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1 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 the Efficacy, Safety, and Immunogenicity of SB3 (Trastuzumab Biosimilar) and Reference Trastuzumab in Patients Treated With Neoadjuvant Therapy for Human Epidermal Growth Factor Receptor 2 Positive Early Breast Cancer Xavier Pivot, Igor Bondarenko, Zbigniew Nowecki, Mikhail Dvorkin, Ekaterina Trishkina, Jin-Hee Ahn, Yuriy Vinnyk, Seock-Ah Im, Tomasz Sarosiek, Sanjoy Chatterjee, Marek Z. Wojtukiewicz, Vladimir Moiseyenko, Yaroslav Shparyk, Maximino Bello III, Vladimir Semiglazov, Sujeong Song, and Jaeyun Lim Author affiliations and support information (if applicable) appear at the end of this article. Published at jco.org on January 26, Clinical trial information: NCT , Corresponding author: Xavier Pivot, MD, PhD, Administrateur de l Institut Régional du Cancer, 3 rue de la porte de l hôpital BP, Strasbourg Cedex, France; xpivot@ strasbourg.unicancer.fr by American Society of Clinical Oncology X/18/3699-1/$20.00 A B S T R A C T Purpose This phase III study compared SB3, a trastuzumab (TRZ) biosimilar, with reference TRZ in patients with human epidermal growth factor receptor 2 positive early breast cancer in the neoadjuvant setting (ClinicalTrials.gov identifier: NCT ). Patients and Methods Patients were randomly assigned to receive neoadjuvant SB3 or TRZ for eight cycles concurrently with chemotherapy (four cycles of docetaxel followed by four cycles of fluorouracil, epirubicin, and cyclophosphamide) followed by surgery, and then 10 cycles of adjuvant SB3 or TRZ. The primary objective was comparison of breast pathologic complete response (bpcr) rate in the per-protocol set; equivalence was declared if the 95% CI of the ratio was within to or the 95% CI of the difference was within 6 13%. Secondary end points included comparisons of total pathologic complete response rate, overall response rate, event-free survival, overall survival, safety, pharmacokinetics, and immunogenicity. Results Eight hundred patients were included in the per-protocol set (SB3, n = 402; TRZ, n = 398). The bpcr rates were 51.7% and 42.0% with SB3 and TRZ, respectively. The adjusted ratio of bpcr was (95% CI, to 1.460), which was within the predefined equivalence margins. The adjusted difference was 10.70% (95% CI, 4.13% to 17.26%), with the lower limit contained within and the upper limit outside 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 or more adverse event, 10.5% and 10.7% had a serious adverse event, and 0.7% and 0.0% had antidrug antibodies (up to cycle 9) with SB3 and TRZ, respectively. Conclusion Equivalence for efficacy was demonstrated between SB3 and TRZ on the basis of the ratio of bpcr rates. Safety and immunogenicity were comparable. J Clin Oncol by American Society of Clinical Oncology ASSOCIATED CONTENT Appendix DOI: Data Supplements DOI: DOI: INTRODUCTION The introduction of trastuzumab (TRZ; Herceptin; Genentech, South San Francisco, CA) into the therapeutic armamentarium for human epidermal growth factor receptor 2 (HER2) positive breast cancer has dramatically changed the natural history of this disease. 1-8 However, biotherapies are expensive and not readily available in some countries. As a result, economical biosimilars may increase patient access to critical therapies in some areas and save costs, thereby facilitating the availability of resources for innovative biotherapies in other countries. 9 SB3 (Samsung Bioepis, Incheon, Republic of Korea), a proposed TRZ biosimilar, has been extensively characterized and compared with reference TRZ. 10 These investigations demonstrated that SB3 and TRZ have highly similar structural and physicochemical characteristics, similarly inhibiting HER2-expressing human tumor cell proliferation 2018 by American Society of Clinical Oncology 1

2 Pivot et al and mediating antibody-dependent cellular cytotoxicity against such tumor cells in vitro. In healthy patients, pharmacokinetic (PK) equivalence was demonstrated between SB3 and European Union sourced TRZ or US-sourced TRZ. 10 The primary objective of the current study was to demonstrate the equivalent clinical efficacy of SB3 and TRZ in terms of the pathologic complete response in the primary breast tumor (bpcr) for women with HER2-positive early breast cancer treated with a neoadjuvant strategy. PATIENTS AND METHODS This study was conducted in compliance with the International Council for Harmonization Good Clinical Practice guidelines and the Declaration of Helsinki. The study was reviewed and approved by an independent ethics committee or institutional review board. Written informed consent was obtained from all patients before any study-related procedures were performed. Patients Eligibility criteria included the following: age 18 to 65 years; Eastern Cooperative Oncology Group performance status of 0 to 1; nonmetastatic, unilateral stage II to III primary breast cancer, including inflammatory breast cancer, with tumor size $ 2 cm; and histologically confirmed primary invasive adenocarcinoma of the breast, with HER2 positivity confirmed by a central laboratory or an accredited local laboratory. 