Introduction: SB3 is a trastuzumab biosimilar approved in Australia, Brazil, Canada, the European Union, the Republic of Korea, Switzerland, and the USA. This real-world study evaluated safety and effectiveness of SB3 as part of the Korean post approval safety management system. Methods: This post-marketing surveillance in Korea included patients in line with approved indications, i.e., patients with early or metastatic breast cancer or metastatic gastric cancer. Safety outcomes were adverse events (AEs) and adverse drug reactions. Effectiveness outcomes were tumor response and event-free survival. Results: 424 patients were evaluated: 366 patients (86%) with early breast cancer, 53 patients (13%) with metastatic breast cancer, and 5 patients (1%) with metastatic gastric cancer. Among patients with breast cancer, AEs (mostly mild) and adverse drug reactions were reported by 158 (37.7%) and 57 (13.6%) patients, respectively. Most patients with an AE (141, 89.2%) had no change in treatment schedule. Treatment was temporarily suspended in 14 (8.9%) patients with an AE and completely discontinued in 7 (4.4%). Among patients with early and metastatic breast cancer who were evaluated for efficacy, objective response rates were 82.7% and 38.3%, respectively. Pathological complete response was 64.6% in patients with early breast cancer. Discussion/Conclusion: Safety and efficacy of SB3 demonstrated in this real-world study were comparable with previous studies of reference trastuzumab.

The human epidermal growth factor receptor 2 (HER2, ERBB2) is overexpressed in a variety of solid tumors, including about 20% of breast cancers (BCs) [1] and 7–34% of gastric cancers (GCs) [2], and associated with poor prognosis and aggressive disease [1, 3]. Trastuzumab (TRZ), a monoclonal antibody, was the first HER2-targeting biological medicine (biologic) approved in the USA and the European Union in 1998 and 2000, respectively [4]. TRZ, alone or in combination with chemotherapy (CT), improved overall survival, progression-free survival, and quality of life of patients with HER2-positive metastatic BC (mBC) [5]. Adjuvant TRZ significantly improved progression-free survival in patients with early BC (eBC) and reduced risk of recurrence, perturbing the natural history of the disease [6]. Based on demonstrated safety and efficacy, TRZ also became the standard-of-care for HER2-positive GC [1, 2, 7]. Although TRZ is an established therapy that revolutionized the treatment of HER2-positive BC and GC, its high cost can limit patient access to therapy [8].

Meanwhile, several TRZ biosimilars have been approved, having the potential to contain rising healthcare expenditure and provide sustainable access to HER2-targeted therapies [9]. A biosimilar is a biologic that is highly similar to an approved biologic called the reference product [10, 11] and demonstrated comparable quality, safety, and efficacy as the reference product [12, 13]. Because of their tailored developmental and approval paths, biosimilars are generally less expensive than the reference products and have been shown to and increase patient access to treatment [14‒16].

SB3 (Ontruzant® [Samfenet® in Korea]; Samsung Bioepis Co., Ltd., Incheon, Republic of Korea) is a TRZ biosimilar approved in Australia, Brazil, Canada, the European Union, the Republic of Korea, Switzerland, and the USA [17‒22]. A phase I, randomized, parallel, single-dose study in healthy volunteers demonstrated pharmacokinetic equivalence of SB3 and reference TRZ [23]. A large, randomized, double-blind, phase III clinical equivalence study of SB3 versus TRZ in combination with CT in women with early or locally advanced HER2-positive BC showed that SB3 was equivalent to TRZ with respect to the breast pathological complete response (bpCR) rates [24]. A 5-year follow-up of the phase III study showed comparable cardiac safety and long-term efficacy [25].

In Korea, post-marketing surveillance (PMS) studies are part of the drug approval process, allowing re-examination of safety and efficacy of new approved medications [26]. The aim of this PMS study was to evaluate the safety and effectiveness of SB3 in real-world clinical practice in Korea.

Study Design

This was a prospective, multi-center, open-label, non-interventional, PMS study conducted in 12 centers in Korea (Study Number: SB3-KO41-PMS) (online suppl. Table A1; for all online suppl. material, see https://doi.org/10.1159/000534626). The final study protocol and the informed consent form were approved by the local Independent Ethics Committees (IECs) or Institutional Review Boards (IRBs), and the study was conducted in accordance with applicable local regulatory requirements and laws, the Declaration of Helsinki (1996), and the International Council for Harmonization Good Clinical Practice guidelines. Written informed consent was obtained from each subject before enrollment.

Study Population

The study population comprised patients >18 years who had tested HER2-positive mBC, eBC, or metastatic GC (mGC) and were planned to receive SB3 in line with approved indications. Patients who signed the informed consent form and were willing to participate in the study were enrolled. Patients with a medical history of hypersensitivity to TRZ, rodent-derived proteins, or excipients, and patients with severe dyspnea at rest or requiring oxygen supplementation due to advanced malignancies were excluded.

