% 95% CI ±13% EBC: 95% CI ±15% MBC: 95% CI ±15%

MBC: 95% CI 0.8–1.25 (risk ratio) 95% CI ±15%

Switch? Y/N Y N N N N

Clearly, the results reported in this issue of the Journal ... · Biocon/Mylan MYL-1401O August...

Documents

Transcript of Clearly, the results reported in this issue of the Journal ... · Biocon/Mylan MYL-1401O August...