11 Other inclusion criteria included known estrogen receptor (ER) and progesterone receptor (PR) status and baseline left ventricular ejection fraction (LVEF) $ 55% measured by echocardiography or multigated acquisition scan. Sentinel node biopsy before initiation of neoadjuvant therapy could be undertaken. A list of exclusion criteria can be found in the Data Supplement. Study Design and Treatment This was a phase III, randomized, double-blind, parallel-group, multicenter study (ClinicalTrials.gov identifier: NCT ; EudraCT No.: ). Random assignment was stratified by breast cancer type (operable v locally advanced) and hormone receptor status (ER and/or PR positive v ER and PR negative). A block stratified randomization method was used with dynamic block allocation by country. Patients were randomly assigned (1:1) to receive either SB3 or European Union sourced TRZ intravenously every 3 weeks in a neoadjuvant setting for eight cycles concurrently with eight cycles of chemotherapy (Fig 1). Study drugs were administered at a loading dose of 8 mg/kg and at 6 mg/kg for subsequent cycles. Chemotherapy consisted of docetaxel 75 mg/m 2 for four cycles followed by four cycles of fluorouracil 500 mg/m 2, epirubicin 75 mg/m 2,and cyclophosphamide 500 mg/m 2. Patients subsequently underwent surgery, followed by an additional 10 cycles of adjuvant treatment with SB3 or TRZ, as per random assignment, to complete 1 year of treatment. Radiotherapy was administered per local practice, as was adjuvant hormonal therapy. Study End Points Efficacy. The primary end point was the bpcr rate, which was defined as no histologic evidence of residual invasive tumor cells in the breast. 12 Pathologic response was assessed by the local pathologist. For quality control, all bpcrs were reviewed by the study pathologist board. Secondary end points included total pathologic complete response (tpcr) rate, defined as no residual invasive tumor cells in breast and axillary lymph nodes; overall response rate (ORR); and event-free survival and overall survival, which were measured from the date of random assignment. Safety. Treatment-emergent adverse events (TEAEs) were monitored throughout the study. Prespecified TEAEs of special interest included infusion-related reactions, congestive heart failure (CHF), and asymptomatic left ventricular systolic dysfunction. The severity of TEAEs was classified by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.0, with the exception of CHF (graded according to NCI-CTCAE v4.0 and the New York Heart Association functional classification) and asymptomatic left ventricular systolic dysfunction (graded according to NCI-CTCAE v3.0). LVEF was assessed every four cycles of study treatment. This report includes safety results during the neoadjuvant treatment period. PK. Blood samples were collected for determination of the predose concentrations (C trough ) at cycles 1, 3, 5, 7, and 8 using a validated enzymelinked immunosorbent assay. WinNonlin v5.2 (Pharsight, Mountain View, CA) was used for data collection and management. Immunogenicity. Immunogenicity testing was performed to search for antidrug antibodies (ADAs) and neutralizing antibodies against SB3 or TRZ. Blood samples were collected before drug administration in cycles 1, 5, 9, and 14, and 30 days after the last dose of study drug and analyzed using the Meso Scale Discovery platform (Rockville, MD). An overall ADA result was defined as positive for a patient with treatment-induced or treatmentboosted ADA, as defined in the Data Supplement. Statistical Analyses The primary analysis was conducted according to protocol amendment (April 2015) using the per-protocol set (PPS), which was defined as all HER2 positive EBC/LABC LVEF 55% Random assignment was stratified by hormone receptor status and disease stage R SB3* 8 cycles Docetaxel 4 cycles FEC 4 cycles TRZ* 8 cycles Docetaxel 4 cycles FEC 4 cycles Surgery SB3 10 cycles TRZ 10 cycles Neoadjuvant Therapy Period Adjuvant Therapy Period pcr assessment EOS Fig 1. Study design. (*) Loading dose of 8 mg/kg and then a maintenance dose of 6 mg/kg every 3 weeks. ( ) Docetaxel 75 mg/m 2.( ) Fluorouracil 500 mg/m 2, epirubicin 75 mg/m 2, and cyclophosphamide 500 mg/m 2. ( ) Primary end point is pathologic complete response (pcr) in breast tumor. EBC, early breast cancer; EOS, end of study; FEC, fluorouracil, epirubicin, and cyclophosphamide; HER2, human epidermal growth factor receptor 2; LABC, locally advanced breast cancer; LVEF, left ventricular ejection fraction; R, random assignment; SB3, trastuzumab biosimilar; TRZ, reference trastuzumab by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

3 SB3 (Trastuzumab Biosimilar) Versus Reference Trastuzumab patients in the full analysis set (FAS) who completed eight cycles of neoadjuvant therapy and surgery without prespecified major protocol deviations. On the basis of a statistical analysis plan that was finalized before unblinding of the study database, 90% CI of the ratio in the bpcr rate was secondarily considered in assessing the primary efficacy. The FAS consisted of all patients who were randomly assigned at the random assignment visit. Equivalence was declared if the 95% CI of the ratio in the bpcr rate between arms was contained within the predefined margin of to or if the 95% CI of the difference in the bpcr rate between treatments was contained within the predefined margin of 6 13%. The equivalence margin of to was based on a meta-analysis of three neoadjuvant studies in which patients were randomly assigned to receive TRZ or non-trz treatment and had bpcr results available. 