Patient Management and Outcome Assessment

An overview of SB3 treatments for each indication is shown in online supplementary Table A2. The primary endpoints were safety of SB3 expressed as incidences of adverse events (AEs), adverse drug reactions (ADRs), serious AEs (SAEs), and serious ADRs (SADRs) for each indication, symptomatic congestive heart failure (CHF) and the proportion of patients with a follow-up left ventricular ejection fraction (LVEF) <50% and a drop by 10%-points or more compared to baseline. AEs of special interests (AESIs) were significant decrease of LVEF, CHF, cardiac dysfunction, infusion-related reactions, hemotoxicity, pulmonary events, and oligohydramnios. The secondary endpoints evaluated effectiveness included objective response rate (ORR) and pathological complete response (pCR). The response evaluation criteria in solid tumors (RECIST) 1.1 guideline served as basis for evaluation of response and classification as complete response (CR), partial response (PR), stable disease, progressive disease, or not evaluable. pCR was assessed as either bpCR (ypT0/is) or total pathologic CR (tpCR) in breast and axillary nodes (tpCR; ypT0/is ypN0) in eBC patients with BC-related surgery and neoadjuvant SB3.

General safety and efficacy were investigated in patients receiving SB3 until week 24. If SB3 treatment was discontinued before week 24, the follow-up visit was 30 days after the last dose, not exceeding week 24 from the first visit.

Statistical Analysis

The safety analysis set included all patients with at least one follow-up was performed for safety after receiving SB3. AEs occurring during and after SB3 administration were coded using the Medical Dictionary for Regulatory Affairs (MedDRA) version 24.0. Seriousness, severity, causal relationship to SB3, and outcome were analyzed and summarized as overall incidence with 95% confidence interval (CI) of all AEs. Differences in the incidences of AEs by factor were analyzed by χ2 test or Fisher’s exact test.

The efficacy analysis set included all patients with at least one effectiveness assessment after SB3 administration. Effectiveness was assessed by the physician in charge at visit 3 (weeks 8–16) and visit 4 (weeks 20–28) or at early termination visit, if applicable.

The exploratory analysis compared safety events, effectiveness, and percent change of LVEF from baseline between patients treated with SB3 (alone or in combination with CT) versus patients on SB3 and pertuzumab ([PTZ] with or without CT). Effectiveness was further compared between patients who were hormone receptor (estrogen receptor [ER] and/or progesterone receptor [PgR]) positive versus patients who were ER and PgR negative. Differences in safety events were analyzed by χ2 test or Fisher’s exact test. For pCR, differences in effectiveness by factor were analyzed by χ2 test or Fisher’s exact test. Differences in safety (LVEF change by factor) were analyzed by t test.

Target sample size was 400 or more patients (but not more than 480) to be enrolled within the official re-examination period of 4 years after domestic approval. All analyses were done using Statistical Analysis Software (SAS®), version 9.4.

Patient Demographics and Baseline Characteristics

Overall, 438 patients were enrolled in 12 sites (13 principal investigators) from November 8, 2017, to November 7, 2021 (online suppl. Table A1). Fourteen enrolled patients not meeting the inclusion/exclusion criteria were excluded from the analysis. In total, 424 were eligible for safety and effectiveness evaluation as shown in Figure 1. The majority of patients had a diagnosis of BC, 366 (86%) with eBC and 53 (13%) with mBC, and 5 patients (1%) had mGC (Table 1). Mean age (standard deviation [StD]) was 52.5 (9.6) years. Baseline LVEF levels were measured for 279 patients, with a median (range) LVEF of 65% (42–79%). Hormone receptor status was tested for 419 BC patients with 62% being ER and/or PgR positive and 37% being ER and PgR negative. Sixty patients (14%), 59 BC and 1 GC patient, were switched from another TRZ product to SB3. Overall, 185 patients (44%) were treated with SB3 (alone or in combination with CT) and 239 (56%) with SB3 and PTZ (with or without CT). A more detailed overview of treatment regimen and treatment settings among patients who received SB3 with or without PTZ is shown in online supplementary Table A3. Due to the small number of mGC patients, only outcomes of BC patients were analyzed in full while outcomes of GC patients are shown as descriptive summary, just for complete presentation of the enrolled study population.

Fig. 1.

Patient disposition.

Fig. 1.

Patient disposition.

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Table 1.

