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A phase III study comparing SB3 (a proposed trastuzumab biosimilar) and trastuzumab reference product in HER2-positive early breast cancer treated with neoadjuvant-adjuvant treatment: Final safety, immunogenicity and survival results
Equivalent efficacy between SB3 and Herceptin® in terms of the breast pathologic complete response rate was established.
•
Event-free survival and overall survival results further support the biosimilarity established between SB3 and Herceptin®.
•
Safety and immunogenicity results were highly comparable with no clinically relevant differences between SB3 and Herceptin®.
Abstract
Background
The equivalent efficacy between SB3, a proposed trastuzumab biosimilar, and the trastuzumab reference product (TRZ) in terms of the breast pathologic complete response rate after neoadjuvant therapy in patients with early or locally advanced human epidermal growth factor receptor 2-positive breast cancer was demonstrated in the previous report. Here, we report the final safety, immunogenicity and survival results after neoadjuvant-adjuvant treatment.
Patients and methods
Patients were randomised 1:1 to receive neoadjuvant SB3 or TRZ for 8 cycles concurrently with chemotherapy (4 cycles of docetaxel followed by 4 cycles of 5-fluorouracil/epirubicin/cyclophosphamide). Patients then underwent surgery, followed by 10 cycles of adjuvant SB3 or TRZ as randomised. End-points included safety, immunogenicity, event-free survival (EFS) and overall survival through the adjuvant period.
Results
Of 875 patients randomised, 764 (SB3, n = 380; TRZ, n = 384) completed the study. The median follow-up duration was 437 days in the SB3 group and 438 days in the TRZ group. The incidence of treatment-emergent adverse events was comparable between groups (SB3, 97.5%; TRZ, 96.1%) during the overall study period. Up to the end of study, the overall incidence of antidrug antibody was low in both treatment groups (3 patients each). EFS was comparable between groups with a hazard ratio (SB3/TRZ) of 0.94 (95% confidence interval, 0.59–1.51) and EFS rates at 12 months of 93.7% for SB3 and 93.4% for TRZ.
Conclusions
Final safety, immunogenicity and survival results of this study further support the biosimilarity established between SB3 and TRZ.
Trastuzumab (Herceptin®; Roche Registration Limited, Welwyn Garden City, UK and Genentech, Inc., South San Francisco, CA, USA) provides benefits in terms of tumour shrinkage, recurrence and survival when administered as neoadjuvant therapy with chemotherapy and continued as adjuvant therapy [
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.
Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831.
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.
] for human epidermal growth factor receptor 2 (HER2)-positive early breast cancer.
SB3 (Samsung Bioepis Co., Ltd., Incheon, Republic of Korea) is a proposed trastuzumab biosimilar with structural and physicochemical characteristics similar to trastuzumab reference product (TRZ) [
]. We conducted a phase III trial comparing SB3 and TRZ (EU-sourced) in patients with early or locally advanced HER2-positive breast cancer treated with neoadjuvant-adjuvant therapy. Equivalent efficacy between SB3 and TRZ in terms of the primary end-point, breast pathologic complete response (bpCR) rate, was demonstrated after neoadjuvant therapy. The bpCR rates in the per-protocol set were 51.7% for SB3 and 42.0% for TRZ, with an adjusted ratio (90% confidence interval [CI]) of 1.259 (1.112–1.426) and an adjusted difference (95% CI) of 10.70% (4.13%–17.26%) [
A randomized, double-blind, phase III study comparing SB3 (trastuzumab biosimilar) with originator trastuzumab in patients treated by neoadjuvant therapy for HER2-positive early breast cancer.
]. Biosimilarity of SB3 and TRZ has been assessed based on the ‘totality of evidence’ approach, taking structural, functional, nonclinical, pharmacokinetic, clinical immunogenicity and comparative clinical study data into consideration [
The objective of the current analysis was to compare safety, immunogenicity, and survival with SB3 and TRZ after neoadjuvant-adjuvant therapy in this phase III trial.
2. Materials and methods
The study and clinical protocols were reviewed and approved by the Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for each study center. This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) guidelines and applicable local regulatory requirements and laws.