1,13,14 In the meta-analysis, the ratio of the bpcr rates of TRZ to non-trz treatment was 2.07, with a 90% CI of to The lower equivalence margin in the current study preserved approximately 50% of the TRZ treatment effect over placebo, and the upper equivalence margin was taken from the lower limit of the 90% CI of the ratio. With an expected bpcr rate of 37.5%, 358 patients per arm were considered evaluable to meet 80% power to detect the equivalence. Considering the nonevaluable patients, 806 patients were to be randomly assigned, incorporating an 11% loss from the primary efficacy analysis. The primary efficacy analysis used a stratified Cochran-Mantel-Haenszel test, with hormone receptor status, breast cancer type, and region as factors to obtain the CI. To assess the robustness of the main results, the following supplementary analyses were planned: bpcr using log-linked binomial model, available patient analysis and nonresponder imputed analysis in the FAS, and tpcr comparison in the PPS and nonresponder imputed analysis in the FAS. Patient demographic and baseline clinical characteristics were compared between the two arms using the x 2 test or F test as appropriate. Safety and immunogenicity data were summarized using descriptive statistics in the safety set, consisting of patients receiving at least one dose of either study drug. PK analysis was performed in all patients who had one or more C trough result. Statistical analysis of the log e -transformed C trough at predose cycle 8 was performed using an analysis of variance model. Equivalence in C trough was concluded if the 90% CI for the ratio of geometric means of SB3 to TRZ was within the acceptance interval of 80% to 125%. Statistical analyses were performed using SAS v9.2 (SAS, Cary, NC). RESULTS Patients and Exposure Between April 2014 and August 2015, 875 patients were randomly assigned to receive either SB3 (n = 437) or TRZ (n = 438) across 97 study centers (Fig 2). A total of 800 patients (SB3, n = 402; TRZ, n = 398) completed neoadjuvant therapy and surgery, representative of the PPS population. Demographics and baseline disease characteristics in the FAS population were well balanced, with no statistical differences between the two arms (Table 1). Overall, the median age was 51 years (range, 22 to 65 years). The majority of patients had T2 disease (52.8%) and clinically involved lymph nodes (79.5%). ER and PR were negative in 40.9% of Screened (N = 1,254) Screening failures Did not meet inclusion criteria Met exclusion criteria Lost to follow-up Withdrew consent Other (n = 379)* (n = 254) (n = 95) (n = 2) (n = 34) (n = 6) Randomly assigned FAS (n = 875) SB3 (n = 437) TRZ (n = 438) Prematurely withdrawn before surgery Progressive disease/disease recurrence Withdrawal of consent Adverse events Administrative/other reasons Lost to follow-up Death (n = 18) (n = 6) (n = 5) (n = 2) (n = 3) (n = 1) (n = 1) Prematurely withdrawn before surgery Progressive disease/disease recurrence Withdrawal of consent Adverse events Administrative/other reasons Lost to follow-up Death (n = 22) (n = 4) (n = 6) (n = 7) (n = 1) (n = 1) (n = 3) Completed neoadjuvant therapy and surgery (n = 419) PPS (n = 402) Completed neoadjuvant therapy and surgery (n = 416) PPS (n = 398) Fig 2. Patient disposition and flow diagram. (*) Patients may have had multiple reasons for screening failure. ( ) Per-protocol set (PPS) defined as all patients in the full analysis set (FAS) who completed eight cycles of neoadjuvant therapy and surgery without prespecified major protocol deviations. SB3, trastuzumab biosimilar; TRZ, reference trastuzumab. jco.org 2018 by American Society of Clinical Oncology 3

4 Pivot et al Table 1. Patient Demographic and Baseline Clinical Characteristics According to Treatment Arm (full analysis set) Characteristic SB3 (n = 437) TRZ (n = 438) Median age, years (range) 51 (24-65) 50 (22-65) Race White 294 (67.3) 289 (66.0) Asian 134 (30.7) 138 (31.5) Other 9 (2.1) 11 (2.5) Menopause 220 (50.3) 216 (49.3) ECOG performance status (83.8) 365 (83.3) 1 71 (16.2) 73 (16.7) Mean LVEF, % (SD) 65.3 (5.12) 65.2 (5.49) Breast cancer type Operable 261 (59.7) 259 (59.1) Locally advanced 160 (36.6) 164 (37.4) Inflammatory 16 (3.7) 15 (3.4) Histopathologic tumor type Invasive ductal carcinoma 417 (95.4) 421 (96.1) Invasive lobular carcinoma 11 (2.5) 6 (1.4) Other 9 (2.1) 11 (2.5) Hormone receptor status ER positive/pr positive 179 (41.0) 170 (38.8) ER positive/pr negative 78 (17.8) 73 (16.7) ER negative/pr positive 9 (2.1) 8 (1.8) ER negative/pr negative 171 (39.1) 187 (42.7) Clinical T stage 1 2 (0.5) 4 (0.9) (53.5) 228 (52.1) 3 84 (19.2) 99 (22.6) (26.8) 107 (24.4) Clinical N stage 0 91 (20.8) 88 (20.1) (55.6) 232 (53.0) 2 69 (15.8) 73 (16.7) 3 34 (7.8) 45 (10.3) Clinical TNM stage IIA 65 (14.9) 62 (14.2) IIB 150 (34.3) 146 (33.3) IIIA 85 (19.5) 99 (22.6) IIIB 103 (23.6) 86 (19.6) IIIC 33 (7.6) 45 (10.3) IV 1 (0.2) 0 NOTE. Data are presented as No. (%) except where otherwise noted. Abbreviations: ECOG, Eastern Cooperative Oncology Group; ER, estrogen receptor; LVEF, left ventricular ejection fraction; PR, progesterone receptor; SB3, trastuzumab biosimilar; SD, standard deviation; TRZ, reference trastuzumab. tumors. The mean LVEF level at baseline was 65.24%. Corresponding data in the PPS population are provided in the Data Supplement. At the time of data cutoff, the median follow-up durations were 337 days (range, 94 to 489 days) and 338 days (range, 24 to 475 days) in the SB3 and TRZ arms, respectively. There were no relevant differences between the two arms in the mean values for the relative dose-intensity of both investigational products and noninvestigational products (Table 2). Efficacy All bpcrs assessed by the local pathologist were reviewed and confirmed by the study pathologist board, with one