Baseline demographics and disease characteristics

ParameterCategoryIndications
eBCmBCmGCTotal
Sex, n (%) Male 0 (0) 3 (60.) 3 (1) 
Female 366 (100) 53 (100) 2 (40) 421 (99) 
Total 366 (100) 53 (100) 5 (100) 424 (100) 
Age, years n 366 53 424 
Mean±SD 52.0±9.3 54.9±11.1 62.4±5.5 52.5±9.6 
Median 52.0 55.0 64.0 52.5 
Min-max 22.0–77.0 27.0–90.0 55.0–69.0 22.0–90.0 
Weight, kg n 366 53 424 
Mean±SD 60.2±10.1 60.6±10.7 59.1±10.3 60.2±10.2 
Median 59.0 60.0 59.7 59.0 
Min-max 41.0–130.0 38.5–87.8 49.0–74.4 38.5–130.0 
Duration of disease, months n 366 53 424 
Mean±SD 5.9±18.8 30.5±44.2 47.6±88.9 9.5±26.0 
Median 3.6 6.4 3.6 3.7 
Min-max 0.1–219.6 0.3–234.2 1.7–205.9 0.1–234.2 
Hormone receptor status, n (%) ER+/PR+ 149 (41) 17 (32)  166 (40) 
ER+/PR− 73 (20) 13 (25)  86 (21) 
ER-/PR+ 7 (2) 1 (2) N/A 8 (2) 
ER−/PR− 135 (37) 20 (38)  155 (37) 
Unknown 2 (1) 2 (4)  4 (1) 
Total 366 (100) 53 (100)  419 (100) 
Menopause, n (%) (only for females) Premenopause 107 (29) 8 (15)  115 (27) 
Postmenopause 199 (54) 37 (70) n/a 236 (56) 
Unknown 60 (16) 8 (15)  68 (16) 
Total 366 (100) 53 (100)  419 (100) 
Baseline NYHA Functional Class, n (%) (if available) 103 (43) 11 (34) 0 (0) 114 (41) 
II 1 (<1) 0 (0) 0 (0) 1 (<1) 
III 0 (0) 0 (0) 0 (0) 0 (0) 
IV 0 (0) 0 (0) 0 (0) 0 (0) 
Unknown 138 (57) 21 (66) 5 (100) 164 (59) 
Total 242 (100) 32 (100) 5 (100) 279 (100) 
Baseline LVEF, % (if available) 242 32 279 
Mean±SD 65.7±5.0 64.6±6.0 66.0±7.2 65.5±5.2 
Median 66 63 64 65 
Min-max 42–79 50–76 57–76 42–79 
ParameterCategoryIndications
eBCmBCmGCTotal
Sex, n (%) Male 0 (0) 3 (60.) 3 (1) 
Female 366 (100) 53 (100) 2 (40) 421 (99) 
Total 366 (100) 53 (100) 5 (100) 424 (100) 
Age, years n 366 53 424 
Mean±SD 52.0±9.3 54.9±11.1 62.4±5.5 52.5±9.6 
Median 52.0 55.0 64.0 52.5 
Min-max 22.0–77.0 27.0–90.0 55.0–69.0 22.0–90.0 
Weight, kg n 366 53 424 
Mean±SD 60.2±10.1 60.6±10.7 59.1±10.3 60.2±10.2 
Median 59.0 60.0 59.7 59.0 
Min-max 41.0–130.0 38.5–87.8 49.0–74.4 38.5–130.0 
Duration of disease, months n 366 53 424 
Mean±SD 5.9±18.8 30.5±44.2 47.6±88.9 9.5±26.0 
Median 3.6 6.4 3.6 3.7 
Min-max 0.1–219.6 0.3–234.2 1.7–205.9 0.1–234.2 
Hormone receptor status, n (%) ER+/PR+ 149 (41) 17 (32)  166 (40) 
ER+/PR− 73 (20) 13 (25)  86 (21) 
ER-/PR+ 7 (2) 1 (2) N/A 8 (2) 
ER−/PR− 135 (37) 20 (38)  155 (37) 
Unknown 2 (1) 2 (4)  4 (1) 
Total 366 (100) 53 (100)  419 (100) 
Menopause, n (%) (only for females) Premenopause 107 (29) 8 (15)  115 (27) 
Postmenopause 199 (54) 37 (70) n/a 236 (56) 
Unknown 60 (16) 8 (15)  68 (16) 
Total 366 (100) 53 (100)  419 (100) 
Baseline NYHA Functional Class, n (%) (if available) 103 (43) 11 (34) 0 (0) 114 (41) 
II 1 (<1) 0 (0) 0 (0) 1 (<1) 
III 0 (0) 0 (0) 0 (0) 0 (0) 
IV 0 (0) 0 (0) 0 (0) 0 (0) 
Unknown 138 (57) 21 (66) 5 (100) 164 (59) 
Total 242 (100) 32 (100) 5 (100) 279 (100) 
Baseline LVEF, % (if available) 242 32 279 
Mean±SD 65.7±5.0 64.6±6.0 66.0±7.2 65.5±5.2 
Median 66 63 64 65 
Min-max 42–79 50–76 57–76 42–79 

eBC, early breast cancer; mBC, metastatic breast cancer; mGC, metastatic gastric cancer; N/A, not applicable; n/a, not available; NYHA, New York Heart Association.