2.1 Patients
Inclusion and exclusion criteria were previously described [
A randomized, double-blind, phase III study comparing SB3 (trastuzumab biosimilar) with originator trastuzumab in patients treated by neoadjuvant therapy for HER2-positive early breast cancer.
], and the key elements follow. Eligible patients were women 18–65 years of age with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1; with non-metastatic, unilateral, newly diagnosed, histologically confirmed, primary invasive breast adenocarcinoma (clinical stages II–III) including inflammatory breast cancer, with tumour size ≥2 cm and confirmed HER2-positivity (immunohistochemistry 3+ or fluorescence in situ hybridisation +); and with known oestrogen receptor (ER) and progesterone receptor (PR) status. All patients provided written informed consent before undergoing any study-related procedures.
2.2 Study design
This phase III, randomised, double-blind, parallel-group, multicentre, study contained a neoadjuvant therapy period, a surgical intervention, and an adjuvant therapy period. Patients were randomised 1:1 to receive neoadjuvant SB3 or TRZ every 3 weeks for 8 cycles concurrently with chemotherapy (4 cycles of docetaxel 75 mg/m2 followed by 4 cycles of 5-fluorouracil 500 mg/m2, epirubicin 75 mg/m2, and cyclophosphamide 500 mg/m2). Randomisation was stratified by hormone receptor status (ER and/or PR positive versus ER and PR negative) and breast cancer stage (operable versus locally advanced).
After neoadjuvant therapy and assessment of clinical response, patients underwent surgery within 6 weeks of the last dose of neoadjuvant therapy, followed by 10 cycles of adjuvant SB3 or TRZ as randomised to complete neoadjuvant-adjuvant therapy. Adjuvant radiation therapy and/or hormone therapy were allowed according to local practice. The present analysis was carried out to assess the safety, immunogenicity, and event-free and overall survival results following the complete 1 year of neoadjuvant-adjuvant therapy.
2.3 Study end-points
The primary end-point, bpCR, and secondary end-points related to primary tumour responses, were analysed previously after completion of the neoadjuvant therapy period [
A randomized, double-blind, phase III study comparing SB3 (trastuzumab biosimilar) with originator trastuzumab in patients treated by neoadjuvant therapy for HER2-positive early breast cancer.
]. Secondary end-points reported in this manuscript include event-free survival (EFS), defined as time from the date of randomisation to the date when an event occurs. An event is a disease recurrence or progression (distant, local, or regional) or death due to any cause. A post hoc search to investigate factors influencing EFS was performed. As an exploratory analysis, the relationship between EFS and pCR was analysed. Other secondary end-points were overall survival (OS), defined as time from the date of randomisation to the date of death, regardless of the cause of death; safety, graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.0 with several exceptions; and immunogenicity, determined by the incidence of antidrug antibodies (ADAs) and neutralising antibodies (NAbs) pre-dose at cycles 1, 5, 9, and 14, and 30 days after the last dose. ADA results were defined as positive for patients with a negative ADA at pre-dose cycle 1 who had ≥1 positive result after dosing at cycle 1 and for patients with a positive ADA at pre-dose cycle 1 who had ≥1 positive result after the dose at cycle 1 with a higher titre level compared with baseline.
2.4 Statistical analysis
The target sample size and power calculations for the primary analysis were reported previously [
A randomized, double-blind, phase III study comparing SB3 (trastuzumab biosimilar) with originator trastuzumab in patients treated by neoadjuvant therapy for HER2-positive early breast cancer.
]. The full analysis set (FAS) was defined as all patients who were randomised at the randomisation visit and was used in the current analysis of survival. The safety set was defined as all patients who received ≥1 dose of double-blind study drug during the study phase and was used in the current analyses of safety and immunogenicity. Treatment-emergent adverse events (TEAEs) were summarised by study periods: the neoadjuvant period (from cycle 1 to before surgery), the adjuvant period (from surgery date to end of study) and the overall study period (neoadjuvant + adjuvant period).