instance of disparity observed of the bpcr result that was recorded after the local pathologist report. In the PPS, the proportions of patients achieving bpcr were 51.7% (208 of 402 patients) in the SB3 group Table 2. Summary of Administration of Investigational Products and Noninvestigational Products During Neoadjuvant Period (full analysis set) Measure SB3 (n = 437) TRZ (n = 438) Investigational product Mean dose intensity, mg/kg/d Mean RDI (SD) (3.18) (3.69) Noninvestigational product Mean RDI of docetaxel (SD) (5.23) (5.76) Mean RDI of FEC (SD) (5.99) (5.87) Abbreviations: FEC, fluorouracil, epirubicin, cyclophosphamide; RDI, relative dose intensity; SB3, trastuzumab biosimilar; SD, standard deviation; TRZ, reference trastuzumab. and 42.0% (167 of 398 patients) in the TRZ group (Table 3). The adjusted ratio of bpcr was (95% CI, to 1.460), which was within the predefined equivalence margins. The adjusted difference was 10.70% (95% CI, 4.13% to 17.26%), with the lower margin contained within and the upper margin outside the predefined equivalence margins. In the FAS, bpcr rates were 49.0% (214 of 437 patients) and 39.7% (174 of 438 patients) for the SB3 and TRZ arms, respectively. The adjusted ratio of the bpcr rate was (95% CI, to 1.444), and the adjusted difference in the bpcr rate was 9.59% (95% CI, 3.26% to 15.91%). In the PPS, tpcr rates were 45.8% and 35.8% for the SB3 and TRZ arms, respectively. The bpcr and tpcr results in the FAS were similar to those seen in the PPS. The bpcr rates were higher in ER- and PR-negative patients than in ER- and/or PR-positive patients (Data Supplement). All complementary sensitivity analyses are presented in Table 3. Eventfree survival and overall survival data were not sufficiently mature for analysis at the time of the data cutoff date. Safety During the neoadjuvant period, TEAEs were reported in 96.6% of patients (422 of 437 patients) in the SB3 group and 95.2% of patients (417 of 438 patients) in the TRZ group (Table 4). The most common TEAEs were neutropenia, alopecia, nausea, and leukopenia. TEAEs resulted in the death of four patients (one suicide in the SB3 group and one death each as a result of myocardial infarction, sudden death, and pulmonary embolism in the TRZ group); none of these events were considered to be related to study drug. The incidence of TEAEs of special interest was similar between the arms. Two patients in the SB3 group presented with CHF. The first patient, with a history of hypertension and diabetes, had the event reported at cycle 5 and recovered from the event 11 days later. The second patient had the event reported at cycle 6 and recovered 11 days later. PK The PK population included 161 and 152 patients in the SB3 and TRZ arms, respectively. Mean C trough profiles from cycle 3 to cycle 8 were similar between the two treatment groups. A total of 99.2% of patients in the SB3 group and 97.3% of patients in the TRZ group had C trough values. 20 mg/ml at predose cycle 8. At cycle 8, the geometric least squares mean ratio of C trough was 110% ( mg/ml and mg/ml in the SB3 and TRZ groups, by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

5 SB3 (Trastuzumab Biosimilar) Versus Reference Trastuzumab Table 3. Comparison of Efficacy Results No. of Patients/Total No. (%) Adjusted Ratio (SB3/TRZ) Adjusted % Difference Result SB3 TRZ Ratio (95% CI) Ratio (90% CI)* (SB3 2 TRZ; 95% CI) Per-protocol set bpcr 208/402 (51.7) 167/398 (42.0) (1.085 to 1.460) (1.112 to 1.426) (4.13 to 17.26) Sensitivity analysis 208/402 (51.7) 167/398 (42.0) (1.062 to 1.432) (1.088 to 1.398) 9.78 (2.90 to 16.66) tpcr 175/382 (45.8) 136/380 (35.8) (1.106 to 1.563) (1.137 to 1.520) (4.44 to 17.66) ORR 369/383 (96.3) 341/374 (91.2) (1.017 to 1.095) (1.023 to 1.088) 5.03 (1.74 to 8.31) Full analysis set Available patients for analysis bpcr 214/419 (51.1) 174/415 (41.9) (1.070 to 1.434) (1.095 to 1.400) 9.86 (3.41 to 16.31) tpcr 180/398 (45.2) 142/397 (35.8) (1.089 to 1.530) (1.119 to 1.489) (3.73 to 16.73) ORR 393/414 (94.9) 368/404 (91.1) (1.001 to 1.080) (1.007 to 1.074) 3.64 (0.28 to 7.00) Nonresponder imputed analysis bpcr 214/437 (49.0) 174/438 (39.7) (1.070 to 1.444) (1.096 to 1.410) 9.59 (3.26 to 15.91) tpcr 180/437 (41.2) 142/438 (32.4) (1.083 to 1.538) (1.114 to 1.495) 9.32 (3.19 to 15.46) ORR 393/421 (93.3) 368/423 (87.0) (1.019 to 1.113) (1.026 to 1.105) 5.66 (1.87 to 9.46) Abbreviations: bpcr, breast pathologic complete response; ORR, overall response rate; SB3, trastuzumab biosimilar; tpcr, total pathologic complete response; TRZ, reference trastuzumab. *Secondary analysis conducted based on a statistical analysis plan that was finalized before data unblinding. For nonresponder imputed analysis, patients with missing assessments were considered to be nonresponders. respectively), and the 90% CI was 102% to 119%, which was contained within the predefined equivalence margins. Immunogenicity Up to cycle 9, positive ADA results were reported for three patients (0.7%) in the SB3 group and zero patients (0.0%) in the TRZ group. One of three patients obtained bpcr; none of these three patients presented significant TEAEs related to immunogenicity, such as infusion-related reaction. The overall incidence of ADAs was too low to perform a statistical analysis of the relationship between the ADA status and efficacy or safety, but there was no significant difference between patients who were ADA positive and negative. DISCUSSION Evaluation of a biosimilar is based on the totality of evidence, 15,16 including the rudimental comparative analytical and functional characterization studies with the supportive nonclinical and clinical studies. The aim of the clinical development of a biosimilar, according to this guiding principle, is to compare its efficacy and safety with the reference product, not to determine patient benefit perse. 