Treatment Pattern

The mean (StD) treatment duration was 142.0 (40.4) days (range 1–196 days) for eBC patients, 139.1 (50.6) days (range 1–196 days) for mBC patients, and 82.4 (75.7) days (range 1–195 days) for mGC patients. Most patients (414, 97.6%) received the treatment every 3 weeks and 10 (2.4%) every week. Among those with treatment every 3 weeks, the mean (StD) number of cycles was 7.2 (1.9), the mean cumulative SB3 dose 2,705.3 (806.6) mg, and the mean dose per cycle 377.6 (64.8) mg. Among those on weekly treatment, the mean number of cycles was 13.6 (2.9), the mean cumulative dose 2,327.3 (879.1) mg, and the mean dose per cycle 165.7 (41.7) mg.

Comorbidities

Overall, 209 patients (49.3) had comorbidities, with hypertension (20.8%), hyperlipidemia (12.5%), and diabetes mellitus (9.7%) being the most frequent (online suppl. Table A4). Renal dysfunction was reported by 4 patients (0.9%), including 3 with chronic kidney disease of whom 2 required dialysis (0.5%). Liver dysfunction was reported by 13 patients (3.1%), including 8 patients with chronic hepatitis or cirrhosis of whom 7 had hepatitis B and 1 had alcoholic hepatitis.

Treatment History including Surgery, Radiation Therapy, and Drug Therapy

Overall, 208 patients (49.1%) had a history of surgical procedures, comprising breast conserving surgery (29.2%), mastectomy (18.9%), central venous catheterization and gastrectomy (0.7%), breast reconstruction (0.5%), and cancer surgery and lymphadenectomy (0.2%), respectively. Twenty-nine patients (6.8%) had prior radiation therapy. Previous drug therapy comprised antineoplastic and immunomodulating agents in 208 patients (49.1%) and endocrine therapy in 5 patients (1.2%).

Concomitant Medications

Among the enrolled patients, 360 (84.9%) received concomitant medications (online suppl. Table A5). The majority received antineoplastic and immunomodulating agents (75.7%). Drugs for acid-related disorders and antihistamines were used by 33.5% and 31.4%, respectively.

Safety Evaluation

Of 419 BC patients in the safety evaluation, 158 (37.7%) reported one or more AEs, 57 reported ADRs (13.6%, 135 events), 21 reported SAEs (5.0%, 43 events), and 7 reported SADRs (1.7%, 14 events) as shown in Table 2. The majority of patients with AEs had mild AEs (152, 36.3%). Frequently reported AEs (>5%) were diarrhea (9.3%), alopecia (9.1%), anemia (6.7%), and nausea (5.7%) (Table 2). AESIs were reported for 60 (14.3%) patients, with hemotoxicity in 43 patients (10.3%) and pulmonary events in 10 patients (2.4%) being the most frequent (Table 2). SADRs were reported for 7 (1.7%) patients and comprised diarrhea in 3 patients (0.7%, 6 events), followed by hypotension (1 patient [0.2%], 2 events), and abdominal pain, abdominal discomfort, pyelonephritis acute, weight decreased, loss of consciousness, and congestive cardiomyopathy (1 patient [0.2%] each). Treatment was temporarily suspended in 14 (8.9%) patients with an AE and completely discontinued in 7 (4.4%). Most patients with an AE (141, 89.2%) had no change in treatment schedule. One patient had a SAE associated with death. This SAE was septic shock and considered by the investigator to be unrelated to SB3.

Table 2.