The survival curves (EFS and OS) were estimated using the Kaplan–Meier method. Estimated hazard ratios (HRs, SB3/TRZ) with 95% CIs were calculated from a stratified Cox proportional hazard model with hormone receptor status, disease stage and region as factors. As exploratory analyses, the EFS HRs were calculated within subgroups dependent on the presence or absence of bpCR and total pathologic complete response (tpCR). In addition, the Cox proportional hazard regression model was estimated to investigate the clinical factors influencing EFS. The clinical factors used for estimation were: bpCR/tpCR (yes versus no); age (<45 versus ≥ 45 years); hormone receptor status (ER and/or PR positive versus ER and PR negative); breast cancer type (operable versus locally advanced); race (Asian versus other); menopausal status (yes versus no); clinical T stage (T1/2 versus T3/4); and clinical N stage (N0 versus N1/2/3). All analyses were performed with the FAS without imputation, and patients who did not have an event at the time of analysis were censored at the date of the last available visit.
3. Results
3.1 Patients
Of 875 patients randomised, 764 (87.3%) completed the study (SB3, n = 380; TRZ, n = 384; Fig. 1). Baseline demographics and disease characteristics were comparable between groups as previously reported, with no statistically significant differences. The majority of patients were ER and/or PR positive (SB3, 60.9%; TRZ, 57.3%), and the most frequent disease stages were IIB (SB3, 34.3%; TRZ, 33.3%), IIIB (SB3, 23.6%; TRZ, 19.6%), and IIIA (SB3, 19.5%; TRZ, 22.6%). The relative dose intensity was comparable between groups during the overall study period (SB3, 98.65%; TRZ, 98.37%).
Fig. 1Consort. *Multiple screening failures were possible. †PPS defined as all patients randomised who completed 8 cycles of neoadjuvant therapy and surgery without pre-specified major protocol deviations. ‡One patient in the SB3 treatment group was lost to follow-up after completion of adjuvant therapy. N, number of patients in the randomised set; n, number of patients; PPS, per-protocol set; TRZ, trastuzumab reference product; SB3, trastuzumab biosimilar.
Surgery completion rate was comparable between two groups (SB3, n = 419 (95.9%); TRZ, n = 416 (95.0%)). During the adjuvant phase, 227 (51.9%) patients and 219 (50.0%) patients received at least 1 dose of radiation therapy in SB3 and TRZ, respectively. A total of 517 patients (SB3, n = 266; TRZ, n = 251) were hormone receptor-positive; of these, 185 (69.5%) in the SB3 group and 169 (67.3%) in the TRZ group received endocrine therapy. The most frequently given hormonal treatment was tamoxifen (SB3, 130 patients; TRZ, 126 patients).
3.2 Efficacy
Data cut-off was at the end of the study, which was 30 days after adjuvant therapy completion. With the median follow-up duration of 438 days, EFS (SB3, 92.2%; TRZ, 91.6%) and OS (SB3, 99.8%; TRZ, 98.9%) rates were similar between groups (Table 1; Fig. 2), with a total of 71 patients experiencing events (SB3, n = 34; TRZ, n = 37). At 12 months, EFS (SB3, 93.7%; TRZ, 93.4%) and OS (SB3, 99.8%; TRZ, 98.8%) rates were also comparable. Within each treatment group, bpCR achievement was related to tendency of favourable EFS outcome (Fig. 3A and B) and tpCR achievement was significantly related to favourable EFS outcome (Fig. 3D and E). In the combined analysis of both treatment groups, the EFS difference by attainment or no attainment of bpCR/tpCR was rather significant: EFS by bpCR (HR 0.43; 95% CI, 0.24–0.77) and EFS by tpCR (HR 0.27; 95% CI, 0.13–0.55; Fig. 3C and F). In the Cox proportional hazard regression model, bpCR or tpCR were the only independent clinical factors influencing EFS. Age, hormone receptor status, breast cancer type, race, clinical T stage, and clinical N stage did not affect EFS. Regardless of treatment group, bpCR (HR 0.46, 95% CI 0.26–0.83; Supplementary Table A) and tpCR (HR 0.29, 95% CI 0.14–0.60; Supplementary Table B) were associated with a reduced risk of an event (disease recurrence/progression and death). OS subgroup analyses were not done because of the short follow-up period, as well as the small number of patients experiencing events. Efficacy results in the per-protocol set are summarised on Supplementary Table C.
Table 1Summary of efficacy results during neoadjuvant-adjuvant treatment (full analysis set).