15,17 A neoadjuvant setting in early breast cancer, compared with a metastatic setting, was chosen because it is a more sensitive and homogenous group with fewer confounding factors influencing the evaluation. 15,17,18 Although controversy still exists regarding whether pathologic complete response (pcr) is a valid surrogate end point related to event-free and overall survival, the primary efficacy evaluation on the basis of the pcr criterion has been acknowledged in HER2-positive breast cancer trials, such as the HannaH and NeoSphere studies In our study, bpcr was selected as the primary end point rather than tpcr to eliminate confounding factors in determining the pcr rate. Axillary lymph node assessments can affect tpcr results depending on the timing of the axillary staging, the techniques of the sentinel lymph node biopsy, and the extent of the axillary dissection. 25 Because these factors are not attributable to actual differences between drugs, bpcr seems to be the most stringent criterion with limited confounding factors. Neoadjuvant chemotherapy was chosen to achieve maximum efficacy with acceptable tolerability and was determined to be TRZ with concomitant administration of a taxane followed by an anthracycline. 13,26 In the HannaH study, the same chemotherapy was used to compare intravenous and subcutaneous TRZ. The results did not show significant safety concerns and led to subcutaneous TRZ Table 4. Safety Profile According to Treatment Arm (safety set) Adverse Event SB3 (n = 437) No. of Patients (%) TRZ (n = 438) Patients with $ 1 TEAE 422 (96.6) 417 (95.2) Frequently reported TEAEs ($ 10% in both groups) Neutropenia 293 (67.0) 279 (63.7) Alopecia 293 (67.0) 277 (63.2) Nausea 136 (31.1) 133 (30.4) Leukopenia 122 (27.9) 107 (24.4) Diarrhea 88 (20.1) 66 (15.1) ALT increased 81 (18.5) 76 (17.4) Anemia 80 (18.3) 89 (20.3) Fatigue 63 (14.4) 67 (15.3) Myalgia 63 (14.4) 64 (14.6) AST increased 61 (14.0) 56 (12.8) Stomatitis 60 (13.7) 49 (11.2) Vomiting 59 (13.5) 49 (11.2) Neutrophil count decreased 55 (12.6) 56 (12.8) Asthenia 51 (11.7) 48 (11.0) TEAEs of special interest Infusion-related reaction 36 (8.2) 44 (10.0) Asymptomatic LVSD 4 (0.9) 3 (0.7) Congestive heart failure 2 (0.5) 0 (0.0) Patients with $ 1 serious TEAE 46 (10.5) 47 (10.7) Death* 1 (0.2) 3 (0.7) Abbreviations: LVSD, left ventricular systolic dysfunction; SB3, trastuzumab biosimilar; TEAE, treatment-emergent adverse event; TRZ, reference trastuzumab. *See main text for details. jco.org 2018 by American Society of Clinical Oncology 5

6 Pivot et al approval. A randomized phase III trial (Z1041) evaluated the effect of the timing of TRZ administration with anthracycline and taxane neoadjuvant chemotherapy. 27 Although the study did not demonstrate added benefit with concomitant administration of anthracycline and TRZ, there were no additional safety concerns. Furthermore, a dose of docetaxel 75 mg/m 2 was used in our study to increase tolerability on the basis of a study in metastatic breast cancer, 28 despite that docetaxel 100 mg/m 2 is considered the standard dose for monotherapy. The progression and survival results were comparable with doses of 60, 75, and 100 mg/m 2, whereas the rates of neutropenia, febrile neutropenia, and infection were notably decreased when the docetaxel dose was reduced from 100 to 75 mg/m 2. Both ratio (relative risk) and absolute difference were used to assess the primary efficacy end point. Although both metrics are valid methods for assessment, the ratio metric provides a better adjustment to the lower event rate in a noninferiority or an equivalence study. 29 The CI of the ratio in the bpcr rates was compared using apredefined asymmetric equivalence margin. An asymmetric interval for the primary efficacy end point is possible when the drug (TRZ) dose level used in the clinical study is near the plateau of the dose-response curve with the unlikelihood of dose-related toxicity, considering that the rest of the results from all other end points, such as efficacy, safety, and immunogenicity, are similar between arms. 15 Overall, neoadjuvant TRZ has been administered in combination with different chemotherapy regimens, resulting in pcr rates ranging from 26% to 65%. 30 The bpcr rates observed in this study (51.7% and 42.0% in the SB3 and TRZ groups, respectively) are within the ranges previously reported in the literature and close to results reported in studies with similar chemotherapy regimens (concomitant administration of TRZ with taxanes and anthracyclines). In the HannaH study, the corresponding rates were 40.7% with intravenous TRZ and 45.4% with subcutaneous TRZ. 22 In the Z1041 study, bpcr rates were 56.5% and 54.2% in the sequential and concurrent TRZ neoadjuvant chemotherapy groups, respectively. 27 The observed bpcr rates demonstrated equivalence between SB3 and TRZ on the basis of the ratio of bpcr rates, with the bpcr rate of the SB3 group numerically 10% higher than that of the TRZ group. Patient demographic and baseline disease characteristics were well balanced between arms; therefore, the difference observed in bpcr rates is difficult to explain. Among numerous lots of TRZ that have been analyzed for physicochemical and biologic properties for. 5 years, certain lots showed a marked downward drift in the level of glycosylation, FcgRIIIa binding activities, and antibody-dependent cell-mediated cytotoxicity activities. Because some of these lots were used as a reference drug in this clinical study, it cannot be excluded that the shifts of these quality attributes in the reference drug did not have an impact on the presented results. 