Safety in BC patients by treatment group

ParameterSB3±CT, N = 180SB3+PTZ±CT, N = 239Switch, N = 59Total, N = 419
AEs 30 (16.7) 128 (53.6) 12 (20.3) 158 (37.7) 
 Mild 27 (15.0) 125 (52.3) 12 (20.3) 152 (36.3) 
 Moderate 5 (2.8) 28 (11.7) 0 (0.0) 33 (7.9) 
 Severe 1 (0.6) 4 (1.7) 0 (0.0) 5 (1.2) 
Frequently reported AEs* 1 (0.6) 77 (32.2) 2 (3.4) 78 (18.6) 
 Diarrhea 0 (0.0) 39 (16.3) 1 (1.7) 39 (9.3) 
 Alopecia 0 (0.0) 38 (15.9) 0 (0.0) 38 (9.1) 
 Anemia 0 (0.0) 28 (11.7) 0 (0.0) 28 (6.7) 
 Nausea 1 (0.6) 23 (9.6) 1 (1.7) 24 (5.7) 
AESIs 7 (3.9) 53 (22.2) 2 (3.4) 60 (14.3) 
 Significant LVEF decrease 0 (0.0) 2 (0.8) 0 (0.0) 2 (0.5) 
 CHF 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 
 Cardiac dysfunction 0 (0.0) 2 (0.8) 0 (0.0) 2 (0.5) 
 Infusion-related reactions 3 (1.7) 13 (5.4) 0 (0.0) 16 (3.8) 
 Hemotoxicity 3 (1.7) 40 (16.7) 1 (1.7) 43 (10.3) 
 Pulmonary events 1 (0.6) 9 (3.8) 1 (1.7) 10 (2.4) 
ADRs 12 (6.7) 45 (18.8) 3 (5.1) 57 (13.6) 
SADRs 0 (0.0) 7 (2.9) 0 (0.0) 7 (1.7) 
 Diarrhea 0 (0.0) 3 (1.3) 0 (0.0) 3 (0.7) 
 Abdominal discomfort 0 (0.0) 1 (0.4) 0 (0.0) 1 (0.2) 
 Abdominal pain 0 (0.0) 1 (0.4) 0 (0.0) 1 (0.2) 
 Congestive cardiomyopathy 0 (0.0) 1 (0.4) 0 (0.0) 1 (0.2) 
 Hypotension 0 (0.0) 1 (0.4) 0 (0.0) 1 (0.2) 
 Loss of consciousness 0 (0.0) 1 (0.4) 0 (0.0) 1 (0.2) 
 Pneumonia 0 (0.0) 1 (0.4) 0 (0.0) 1 (0.2) 
 Weight decreased 0 (0.0) 1 (0.4) 0 (0.0) 1 (0.2) 
SAEs 3 (1.7) 18 (7.5) 1 (1.7) 21 (5.0) 
 Death 0 (0.0) 1 (0.4) 0 (0.0) 1 (0.2) 
ParameterSB3±CT, N = 180SB3+PTZ±CT, N = 239Switch, N = 59Total, N = 419
AEs 30 (16.7) 128 (53.6) 12 (20.3) 158 (37.7) 
 Mild 27 (15.0) 125 (52.3) 12 (20.3) 152 (36.3) 
 Moderate 5 (2.8) 28 (11.7) 0 (0.0) 33 (7.9) 
 Severe 1 (0.6) 4 (1.7) 0 (0.0) 5 (1.2) 
Frequently reported AEs* 1 (0.6) 77 (32.2) 2 (3.4) 78 (18.6) 
 Diarrhea 0 (0.0) 39 (16.3) 1 (1.7) 39 (9.3) 
 Alopecia 0 (0.0) 38 (15.9) 0 (0.0) 38 (9.1) 
 Anemia 0 (0.0) 28 (11.7) 0 (0.0) 28 (6.7) 
 Nausea 1 (0.6) 23 (9.6) 1 (1.7) 24 (5.7) 
AESIs 7 (3.9) 53 (22.2) 2 (3.4) 60 (14.3) 
 Significant LVEF decrease 0 (0.0) 2 (0.8) 0 (0.0) 2 (0.5) 
 CHF 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 
 Cardiac dysfunction 0 (0.0) 2 (0.8) 0 (0.0) 2 (0.5) 
 Infusion-related reactions 3 (1.7) 13 (5.4) 0 (0.0) 16 (3.8) 
 Hemotoxicity 3 (1.7) 40 (16.7) 1 (1.7) 43 (10.3) 
 Pulmonary events 1 (0.6) 9 (3.8) 1 (1.7) 10 (2.4) 
ADRs 12 (6.7) 45 (18.8) 3 (5.1) 57 (13.6) 
SADRs 0 (0.0) 7 (2.9) 0 (0.0) 7 (1.7) 
 Diarrhea 0 (0.0) 3 (1.3) 0 (0.0) 3 (0.7) 
 Abdominal discomfort 0 (0.0) 1 (0.4) 0 (0.0) 1 (0.2) 
 Abdominal pain 0 (0.0) 1 (0.4) 0 (0.0) 1 (0.2) 
 Congestive cardiomyopathy 0 (0.0) 1 (0.4) 0 (0.0) 1 (0.2) 
 Hypotension 0 (0.0) 1 (0.4) 0 (0.0) 1 (0.2) 
 Loss of consciousness 0 (0.0) 1 (0.4) 0 (0.0) 1 (0.2) 
 Pneumonia 0 (0.0) 1 (0.4) 0 (0.0) 1 (0.2) 
 Weight decreased 0 (0.0) 1 (0.4) 0 (0.0) 1 (0.2) 
SAEs 3 (1.7) 18 (7.5) 1 (1.7) 21 (5.0) 
 Death 0 (0.0) 1 (0.4) 0 (0.0) 1 (0.2) 

ADRs, adverse drug reactions; AEs, adverse events; AESIs, adverse events of special interest; CHF, congestive heart failure; CT, chemotherapy; LVEF, left ventricular ejection fraction; N, number of subjects in subgroup in the analysis set; N/A, not applicable; PTZ, pertuzumab; SADRs, serious adverse reactions; SAEs, serious adverse events.