Fig. 3EFS by bpCR and tpCR. (A) EFS by bpCR in SB3 group; (B) EFS by bpCR in TRZ group; (C) EFS by bpCR in combined SB3 and TRZ groups; (D) EFS by tpCR in SB3 group; 3 (E) EFS by tpCR in TRZ group; (F) EFS by tpCR in combined SB3 and TRZ groups. bpCR, breast pathologic complete response; tpCR, total pathologic complete response; EFS, event-free survival; TRZ, trastuzumab reference product.
Safety was comparable between groups throughout the overall treatment period; at least 1 TEAE was reported by 426 (97.5%) patients in the SB3 group and by 421 (96.1%) patients in the TRZ group (Table 2). The most common TEAEs were alopecia and neutropenia. TEAEs of grade 1 severity occurred most often—2844 (52.3%) events in the SB3 group and 2805 (53.5%) events in the TRZ group. Safety was also comparable between groups during the adjuvant treatment period; at least 1 TEAE was reported by 246 (56.3%) patients in the SB3 group and by 241 (55.0%) patients in the TRZ group (Table 3). Again, TEAEs of grade 1 severity occurred most often—664 (63.7%) events with SB3 and 644 (65.9%) events with TRZ. Common TEAEs were radiation skin injury, procedural pain, and lymphorrhea, which were mostly due to surgery or adjuvant radiation therapy rather than trastuzumab (SB3 or TRZ) administration. The TEAEs of special interest (AESI) were infusion-related reaction, asymptomatic left ventricular systolic dysfunction (LVSD) and congestive heart failure (CHF), for which incidence was comparable between groups during the overall treatment period and during the adjuvant monotherapy period (Table 2, Table 3).
Table 2Summary of TEAEs during the overall treatment period.
Safety parameters
SB3 (N = 437)
TRZ (N = 438)
Patients with ≥1 TEAE, n (%)
426 (97.5)
421 (96.1)
Grade 1
19 (4.3)
25 (5.7)
Grade 2
82 (18.8)
81 (18.5)
Grade 3
119 (27.2)
129 (29.5)
Grade 4
205 (46.9)
181 (41.3)
Grade 5
1 (0.2)
5 (1.1)
Frequently reported TEAEs ≥20% in either group, n (%)
Alopecia
299 (68.4)
283 (64.6)
Neutropenia
294 (67.3)
282 (64.4)
Nausea
144 (33.0)
135 (30.8)
Leukopenia
125 (28.6)
114 (26.0)
Anaemia
96 (22.0)
95 (21.7)
Diarrhoea
92 (21.1)
67 (15.3)
Fatigue
88 (20.1)
80 (18.3)
TEAEs of special interest, n (%)
48 (11.0)
53 (12.1)
Infusion-related reaction
37 (8.5)
44 (10.0)
Asymptomatic LVSD
11 (2.5)
8 (1.8)
Congestive heart failure
3 (0.7)
1 (0.2)
Serious TEAEs, n (%)
56 (12.8)
58 (13.2)
Deaths, n (%)
1 (0.2)
5 (1.1)
Abbreviations: LVSD, left ventricular systolic dysfunction; N, number of patients in the randomised set; n, number of patients; TEAE, treatment-emergent adverse event; TRZ, trastuzumab reference product; SB3, trastuzumab biosimilar.
Table 3Summary of TEAEs during the adjuvant period.
Safety parameters
SB3 (N = 437)
TRZ (N = 438)
Patients with ≥1 TEAE, n (%)
246 (56.3)
241 (55.0)
Grade 1
93 (21.3)
80 (18.3)
Grade 2
126 (28.8)
125 (28.5)
Grade 3
24 (5.5)
32 (7.3)
Grade 4
3 (0.7)
2 (0.5)
Grade 5
0
2 (0.5)
Frequently reported TEAEs ≥5% in either group, n (%)
Radiation skin injury
48 (11.0)
36 (8.2)
Procedural pain
38 (8.7)
53 (12.1)
Fatigue
37 (8.5)
31 (7.1)
Lymphorrhea
32 (7.3)
30 (6.8)
Anaemia
28 (6.4)
20 (4.6)
Joint range of motion decreased
26 (5.9)
20 (4.6)
Postoperative wound complication
26 (5.9)
21 (4.8)
Upper respiratory tract infection
25 (5.7)
21 (4.8)
TEAEs of special interest, n (%)
11 (2.5)
6 (1.4)
Infusion-related reaction
2 (0.5)
0
Asymptomatic LVSD
8 (1.8)
5 (1.1)
Congestive heart failure
1 (0.2)
1 (0.2)
Serious TEAEs, n (%)
15 (3.4)
14 (3.2)
Deaths, n (%)
0
2 (0.5)
Abbreviations: LVSD, left ventricular systolic dysfunction; N, number of patients in the randomised set; n, number of patients; TEAE, treatment-emergent adverse event; TRZ, trastuzumab reference product; SB3, trastuzumab biosimilar.