31 The physicochemical and biologic properties of the SB3 lots used for the clinical study were also intensively analyzed and have demonstrated similarity to predrifted TRZ lots. The safety profiles of SB3 and TRZ during the neoadjuvant treatment period were similar. The TEAEs were as expected for this study population and for this anticancer regimen. Immunogenicity was markedly low in both treatment groups. Patients who were ADA positive did not show a significant difference in efficacy and safety results compared with patients who were ADA negative, even though the relationship between immunogenicity and treatment efficacy and safety could not be statistically analyzed. A comprehensive evaluation of the full data, including similarity in clinical efficacy, safety, PK, and immunogenicity of the proposed biosimilar and the reference drug, is recommended. 15,17 In conclusion, this study demonstrated similarity between SB3 and TRZ. Patients may continue in a long-term extension study (ClinicalTrials.gov identifier: NCT ) that will further monitor safety, event-free survival, and overall survival. 32 AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Disclosures provided by the authors are available with this article at jco.org. AUTHOR CONTRIBUTIONS Conception and design: Xavier Pivot, Jaeyun Lim Provision of study materials or patients: Igor Bondarenko, Zbigniew Nowecki, Tomasz Sarosiek Collection and assembly of data: Igor Bondarenko, Zbigniew Nowecki, Mikhail Dvorkin, Ekaterina Trishkina, Jin-Hee Ahn, Yuriy Vinnyk, Seock- Ah Im, Tomasz Sarosiek, Sanjoy Chatterjee, Marek Z. Wojtukiewicz, Vladimir Moiseyenko, Yaroslav Shparyk, Maximino Bello III, Vladimir Semiglazov Data analysis and interpretation: Xavier Pivot, Sujeong Song, Jaeyun Lim Manuscript writing: All authors Final approval of manuscript: All authors Accountable for all aspects of the work: All authors REFERENCES 1. Gianni L, Eiermann W, Semiglazov V, et al: Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): A randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet 375: , Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al: Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353: , Gianni L, Dafni U, Gelber RD, et al: Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: A 4- year follow-up of a randomised controlled trial. Lancet Oncol 12: , Marty M, Cognetti F, Maraninchi D, et al: RandomizedphaseII trial ofthe efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: The M77001 study group. J Clin Oncol 23: , Romond EH, Jeong JH, Rastogi P, et al: Seven-year follow-up assessment of cardiac function in NSABP B-31, a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel (ACP) with ACP plus trastuzumab as adjuvant therapy for patients with node-positive, human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol 30: , Slamon DJ, Leyland-Jones B, Shak S, et al: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344: , Slamon D, Eiermann W, Robert N, et al: Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 365: , Smith I, Procter M, Gelber RD, et al: 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: A randomised controlled trial. Lancet 369:29-36, Jacobs I, Ewesuedo R, Lula S, et al: Biosimilars for the treatment of cancer: A systematic review of published evidence. BioDrugs 31:1-36, by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

7 SB3 (Trastuzumab Biosimilar) Versus Reference Trastuzumab 10. Pivot X, Curtit E, Lee YJ, et al: A randomized phase I pharmacokinetic study comparing biosimilar candidate SB3 and trastuzumab in healthy male subjects. Clin Ther 38: e3, Wolff AC, Hammond ME, Hicks DG, et al: Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol 31: , von Minckwitz G, Untch M, Blohmer JU, et al: Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol 30: , Buzdar AU, Ibrahim NK, Francis D, et al: Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: Results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol 23: , Chang HR, Slamon D, Gornbein JA, et al: Preferential pathologic complete response (pcr) by triple-negative (-) breast cancer to neoadjuvant docetaxel (T) and carboplatin (C). J Clin Oncol 26, 2008 (suppl 15; abstr 604) 15. US Food and Drug Administration: Scientific considerations in demonstrating biosimilarity to a reference product. Guidance for industry. fda.gov/downloads/drugsguidancecompliance RegulatoryInformation/Guidances/UCM pdf 16. Holzmann J, Balser S, Windisch J: Totality of the evidence at work: The first US biosimilar. Expert Opin Biol Ther 16: , European Medicines Agency: Guideline on similar biological medicinal products containing monoclonal antibodies: Non-clinical and clinical issues. Scientific_guideline/2012/06/WC pdf 18. Pivot X, Aulagner G, Blay JY, et al: Challenges in the implementation of trastuzumab biosimilars: An expert panel s recommendations. Anticancer Drugs 26: , Cortazar P, Zhang L, Untch M, et al: Pathological complete response and long-term clinical benefit in breast cancer: The CTNeoBC pooled analysis. Lancet 384: , Jackisch C, Hegg R, Stroyakovskiy D, et al: HannaH phase III randomised study: Association of