Data shown as n (%).

*>5% in any group, p value for difference between SB3 ± CT versus SB3+PTZ ± CT.

A logistic regression analysis of all ADRs versus patient baseline characteristics showed no impact of age, comorbidities, menopause, ER status, surgery, concomitant medication, or PTZ-treatment in both patients with eBC and mBC. Only prior drug use correlated with ADRs in patients with eBC (0.255, 95% CI 0.075–0.872; mBC 0.525, 95% CI 0.029–9.603) (online suppl. Table A6).

Safety Evaluation by Treatment Groups

Among BC patients, proportions of reported AEs, ADRs, SAEs, and SADRs were numerically higher in the group treated with SB3 and PTZ (53.6% AEs, 18.8% ADRs, 7.5% SAEs, 2.9% SADRs) compared to the group treated with SB3 (16.7% AEs, 6.7% ADRs, 1.7% SAEs, 0.0% SADRs) (Table 2). Mean of percent changes from baseline of LVEF is comparable between the two treatment groups (−5.2 and −3.2, respectively; p = 0.3192) as shown in Figure 2. Among the 59 patients who switched from other TRZ products to SB3, 12 patients (20.3%) reported AEs, 3 patients (5.1%) reported ADRs, 2 patients (3.4%) reported AESIs and one SAE was reported. No SADR was reported (Table 2).

Fig. 2.

Plot of individual change from baseline of LVEF by treatment group. a SB3 ± CT (N = 65). b SB3+PTZ ± CT (N = 32). CT, chemotherapy; LVEF, left ventricular ejection fraction; PTZ, pertuzumab.

Fig. 2.

Plot of individual change from baseline of LVEF by treatment group. a SB3 ± CT (N = 65). b SB3+PTZ ± CT (N = 32). CT, chemotherapy; LVEF, left ventricular ejection fraction; PTZ, pertuzumab.

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Effectiveness Evaluation in eBC and mBC Patients

Among patients who had been assessed for overall response, objective response was reported for 124 (ORR 82.7%) eBC patients (CR 4.7%, PR 78.0%) and 18 (38.3%) mBC patients (CR 4.3%, PR 34.0%). Among the 96 eBC patients who underwent BC-related surgery during the study and had confirmed assessments of pathological tumor response, 62 (64.6%) had tpCR or bpCR (40 tpCR and 22 bpCR, respectively) and 34 (35.4%) had neither tpCR nor bpCR. In 69 patients who underwent BC-related surgery, pathological tumor response assessments could not be confirmed (Table 3). Among patients with confirmed hormone receptor status, pCR rate (tpCR or bpCR) was significantly lower in hormone receptor positive eBC patients compared to hormone receptor negative patients (55.4 vs. 77.5%, p = 0.0253) (Table 4).

Table 3.

Effectiveness

ParameterCategoryn (%), 95% CI
eBCmBC
Best overall response CR 7 (4.7) 1.9–9.4 2 (4.3) 0.5–14.5 
PR 117 (78.0) 70.5–84.4 16 (34.0) 20.9–49.3 
SD 25 (16.7) 11.1–23.6 25 (53.2) 38.1–67.9 
PD 1 (0.7) 0.0–3.7 4 (8.5) 2.4–20.4 
Not evaluable 0 (0.0) 0.0–2.4 0 (0.0) 0.0–7.6 
Total 150 (100.0)  47 (100.0)  
Pathological response tpCR or bpCR 62 (37.6) 30.2–45.4 N/A 
tpCR 40 (24.2) 17.9–31.5 
bpCR 22 (13.3) 8.6–19.5 
Neither tpCR nor bpCR 34 (20.6) 14.7–27.6 
Unknown 69 (41.8) 34.2–49.7 
Total 165 (100.0)  
Recurrence Yes 0 (0.0) 0.0–3.2 
No 113 (100.0) 96.8–100.0 
Total 113 (100.0)  
ParameterCategoryn (%), 95% CI
eBCmBC
Best overall response CR 7 (4.7) 1.9–9.4 2 (4.3) 0.5–14.5 
PR 117 (78.0) 70.5–84.4 16 (34.0) 20.9–49.3 
SD 25 (16.7) 11.1–23.6 25 (53.2) 38.1–67.9 
PD 1 (0.7) 0.0–3.7 4 (8.5) 2.4–20.4 
Not evaluable 0 (0.0) 0.0–2.4 0 (0.0) 0.0–7.6 
Total 150 (100.0)  47 (100.0)  
Pathological response tpCR or bpCR 62 (37.6) 30.2–45.4 N/A 
tpCR 40 (24.2) 17.9–31.5 
bpCR 22 (13.3) 8.6–19.5 
Neither tpCR nor bpCR 34 (20.6) 14.7–27.6 
Unknown 69 (41.8) 34.2–49.7 
Total 165 (100.0)  
Recurrence Yes 0 (0.0) 0.0–3.2 
No 113 (100.0) 96.8–100.0 
Total 113 (100.0)  

bpCR, breast pathological complete response; CI, confidence interval; CR, complete response; eBC, early breast cancer; mBC, metastatic breast; N/A, not applicable; PD, progressive disease; PR, partial response; SD, stable disease; tpCR, total pathologic complete response in breast and axillary nodes.

Data shown as n (%).

Table 4.

pCR rates depending on hormone receptor status*

ParameterHormone receptor positive, N = 56Hormone receptor negative, N = 40p valueTotal, N = 96
tpCR or bpCR 31 (55.4) 31 (77.5) 0.0253 62 (64.6) 
Neither tpCR nor bpCR 25 (44.6) 9 (22.5)  34 (35.4) 
ParameterHormone receptor positive, N = 56Hormone receptor negative, N = 40p valueTotal, N = 96
tpCR or bpCR 31 (55.4) 31 (77.5) 0.0253 62 (64.6) 
Neither tpCR nor bpCR 25 (44.6) 9 (22.5)  34 (35.4) 

Hormone receptor status was determined as reported by local institution.

bpCR, breast pathological complete response; ER, estrogen receptor; PR, progesterone receptor; tpCR, total pathologic complete response in breast and axillary nodes.

Switch refers to group of patients who were previously treated with another trastuzumab besides SB3.

*Hormone receptor positive = ER and/or PR positive; hormone receptor negative = ER and PR negative.

Data shown as n (%).

Descriptive Summary of mGC Patients’ Outcome

Among 5 patients with mGC, 3 had comorbidities, comprising chronic hepatitis B, diabetes mellitus, arthritis, and asthma. All received concomitant medications, mostly antineoplastic agents, antiemetics or antinauseants, and drugs for acid-related disorders. Three patients reported AEs (diarrhea, nausea, and malignant neoplasm progression), all of them considered moderate. Among 4 mGC patients assessed for overall response, two had CR.

This study collected first real-world data of SB3 TRZ biosimilar from Korea in 419 patients with eBC or mBC and 5 patients with mGC. The study included patients, who were TRZ-naïve or switched from another TRZ product, and patients who received SB3 as single anti-HER2 therapy or together with PTZ as dual anti-HER2 therapy. Overall, this study demonstrated that safety and efficacy of SB3 are consistent with that of TRZ in the real-world practice setting.

No new safety signals were detected in this study. Frequently reported AEs (diarrhea, alopecia, anemia, and nausea) are consistent with previous clinical trials of TRZ in eBC [27‒29], mBC [5, 30], and mGC [2], comparative trials of TRZ and TRZ biosimilars [31], and the labels of TRZ and SB3 [17, 32]. In general, TRZ does not increase the overall frequency or severity of noncardiac adverse effects associated with CT regimens. The reported SADRs are consistent with the known safety profile and reflected in the product information [17, 20‒22] except loss of consciousness that was reported along with hypotension. However, hypotension is already included in the label as infusion-related reaction and may have been the underlying reason for loss of consciousness. Furthermore, concomitant medication was reported as related factor to loss of consciousness, the patient recovered without sequelae, and treatment was continued as planned. Comparable cardiac safety profiles of SB3 (as monotherapy or together with PTZ) and TRZ have been previously demonstrated in clinical trials and real-world settings [24, 31, 33‒36]. In this 4-year PMS study, two events of decreased LVEF but no CHF or cardiac dysfunction were reported, confirming the cardiac safety of SB3. Among the 60 patients who switched from another TRZ product to SB3, no SADR and no notable safety signals were reported.

Unlike the PMS study for TRZ conducted in Korea [37], this PMS study for SB3 included patients treated with dual SB3 and PTZ blockade. Since 2012, PTZ combined with TRZ and CT has been increasingly adopted [35], and the TCHP regimen (Taxotere®+Carboplatin+Herceptin®+Pertuzumab) became the most common neoadjuvant therapy in Korea. Also in this study, TCHP was used frequently in the neoadjuvant setting (up to 70.7%) while SB3 monotherapy was used mostly in the adjuvant setting. These differences in treatment setting and concomitant medication may have contributed to higher AEs for SB3 and PTZ compared to those on SB3 alone (Table 2). The Korean PMS data reported for PTZ also demonstrated that PTZ combination had higher incidence rates of AEs and SAEs (81.4% and 19.2%, respectively) compared to the Korean PMS data reported for TRZ when PTZ was not available (37.7% and 0.7%, respectively) [37, 38].

In terms of effectiveness, the 82.7% ORR among eBC patients treated with SB3 or SB3 plus PTZ (alone or with CT) in this study is comparable with the ORR in eBC patients of the NeoSphere trial treated with TRZ or TRZ plus PTZ (with CT) [39]. The pCR among eBC patients in this PMS is higher than that for patients in the NeoSphere trial and comparable with that in the TRYPHAENA study with TRZ plus PTZ (plus anthracycline-containing or anthracycline-free CT) [39, 40]. In mBC, ORR was 38.3% which is slightly lower than in phase III studies of TRZ and CT in mBC patients (50.2–57.4%) [6, 41]. However, patients in those studies had not received previous CT for metastatic disease, whereas this PMS study enrolled patients with or without prior CT for their mBC which may explain the somewhat lower ORR among mBC patients. Effectiveness of SB3 in terms of pCR was greater in hormone receptor negative than hormone receptor positive eBC patients (77.5% and 55.4%, respectively). These findings support earlier real-world and clinical trial evidence suggesting that positive hormone receptor status is associated with lower response [35, 42] and that hormone receptor status could be a predictive factor for pCR achievement. For mGC patients, the study was not sufficiently powered to evaluate efficacy. The consistency of SB3 results in this PMS study with clinical data of SB3 and TRZ supports that SB3 is highly similar to the reference product in terms of safety and effectiveness [14‒16, 41, 43].

Approved biosimilars can reduce treatment costs and increase patient access [14‒16, 41, 43, 44]. TRZ has changed the natural history of BC, but its high costs (estimated to be at least US 70,000 USD for 1 year of therapy in the USA) represent a barrier for patient access to treatment [45]. TRZ biosimilars including SB3 provide the opportunity for expanded utilization of HER2-targeted therapy at a lower cost than the reference product [15, 41, 43, 44].

This study is limited by its heterogeneous nature, small sample size, and relatively short follow-up period. In addition, the efficacy evaluation was not powered, and the subgroup analyses were not preplanned.

This study reports first real-world evidence about the safety and effectiveness of the TRZ biosimilar SB3 in patients with mBC, eBC, or mGC in Korea. No new safety signals have been detected and SB3 was well tolerated in patients who were TRZ-naïve or switched from other TRZ products or treated in combination with PTZ. The results were comparable to previous clinical data of TRZ, and further support that SB3 is highly similar to reference TRZ.

We appreciate all the patients and co-investigators for their participation and contribution to this study. Medical writing support was provided by Walter Fürst, SFL Regulatory Affairs & Scientific Communications, Switzerland, and funded by Samsung Bioepis.

The final study protocol and the informed consent form were approved by the local Independent Ethics Committees (IECs) or Institutional Review Boards (IRBs) of the study sites (online suppl. Table A1, committees/boards do not have separate names or reference numbers). The study was conducted in accordance with applicable local regulatory requirements and laws, the Declaration of Helsinki (1996), and the International Council for Harmonization Good Clinical Practice guidelines. Written informed consent was obtained from each subject before enrollment.

The study was sponsored by Samsung Bioepis. ChangWan Jeon, Min Ho Park, Su Hwan Kang, Sung-Bae Kim, Nam-Sun Paik, Ilkyun Lee, Seung Ki Kim, Eun Young Kim, Gil Soo Son, Young Bum Yoo, and Kyung-Hee Lee have received financial support for research from Samsung Bioepis. Jeongsoo Shin, Yechan Yoon, and Harah Jang are employees of Samsung Bioepis. Sung-Bae Kim received research funding from Novartis, Sanofi-Aventis, and DongKook Pharm Co., and participated in consultant in advisory boards of Novartis, AstraZeneca, Lilly, Dae Hwa Pharmaceutical Co. Ltd, ISU Abxis, Beigene, OBI Pharma and Daiichi-Sankyo. Sung-Bae Kim holds Stocks in Genopeaks, NeogeneTC. Changwan Jeon received speaker honoraria from Pfizer and participated in advisory boards of Eisai.

The study was sponsored by Samsung Bioepis.

Jeongsoo Shin and Harah Jang contributed to study conception and design. ChangWan Jeon, Min Ho Park, Kang Su Hwan, Sung-Bae Kim, Nam-Sun Paik, Ilkyun Lee, Seung Ki Kim, Eun Young Kim, Gil Soo Son, Young Bum Yoo, and Kyung-Hee Lee served as investigators in this study and contributed to acquisition of data. ChangWan Jeon, Min Ho Park, Kang Su Hwan, Sung-Bae Kim, Nam-Sun Paik, Ilkyun Lee, Seung Ki Kim, Eun Young Kim, Gil Soo Son, Young Bum Yoo, Kyung-Hee Lee, Jeongsoo Shin, Sungil Ju, and Harah Jang contributed to acquisition of data, analysis, and interpretation/reporting of data, drafting the manuscript, and revising it critically for important intellectual content. ChangWan Jeon acted as coordinating investigator of this study and provided important intellectual contributions to the study.

Additional Information

Trial registration number: SB3-KO41-PMS.

Data are not publicly available for protection of sensitive personal data. Further inquiries can be directed to the corresponding author.

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