The analysis focused on cardiac dysfunction, asymptomatic left ventricular dysfunction events were reported as LVSD. In the SB3 group, 14 LVSD events were reported in 11 (2.5%) patients and, in the TRZ group, 9 LVSD events were reported in 8 (1.8%) patients. A total of 4 patients (SB3, n = 3; TRZ, n = 1) reported CHF. The incidence of CHF observed in this study was within the expected ranges as reported in previous literature (0%–0.7%) with neoadjuvant trastuzumab given concurrently with taxanes and anthracyclines [
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.
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.
Pathologic complete response after neoadjuvant chemotherapy plus trastuzumab predicts favorable survival in human epidermal growth factor receptor 2-overexpressing breast cancer: results from the TECHNO trial of the AGO and GBG study groups.
]. All 4 patients had a history of hypertension or diabetes/glucose intolerance, and no CHF cases were fatal. Three CHF cases in the SB3 group resolved or improved and 1 CHF case in the TRZ group did not resolve. The overall incidence of a significant decrease in LVEF ≥10% points from baseline and resulting in LVEF <50% was comparable between treatment groups (SB3, n = 16 [3.7%]; TRZ, n = 12 [2.8%]). The mean LVEF was slightly decreased from baseline (65.3% in the SB3 group and 65.2% in the TRZ group) to cycle 14 and maintained until the end of the study (62.9% in the SB3 group and 63.0% in the TRZ group) in both treatment groups (Fig. 4).
Serious adverse events occurred in 12.8% and 13.2% of patients in the SB3 and TRZ groups, respectively. Most common events were due to neutrophil count decrease. Six deaths were reported during study. One patient (0.2%) in the SB3 group died from suicide, and 5 patients (1.1%) in the TRZ group died from myocardial infarction, sudden death, haemorrhagic stroke, pneumonitis and pulmonary embolism (1 patient each). No death was related to progressive disease/disease recurrence.
3.4 Immunogenicity
Up to end of study, immunogenicity was low and comparable between groups. The overall incidence of ADAs and NAbs was 0.7% (n = 3) and 0.5% (n = 2), respectively, in each treatment group.
4. Discussion
In our previous report, equivalence of efficacy was demonstrated between SB3 and TRZ based on the ratio of bpCR rates in primary breast tumour in the neoadjuvant setting [
A randomized, double-blind, phase III study comparing SB3 (trastuzumab biosimilar) with originator trastuzumab in patients treated by neoadjuvant therapy for HER2-positive early breast cancer.
Current analysis shows results with data cut-off 30 days post adjuvant therapy completion. EFS (SB3, 92.2%; TRZ, 91.6%) and OS (SB3, 99.8%; TRZ, 98.9%) rates were comparable, supporting the similarity of SB3 and TRZ in addition to pCR results. The survival rates are consistent with those of previous randomised controlled trials of trastuzumab therapy for HER2-positive breast cancer [
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.
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.
]. As exploratory analyses, EFS rates were analysed by subgroups with and without bpCR or tpCR. Within each treatment group, bpCR achievement was related to tendency of favourable EFS, and tpCR achievement was significantly related to favourable EFS. In the combined analysis, the clinical benefit of bpCR/tpCR attainment was magnified. A Cox proportional hazard regression model that estimated the HR with the clinical factors of treatment group, bpCR or tpCR, region, hormone receptor status, age group, breast cancer type, race, menopausal status, and clinical T, N stage showed that bpCR (HR 0.46, 95% CI 0.26–0.83, P = 0.0099) and tpCR (HR 0.29, 95% CI 0.14–0.60, P = 0.0009) were the only statistically significant factors related to EFS. This result suggests that bpCR and tpCR are surrogate markers for survival and are consistent with historical results showing that pCR achievement is associated with improved long-term survival in HER2-positive breast cancer [
Pathologic complete response after neoadjuvant chemotherapy plus trastuzumab predicts favorable survival in human epidermal growth factor receptor 2-overexpressing breast cancer: results from the TECHNO trial of the AGO and GBG study groups.
Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response.
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.
Survival after adding capecitabine and trastuzumab to neoadjuvant anthracycline-taxane-based chemotherapy for primary breast cancer (GBG 40–GeparQuattro).
The overall safety data are reassuring, in that TEAEs were as expected for this population and treatment including combined chemotherapeutic agents. All safety parameters did not show any unexpected safety issues regarding SB3 administration. For AESI, there was no serious infusion-related reaction to SB3. LVEF change during the overall study period was not substantial (about 2–3% points decrease) and was similar in degree between treatment groups, and the incidence of symptomatic LVSD (CHF) in the SB3 group was low (0.7%) and comparable to the TRZ group. In addition, safety data collected during the adjuvant monotherapy period appeared to show comparability between SB3 and TRZ. In the development of therapeutic protein products, immunogenicity assessment is important as generation of an immune response to the drug might induce adverse events and decrease efficacy [
]. However, the clinical relevance of ADAs to trastuzumab is not fully understood in cancer patients. In this study, the overall incidence of ADAs was low (0.7%), consistent with published studies of intravenous trastuzumab (0–3.4%) [
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.
Effect of a proposed trastuzumab biosimilar compared with trastuzumab on overall response rate in patients with ERBB2 (HER2)-positive metastatic breast cancer: a randomized clinical trial.
Even though the sample size of this study is the largest ever among neoadjuvant clinical trials, a limitation of this study is a relatively short follow-up. However, an extension of the present study is ongoing, which is a 5-year follow-up study (NCT02771795) observing the incidence of symptomatic CHF and significant LVEF decrease and EFS/OS.
5. Conclusion
Using the totality of evidence approach, the final safety, immunogenicity and survival results of this study further support the biosimilarity established between SB3 and TRZ.
Conflict of interest statement
Z. Nowecki has received honoraria from Samsung Bioepis. S.-A. Im has received consulting or advisory payments from Novartis, Hanmi, and Spectrum. Y. Lee and J. Lim are employees of Samsung Bioepis and stockowners of Samsung Biologics. All other authors declare no conflict of interest.
Acknowledgements
This study was funded by Samsung Bioepis Co., Ltd. Medical writing assistance was provided by Stephanie Leinbach, PhD, of C4 MedSolutions, LLC (Yardley, PA), a CHC Group company, and funded by Samsung Bioepis Co., Ltd.
Appendix A. Supplementary data
The following is the supplementary data related to this article:
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.
Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831.
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.
A randomized, double-blind, phase III study comparing SB3 (trastuzumab biosimilar) with originator trastuzumab in patients treated by neoadjuvant therapy for HER2-positive early breast cancer.
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.
Pathologic complete response after neoadjuvant chemotherapy plus trastuzumab predicts favorable survival in human epidermal growth factor receptor 2-overexpressing breast cancer: results from the TECHNO trial of the AGO and GBG study groups.
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.
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.
Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response.
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.
Survival after adding capecitabine and trastuzumab to neoadjuvant anthracycline-taxane-based chemotherapy for primary breast cancer (GBG 40–GeparQuattro).
Effect of a proposed trastuzumab biosimilar compared with trastuzumab on overall response rate in patients with ERBB2 (HER2)-positive metastatic breast cancer: a randomized clinical trial.
As the patent life ends or is close to ending on a number of novel biologic therapies for cancer therapy, the number of biosimilars in development has exploded, creating a new playing field important to providers, payers and patients [1]. What is a biosimilar? We are used to the concept of generic medications, where small molecules and simple chemicals are recreated, requiring only that the chemical structure and pharmacokinetics are the same as the original product. Biologics are large, complex molecules made in living cells, and owing to variations in production and post-translational modifications, even the branded or reference product may be different depending on when and where it was produced [2].
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