total pathological complete response with event-free survival in HER2-positive early breast cancer treated with neoadjuvant-adjuvant trastuzumab after 2 years of treatment-free follow-up. Eur J Cancer 62:62-75, Gianni L, Eiermann W, Semiglazov V, et al: Neoadjuvant and adjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer (NOAH): Follow-up of a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet Oncol 15: , Ismael G, Hegg R, Muehlbauer S, et al: Subcutaneous versus intravenous administration of (neo) adjuvant trastuzumab in patients with HER2-positive, clinical stage I-III breast cancer (HannaH study): A phase 3, open-label, multicentre, randomised trial. Lancet Oncol 13: , Gianni L, Pienkowski T, Im YH, et al: Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): A randomised multicentre, open-label, phase 2 trial. Lancet Oncol 13:25-32, Gianni L, Pienkowski T, Im YH, et al: 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): A multicentre, open-label, phase 2 randomised trial. Lancet Oncol 17: , Kuehn T, Bauerfeind I, Fehm T, et al: Sentinellymph-node biopsy in patients with breast cancer before and after neoadjuvant chemotherapy (SEN- TINA): A prospective, multicentre cohort study. Lancet Oncol 14: , Buzdar AU, Valero V, Ibrahim NK, et al: Neoadjuvant therapy with paclitaxel followed by 5- fluorouracil, epirubicin, and cyclophosphamide chemotherapy and concurrent trastuzumab in human epidermal growth factor receptor 2-positive operable breast cancer: An update of the initial randomized study population and data of additional patients treated with the same regimen. Clin Cancer Res 13: , Buzdar AU, Suman VJ, Meric-Bernstam F, et al: Fluorouracil, epirubicin, and cyclophosphamide (FEC-75) followed by paclitaxel plus trastuzumab versus paclitaxel plus trastuzumab followed by FEC- 75 plus trastuzumab as neoadjuvant treatment for patients with HER2-positive breast cancer (Z1041): A randomised, controlled, phase 3 trial. Lancet Oncol 14: , Harvey V, Mouridsen H, Semiglazov V, et al: Phase III trial comparing three doses of docetaxel for second-line treatment of advanced breast cancer. J Clin Oncol 24: , US Food and Drug Administration: Noninferiority clinical trials to establish effectiveness: Guidance for industry. Drugs/Guidances/UCM pdf 30. Valachis A, Mauri D, Polyzos NP, et al: Trastuzumab combined to neoadjuvant chemotherapy in patients with HER2-positive breast cancer: A systematic review and meta-analysis. Breast 20: , Kim S, Song J, Park S, et al: Drifts in ADCCrelated quality attributes of Herceptin: Impact on development of a trastuzumab biosimilar. MAbs 9: , ClinicalTrials.gov: A long-term follow-up study for cardiac safety in the patients with HER2 (+) breast cancer who have completed the SB3-G31-BC. Affiliations Xavier Pivot, University Hospital Jean Minjoz, Institut National de la Santé et de la Recherche Médicale 1098, Besançon, France; Igor Bondarenko, State Institution Dnipropetrovsk Medical, Academy of the Ministry of Health of Ukraine, Communal Institution Dnipropetrovsk City Multifield Clinical Hospital No. 4 of Dnipropetrovsk Regional Council, Dnipropetrovsk; Yuriy Vinnyk, Communal Healthcare Institution Kharkiv, Regional Clinical Oncological Center, Kharkiv; Yaroslav Shparyk, Lviv State Oncological Regional Treatment and Diagnostic Center, Lviv, Ukraine; Zbigniew Nowecki, Centrum Onkologii-Instytutim. M. Sklodowskiej Curie; Tomasz Sarosiek, Magodent, Warsaw; Marek Z. Wojtukiewicz, Comprehensive Cancer Center, Medical University, Bialystok, Poland; Mikhail Dvorkin, BHI of Omsk Region, Clinical Oncology Dispensary, Omsk; Ekaterina Trishkina, SBHI Leningrad Regional Oncology Dispensary; Vladimir Moiseyenko, SBHI Saint Petersburg Scientific and Practical Center of Specialized Methods of Medical Help; Vladimir Semiglazov, FSI Scientific and Research Institution of Oncology n.a. N.N. Petrov of Ministry of Healthcare and SD of RF, St Petersburg, Russia; Jin-Hee Ahn, Asan Medical Center; Seock-Ah Im, Seoul National University Hospital, Seoul; Sujeong Song and Jaeyun Lim, Samsung Bioepis, Incheon, Republic of Korea; Sanjoy Chatterjee, Tata Medical Centre, Kolkata, India; and Maximino Bello III, St Luke s Medical Center, Quezon City, Philippines. Support Supported by Samsung Bioepis. Prior Presentation Presented, in part, at the 53rd Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 2-6, nnn jco.org 2018 by American Society of Clinical Oncology 7

8 Pivot et al AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Phase III, Randomized, Double-Blind Study Comparing the Efficacy, Safety, and Immunogenicity of SB3 (Trastuzumab Biosimilar) and Reference Trastuzumab in Patients Treated With Neoadjuvant Therapy for Human Epidermal Growth Factor Receptor 2 Positive Early Breast Cancer The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO s conflict of interest policy, please refer to or ascopubs.org/jco/site/ifc. Xavier Pivot Consulting or Advisory Role: Samsung Igor Bondarenko Zbigniew Nowecki Honoraria: Samsung, Roche Mikhail Dvorkin Ekaterina Trishkina Jin-Hee Ahn Yuriy Vinnyk Honoraria: Samsung Seock-Ah Im Consulting or Advisory Role: Spectrum Pharmaceuticals, Novartis, Hanmi Tomasz Sarosiek Research Funding: Samsung, Samsung (Inst) Sanjoy Chatterjee Consulting or Advisory Role: Novartis, Pfizer Marek Z. Wojtukiewicz Vladimir Moiseyenko Yaroslav Shparyk Maximino Bello III Research Funding: Eisai Vladimir Semiglazov Sujeong Song Employment: Samsung Bioepis Stock or Other Ownership: Samsung Biologics Jaeyun Lim Employment: Samsung Bioepis Stock or Other Ownership: Samsung Biologics 2018 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

9 SB3 (Trastuzumab Biosimilar) Versus Reference Trastuzumab Acknowledgment Medical writing assistance was provided by Michael S. McNamara of C4 MedSolutions (Yardley, PA), a CHC Group company, with funding from Samsung Bioepis. Appendix Study Investigators per Country Bosnia: Berisa Hasanbegovic, Uni Clinic Centre Sarajevo; Sasa Jungic, Uni Hosp ClinCenter Banja Luka. Bulgaria: Kalev Dimitar, UMHAT Sv.Marina, EAD; Ignatova Nikolinka, Complex Oncological Center-Vratsa, EOOD; Spartak Valev, MHAT Nadezhda, EOOD. Czechoslovakia: Renata Kozevnikovova, ONKOCENTRUM Medicon services s.r.o.; Martin Safanda, Nemocnice Na Homolce. France: Fernando Bazan, CHU Montbéliard Site du Mittan. India: Jyoti Bajpai, Tata Memorial Hospital; Rakesh Chopra, Artemis Health Institute; Amol Dumbre, KEM Hospital Research Centre; Mukul Goyal; Apex Hospital Pvt. Ltd.; Krishna Kamble, Government Medical College and Hospital; Dhananjay Kelkar, Deenanath Mangeshkar Hospital; Vijay Kumar, King George Medical University; Vinayak Maka, M S Ramaiah Medical College and Hospitals; Ravi Mohan Pedapenki, King George Hospital; Krishna Prasad, Kasturba Medical College Hospital; Vinod Raina, Fortis Memorial Research Institute; H. P. Shashidhara, HCG Bangalore Institute of Oncology; Jeba Singh, Ashirvatham Speciality Hospital; Kishore Singh, Lok Nayak Hospital, Maulana Azad Medical College; Wesley M. Jose, Amrita Institute of Medical Sciences. Korea: Jin Seok Ahn, Samsung Medical Center; Yee Soo Chae, Kyungpook National University Medical Center; Ki Hyeong Lee, Chungbuk National University Hospital. Malaysia: Jayendran Dharmaratnam, Nilai Medical Centre; Gwo Fuang Ho, University Malaya Medical Centre; Bhavaraju Venkata Krishna, Hospital Universiti Sains Malaysia. Mexico: Francisco Medina Soto, Winsett Rethman, S.A. de C.V. Philippines: Tudtud Dennis, Perpetual Succour Hospital; Lapus Felycette Gay, Davao Doctors Hospital; Adonis Guancia, Dr. Pablo O. Torre Memorial Hospital; Noemi Uy Ma, Cebu Doctors University Hospital; Juat Necy, National Kidney and Transplant Institute. Poland: Ida Cedrych, Centrum Onkologii-Instytut im. M. Sklodowskiej-Curie; Senkus Konefka Elzbieta, Uniwersyteckie Centrum Kliniczne; Chmielowska Ewa, Centrum Onkologii im. Prof. F. Lukaszczyka w Bydgoszczy; Maria Litwiniuk, Wielkopolskie Centrum Onkologii im Marii Sklodowskiej-Curie, Oddzial Chemioterapii; Miacz Malgorzata, Wojewodzki Szpital Specjalistyczny im. Stefana Kardynala Wyszynskiego SPZOZ w Lublinie; Barbara Radecka, Opolskie Centrum Onkologii im. Prof. T. Koszarowskiego; Anna Slowinska, SPZOZ MSW zwarmińsko-mazurskimcen. Onko. wolsztynie. Romania: Grecea Daniela, Institutul Oncologic Prof. Dr. Ion Chiricuta Cluj-Napoca; Filip Dumitru, Spitalul Judetean de Ugenta; Dragos Mircea Median, Spitalul Clinic Filantropia; Simona Mihutiu, Spitalul Clinic Municipal; Cristina Marinela Oprean, Oncomed SRL; Roxana Ioana Scheusan, Municipal de Urgenta Timisoara; Alina Cristina Turcu, Spitalul Municipal Ploiesti; Maria Turdean, Spitalul Clinic Judetean; Daniela Luminita Zob, Centrul Medical Unirea SRL. Russia: Larisa Bolotina, FSBI Moscow Scientific Research Oncology Institute named after P.A. Herzen of MoH of RF; Sergey Cheporov, Yaroslavl Regional Clinical Oncology Hospital; Eugeny Gotovkin, Ivanovo Regional Oncology Dispensary; Mikhail Kopp, State healthcare institution Samara regional clinical oncology dispensary ; Evgeny Kulikov, SBI of Ryazan Region Regional Clinical Oncological Dispensary ; Yuriy Latsukhay, MRC for Oncology and Neurology Biotherapy ; Mikhail Lichinitser, S.I. Russian Oncological Research Center n.a. N.N. Blokhin; Oleg Lipatov, Republican Clinical Oncology Dispensary of MoH of Bashkortostan; Alexey Manikhas, St. Petersburg SHI City Clinical Oncology Dispensary ; Guzel Mukhametshina, SHI Republican Clinical Oncological Dispensary of HM RT ; Sergei Orlov, Pavlov First Saint Petersburg State Medical University; Irina Selezneva, NSHI Central Clinical Hospital #2 of JSC Russian Railways n.a. N.A. Semashko ; Daniil Stroyakovskiy, SBHI of Moscow City Moscow City Oncology Hospital No 62 of Moscow Healthcare Department; Vladimir Vladimirov, Pyatigorsky Oncologic Dispensary; Alexander Vasiliev, Non-State Healthcare Institution Road Clinical Hospital of JSC Russian Railways. Ukraine: Orest Andrusenko, Lviv State Oncological Regional Treatment and Diagnostic Center; Natalya Banahevych, Kyiv City Clinical Oncological Center; Yevgen Butenko, CCTPI Donetsk Regional Antitumor Center; Yevhen Hotko, CCCH City Oncological Center SHEI Uzhgorod NU; Oleksandr Ivashchuk, CIChernivtsi RC Oncological Dispensary Bukovinian SMU Ch of Oncology and Radiology; Olexiy Kovalyov, MI Zaporizhzhia Regional Clinical Oncology Dispensary SI Zaporizhzhia MA of PGE of MoHU; Andriy Kurochkin, RCI Sumy Regional Clinical Oncological Dispensary; Viktor Paramonov, CI Cherkasy Regional Oncological jco.org 2018 by American Society of Clinical Oncology

10 Pivot et al Dispensary of CRC; Tetiana Popovska, Kharkiv MA of PGE Ch of Oncology and Child Oncology; Voloshin Sergey, CT&PI City Interdistrict Oncological Dispensary of Mariupol; Volodymyr Shamrai, Vinnytsia Regional Clinical Oncological Dispensary; Iryna Sokur, Kherson Regional Oncologic Dispensary. Vietnam: Minh Le, HCMC Oncology Hospital; Khoa Mai, Bach Mai Hospital; Tung Nguyen, Hue Central Hospital; Tuyen Nguyen, National Cancer Hospital by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY