This secondary analysis of a randomized clinical trial compares long-term safety and efficacy of SB3, a trastuzumab biosimilar, with reference trastuzumab for treatment of patients with ERBB2-positive early or locally advanced breast cancer.
Key Points
Question
Does SB3, a trastuzumab biosimilar, have long-term cardiac safety and efficacy comparable to those of reference trastuzumab for treatment of patients with ERBB2-positive early or locally advanced breast cancer?
Findings
In this secondary analysis of a randomized clinical trial comparing outcomes of SB3 and reference trastuzumab in 538 patients, long-term cardiac safety and efficacy of SB3 and reference trastuzumab were comparable after up to 6 years of follow-up.
Meaning
These findings support the similarity of SB3 and reference trastuzumab.
Abstract
Importance
Trastuzumab has been the standard of care for the treatment of patients with ERBB2-positive breast cancer; however, cardiac events have been reported. This long-term follow-up study provides clinical evidence supporting the similarity of a trastuzumab biosimilar (SB3) to reference trastuzumab (TRZ).
Objective
To compare cardiac safety and efficacy between SB3 and TRZ for patients with ERBB2-positive early or locally advanced breast cancer after up to 6 years of follow-up.
Design, Setting, and Participants
This prespecified secondary analysis of a randomized clinical trial, conducted from April 2016 to January 2021, included patients with ERBB2-positive early or locally advanced breast cancer from a multicenter double-blind, parallel-group, equivalence phase 3 randomized clinical trial of SB3 vs TRZ with concomitant neoadjuvant chemotherapy who completed neoadjuvant and adjuvant treatment.
Interventions
In the original trial, patients were randomized to either SB3 or TRZ with concomitant neoadjuvant chemotherapy for 8 cycles (4 cycles of docetaxel followed by 4 cycles of fluorouracil, epirubicin, and cyclophosphamide). After surgery, patients continued SB3 or TRZ monotherapy for 10 cycles of adjuvant treatment per previous treatment allocation. Following neoadjuvant and adjuvant treatment, patients were monitored for up to 5 years.
Main Outcomes and Measures
The primary outcomes were the incidence of symptomatic congestive heart failure and asymptomatic, significant decrease in left ventricular ejection fraction (LVEF). The secondary outcomes were event-free survival (EFS) and overall survival (OS).
Results
A total of 538 female patients were included (median age, 51 years [range, 22-65 years]). Baseline characteristics were comparable between the SB3 and TRZ groups. Cardiac safety was monitored for 367 patients (SB3, n = 186; TRZ, n = 181). Median follow-up was 68 months (range, 8.5-78.1 months). Asymptomatic, clinically significant LVEF decreases were rarely reported (SB3, 1 patient [0.4%]; TRZ, 2 [0.7%]). No patient experienced symptomatic cardiac failure or death due to a cardiovascular event. Survival was evaluated for the 367 patients in the cardiac safety cohort and an additional 171 patients enrolled after a protocol amendment (538 patients [SB3, n = 267; TRZ, n = 271]). No difference was observed in EFS or OS between treatment groups (EFS: hazard ratio [HR], 0.84; 95% CI, 0.58-1.20; P = .34; OS: HR, 0.61; 95% CI, 0.36-1.05; P = .07). Five-year EFS rates were 79.8% (95% CI, 74.8%-84.9%) in the SB3 group and 75.0% (95% CI, 69.7%-80.3%) in the TRZ group, and OS rates were 92.5% (95% CI, 89.2%-95.7%) in the SB3 group and 85.4% (95% CI, 81.0%-89.7%) in the TRZ group.
Conclusions and Relevance
In this secondary analysis of a randomized clinical trial, SB3 demonstrated cardiac safety and survival comparable to those of TRZ after up to 6 years of follow-up in patients with ERBB2-positive early or locally advanced breast cancer.
Trial Registration
ClinicalTrials.gov Identifier: NCT02771795
Introduction
Trastuzumab is a monoclonal antibody binding to the extracellular juxtamembrane domain of ERBB2. Trastuzumab has been the standard of care for the treatment of patients with ERBB2-positive breast cancer and ERBB2-positive advanced gastric cancer due to its effectiveness and favorable toxicity profile.1 Although trastuzumab does not increase the risk of chemotherapy-related adverse events, cardiac events have been reported more frequently with trastuzumab.2,3,4 Thus, routine cardiac monitoring is recommended for patients.2,3,4,5,6
SB3 is a widely approved trastuzumab biosimilar. In the phase 3 SB3-G31-BC trial,7 patients with ERBB2-positive early and locally advanced breast cancer were randomized to receive either SB3 or reference trastuzumab (TRZ) with a concomitant chemotherapy regimen of docetaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide as neoadjuvant treatment. Efficacy of SB3 was equivalent to that of TRZ with respect to the risk ratio of breast pathological complete response (bpCR) rates. However, the 95% CI of the bpCR risk difference exceeded the upper limit of the predefined equivalence margin.7 The Committee for Medicinal Products for Human Use considered that the observed difference in bpCR could have been confounded by patients who were given TRZ with downward drift in antibody-dependent cell-mediated cytotoxic (ADCC) activity for a certain period in the phase 3 trial and concluded that the similarity between SB3 and TRZ in terms of efficacy was sufficiently established.8,9 A similar trend was observed in a 3-year follow-up of the phase 3 trial,10 in which a greater event-free survival (EFS) rate was observed with SB3 compared with TRZ. A downward drift observed in ADCC activity of TRZ was a possible factor explaining the difference between the SB3 and TRZ groups.10 Here, we report long-term cardiac safety and survival outcomes among patients from the SB3-G31-BC trial who received SB3 or TRZ for the treatment of ERBB2-positive early or locally advanced breast cancer.
Methods
Study Design and Patients
This study was a prespecified secondary analysis of a multicenter phase 3 randomized clinical trial (April 2014 to February 2017),7 in which patients with ERBB2-positive early or locally advanced breast cancer were randomly assigned to receive either SB3 or TRZ with concomitant neoadjuvant chemotherapy for 8 cycles (NCT02149524). Randomization was stratified by breast cancer type (operable vs locally advanced) and hormone receptor status (estrogen receptor [ER] positive and/or progesterone receptor [PR] positive vs ER and PR negative). A block stratified randomization method was used with dynamic block allocation by country. After surgery, patients continued SB3 or TRZ monotherapy for 10 cycles of adjuvant treatment as per previous treatment allocation. Upon completion of the neoadjuvant and adjuvant treatment, patients from preselected countries were eligible to participate in the treatment-free follow-up study, SB3-G31-BC-E, after providing written informed consent (NCT02771795). In this study (April 2016 to January 2021), patients were monitored for 5 years after the last administration of the investigational product (SB3 or TRZ) in the main phase 3 trial unless they were lost to follow-up, withdrew informed consent, or died. Follow-up visits were recommended every 6 months for the first 2 years, then once yearly for 3 years. During the visits, physical examination including clinical breast examination, mammography, left ventricular ejection fraction (LVEF) measurement (2-dimensional echocardiography or multigated acquisition scan), and monitoring of cardiac events were performed according to the routine care setting based on local guidelines. The study protocol and its amendments were reviewed and approved by independent ethics committees or institutional review boards at participating institutions. The study was performed in accordance with the International Council for Harmonisation Good Clinical Practice guidelines and the Declaration of Helsinki.11 This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.
The study end date was earlier than planned due to an increased risk of exposure to SARS-CoV-2 as the patients were required to visit the sites for cardiac assessments. Based on a COVID-19–pertaining risk assessment, considering the observational nature of the study and the life-threatening risk associated with COVID-19 among the study population, the study sponsor concluded that the risk to the patients’ safety outweighed the benefit of continuing the remaining year of the study. This early termination of the SB3-G31-BC-E study was approved by the European Medicines Agency on November 26, 2020.
To collect survival data from a larger patient population, the protocol (Supplement 1) was amended to include additional patients who had received treatment in the main phase 3 trial but initially were not included in the follow-up study. For these patients, data were collected prospectively from the date of enrollment to the follow-up study, whereas the data before the date of enrollment to the follow-up study were obtained retrospectively. In case data could not be collected prospectively due to death or loss to follow-up, a waiver of informed consent was requested for retrospective data collection from medical records when applicable and in accordance with national regulations and local ethics guidelines. If the requested waiver of informed consent for the deceased patient was rejected, the next of kin was asked to give consent in accordance with national regulations.
Patient race and ethnicity were based on self-report and included in the analysis captured information. Race categories included Asian, White, and other (self-reported information did not allow for a more detailed specification of the “other” category).
Study End Points
The primary end points of this study were defined as the incidence of symptomatic congestive heart failure (New York Heart Association functional class II-IV, confirmed by a cardiologist and accompanied by a significant LVEF decrease) and the incidence of asymptomatic significant LVEF decrease, defined as a decrease of 10% or more from baseline with a resulting value less than 50%. The secondary end points included the incidence of any death due to a cardiovascular event and other significant cardiac conditions, such as acute myocardial infarction, severe arrhythmia, ischemic heart disease, or valvular dysfunction; EFS, defined as time from the date of randomization to the date of disease recurrence; progression (local, regional, distant, or contralateral) or death; and overall survival (OS), defined as time from the date of randomization to the date of death from any cause. Post hoc subgroup analyses assessed EFS and OS by bpCR, hormone receptor status, and ADCC drift status of TRZ.
Statistical Analysis
Two cohorts were defined. The first cohort consisted of patients who had completed the main phase 3 trial and were enrolled in the follow-up study according to the protocol (Supplement 1). The second cohort consisted of patients who had received the treatment in the main phase 3 trial but were enrolled in the follow-up study at a later stage (ie, after the protocol amendment). Cardiac safety data were collected for only the first cohort. Survival analyses, including post hoc analyses, were conducted based on the combined set of the first and second cohort. The EFS and OS rates were estimated using the Kaplan-Meier method. Hazard ratios (HRs) with corresponding 95% CIs and P values were estimated using a stratified Cox proportional hazards regression model. As part of the post hoc analyses, the treatment groups were pooled to investigate the correlations between bpCR and EFS and between hormone receptor status and EFS. In patients treated with TRZ, the association between ADCC drift status and EFS was also assessed. Patients who received at least 1 vial of TRZ from a lot associated with a downward drift in ADCC activity during neoadjuvant treatment were labeled as the drifted TRZ subgroup, whereas patients who did not receive a vial of TRZ from a lot associated with a downward drift in ADCC activity were labeled as the nondrifted TRZ subgroup. Detailed statistical considerations related to ADCC activity were previously reported.10
Data were analyzed using SAS, version 9.4 (SAS Institute). All P values were computed from 2-sided tests, and statistical significance was set at P < .05.
Results
Patients and Follow-up
Demographics and baseline disease characteristics were comparable between the SB3 and TRZ groups (Table and eTable 1 in Supplement 2). Of 875 patients randomized in the main phase 3 trial, 538 (61.5%; SB3, n = 267; TRZ, n = 271) were enrolled in the follow-up SB3-G31-BC-E study. The median age of patients was 51 years (range, 22-65 years). All were female; 111 (20.6%) were Asian, 410 (76.2%) were White, and 17 (3.2%) were other race and ethnicity. Among 111 Asian patients, 14 (12.6%) were Indian (eTable 1 in Supplement 2). Of the 538 patients, 367 (SB3, 186 [50.7%]; TRZ, 181 [49.3%]) were enrolled following completion of adjuvant treatment in the main study (first cohort) and 171 were enrolled after the protocol amendment (second cohort). Eleven patients (1.9%; SB3, 6 [1.1%]; TRZ, 5 [0.9%]) were lost to follow-up (Figure 1). Comorbid conditions known to be associated with increased risk of cardiac events are listed in eTable 2 in Supplement 2. The numbers of patients with comorbid conditions were comparable between the 2 groups. Notably, 50 patients in the SB3 group (18.7%) and 56 patients in the TRZ group (20.7%) had hypertension. Ten patients in the SB3 group (3.8%) and 14 in the TRZ group (5.2%) had obesity, and 5 (1.9%) and 9 (3.3%) had diabetes, respectively.
Table. Summary of Demographic and Baseline Disease Characteristics in the Survival Analysis.
| Characteristic | Patients, No. (%) | |||
|---|---|---|---|---|
| SB3 (n = 267) | TRZ (n = 271) | |||
| All | Nondrifted (n = 107) | Drifted (n = 164) | ||
| Age, median (range), y | 51 (27-65) | 52 (22-65) | 52 (22-65) | 53 (22-65) |
| Race | ||||
| Asian | 52 (19.5) | 59 (21.8) | 34 (31.8) | 25 (15.2) |
| White | 207 (77.5) | 203 (74.9) | 67 (62.6) | 136 (82.9) |
| Othera | 8 (3.0) | 9 (3.3) | 6 (5.6) | 3 (1.8) |
| Menopause | 132 (49.4) | 141 (52.0) | 52 (48.6) | 89 (54.3) |
| ECOG performance status | ||||
| 0 | 234 (87.6) | 232 (85.6) | 95 (88.8) | 137 (83.5) |
| 1 | 33 (12.4) | 39 (14.4) | 12 (11.2) | 27 (16.5) |
| >1 | 0 | 0 | 0 | 0 |
| LVEF, mean (SD) | 65.6 (5.0) | 65.4 (5.5) | 66.1 (6.0) | 64.9 (5.1) |
| Breast cancer type | ||||
| Operable | 170 (63.7) | 159 (58.7) | 62 (57.9) | 97 (59.1) |
| Locally advanced | 87 (32.6) | 104 (38.4) | 42 (39.3) | 62 (37.8) |
| Inflammatory | 10 (3.7) | 8 (3.0) | 3 (2.8) | 5 (3.0) |
| Histopathological tumor classification | ||||
| Invasive ductal carcinoma NOS | 257 (96.3) | 261 (96.3) | 103 (96.3) | 158 (96.3) |
| Invasive lobular carcinoma | 5 (1.9) | 4 (1.5) | 0 | 4 (2.4) |
| Other | 5 (1.9) | 6 (2.2) | 4 (3.7) | 2 1.2) |
| Hormone receptor status | ||||
| ER positive, PR positive | 118 (44.2) | 99 (36.5) | 34 (31.8) | 65 (39.6) |
| ER positive, PR negative | 44 (16.5) | 49 (18.1) | 24 (22.4) | 25 (15.2) |
| ER negative, PR positive | 5 (1.9) | 7 (2.6) | 1 (0.9) | 6 (3.7) |
| ER negative, PR negative | 100 (37.5) | 116 (42.8) | 48 (44.9) | 68 (41.5) |
| Clinical T stage | ||||
| cT1 | 1 (0.4) | 2 (0.7) | 1 (0.9) | 1 (0.6) |
| cT2 | 164 (61.4) | 153 (56.5) | 57 (53.3) | 96 (58.5) |
| cT3 | 47 (17.6) | 58 (21.4) | 29 (27.1) | 29 (17.7) |
| cT4 | 55 (20.6) | 58 (21.4) | 20 (18.7) | 38 (23.2) |
| Clinical N stage | ||||
| cN0 | 63 (23.6) | 53 (19.6) | 17 (15.9) | 36 (22.0) |
| cN1 | 140 (52.4) | 138 (50.9) | 57 (53.3) | 81 (49.4) |
| cN2 | 46 (17.2) | 49 (18.1) | 21 (19.6) | 28 (17.1) |
| cN3 | 18 (6.7) | 31 (11.4) | 12 (11.2) | 19 (11.6) |
| Clinical TNM stage | ||||
| 2A | 49 (18.4) | 41 (15.1) | 14 (13.1) | 27 (16.5) |
| 2B | 100 (37.5) | 93 (34.3) | 37 (34.6) | 56 (34.1) |
| 3A | 50 (18.7) | 60 (22.1) | 26 (24.3) | 34 (20.7) |
| 3B | 50 (18.7) | 46 (17.0) | 18 (16.8) | 28 (17.1) |
| 3C | 18 (6.7) | 31 (11.4) | 12 (11.2) | 19 (11.6) |
| Main trial population, No./total No. (%) | ||||
| bpCRb | 137/265 (51.7) | 113/266 (42.5) | 51/104 (49.0) | 62/162 (38.3) |
| tpCRc | 114/247 (46.2) | 91/253 (36.0) | 42/97 (43.3) | 49/156 (31.4) |
Abbreviations: bpCR, pathological complete response in the breast; ECOG, Eastern Cooperative Oncology Group; ER, estrogen receptor; LVEF, left ventricular ejection fraction; NOS, not otherwise specified; PR, progesterone receptor; SB3, trastuzumab biosimilar; tpCR, total pathological complete response; TRZ, reference trastuzumab.
Patients’ self-reported information did not allow for a more detailed specification of other race and ethnicity.
Seven patients with missing data about bpCR were excluded from the analysis.
Thirty-eight patients with missing data about tpCR were excluded from the analysis.
Figure 1. Study Flow Diagram.
SB3 indicates trastuzumab biosimilar and TRZ, reference trastuzumab.
As a result of early termination of the SB3-G31-BC-E study, 353 patients prematurely discontinued the study (SB3, 185 of 267 [69.3%]; TRZ, 168 of 271 [62.0%]). Median follow-up duration from randomization to study discontinuation was 68 months (range, 8.5-78.1 months).
Cardiac Safety
Cardiac safety data were collected for 367 patients. Overall, the cardiac safety profile of patients treated with SB3 was comparable to that of patients treated with TRZ. Symptomatic congestive heart failure was not reported in either the SB3 or the TRZ group. At baseline, median LVEF was 65% (range, 55%-76%) in the SB3 group and 65% (range, 55%-85%) in the TRZ group, and LVEF changes from baseline were comparable between the 2 groups throughout the follow-up period. The lowest median value of LVEF during the follow-up period was 60% (range, 42%-70%) in the SB3 group and 60% (range, 47%-70%) in the TRZ group. Three asymptomatic, significant LVEF decreases were reported during the present study (SB3, 1 patient [0.4%]; TRZ, 2 patients [0.7%]). All 3 events occurred within 2 years after the first administration of the investigational products. No death due to cardiovascular event was reported. One other significant cardiac events, termed “associated with palliative chemotherapy cardiofibrosis,” was reported in the TRZ group.
Survival Outcomes
A total of 538 patients were analyzed for long-term survival outcomes. Comparable EFS was observed between the 2 groups (Figure 2A), with 54 events (20.2%) in the SB3 group and 67 events (24.7%) in the TRZ group (HR, 0.84; 95% CI, 0.58-1.20; P = .34). Five-year EFS rates were 79.8% (95% CI, 74.8%-84.9%) in the SB3 group and 75.0% (95% CI, 69.7%-80.3%) in the TRZ group (a difference of 4.8 percentage points). Furthermore, no significant difference in OS was found, with 22 deaths (8.2%) and 38 deaths (14.0%) reported in the SB3 and TRZ groups, respectively (HR, 0.61; 95% CI, 0.36-1.05; P = .07) (Figure 2B). Five-year OS rates were 92.5% (95% CI, 89.2%-95.7%) in the SB3 group and 85.4% (95% CI, 81.0%-89.7%) in the TRZ group (a difference of 7.1 percentage points). The most common cause of death was breast cancer in both treatment groups (SB3, 19 [7.1%)]; TRZ, 31 [11.4%]). Two deaths due to cardiovascular events were reported (SB3, 1 [0.4%]; TRZ, 1 [0.4%]).
Figure 2. Event-Free Survival and Overall Survival During and After Treatment With Trastuzumab Biosimilar (SB3) or Reference Trastuzumab (TRZ).
Tick marks represent censored patients. Hazard ratios (HRs) with corresponding 95% CIs and P values were estimated using a stratified Cox proportional hazards regression model.
bpCR and Long-term Efficacy
Five-year EFS rates were similar between patients in the SB3 group and patients in the TRZ group who had bpCR. Likewise, patients with residual disease after neoadjuvant treatment had comparable 5-year EFS rates (Figure 3A).
Figure 3. Event-Free Survival Among Patients Who Achieved Pathological Complete Response in the Breast (bpCR) Compared With Patients Who Did Not.
Tick marks represent censored patients. SB3 indicates trastuzumab biosimilar and TRZ, reference trastuzumab.
Patients in the SB3 and TRZ groups were pooled for further analysis. In the pooled group, patients who achieved bpCR had a higher 5-year EFS rate compared with those with residual disease after neoadjuvant treatment (Figure 3B). The HR of EFS comparing patients with bpCR and patients with residual disease was 0.26 (95% CI, 0.14-0.47) among patients with the hormone receptor–negative subtype and 0.72 (95% CI, 0.44-1.20) among patients with the hormone receptor–positive subtype (eTable 3 in Supplement 2).
ADCC and Long-term Efficacy
Of 271 patients in the TRZ group, 164 (60.5%) were in the drifted TRZ subgroup and 107 (39.5%) were in the nondrifted TRZ subgroup during the neoadjuvant treatment period. The drifted TRZ subgroup had an increased risk of events compared with the nondrifted TRZ subgroup (HR, 2.57; 95% CI, 1.28-5.14; P = .008), with 19 patients (17.8%) in the nondrifted TRZ subgroup and 48 (29.3%) in the drifted TRZ subgroup experiencing an event (Figure 4A). A total of 9 deaths (8.4%) in the nondrifted TRZ subgroup and 29 deaths (17.7%) in the drifted TRZ subgroup were reported (HR, 3.87; 95% CI, 1.37-10.93; P = .011) (Figure 4B).
Figure 4. Event-Free Survival and Overall Survival Among Patients Receiving Reference Trastuzumab (TRZ), by Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) Status.
Tick marks represent censored patients. Hazard ratios (HRs) with corresponding 95% CIs and P values were estimated using a stratified Cox proportional hazards regression model. ADCC status was assigned based on occurrence of downward drift of TRZ during the neoadjuvant treatment period. SB3 indicates trastuzumab biosimilar.
The SB3 group and the nondrifted TRZ subgroup were also compared. The HRs for EFS and OS were 1.28 (95% CI, 0.73-2.22; P = .39) and 0.99 (95% CI, 0.42-2.31; P = .98), respectively (Figure 4C and D). A difference of 2.7 percentage points for the 5-year EFS rate and 1.1 percentage points for the OS rate was observed between the SB3 group and nondrifted TRZ group.
Discussion
To our knowledge, this study was the largest and longest follow-up study to date comparing a trastuzumab biosimilar and the reference product in the context of ERBB2-positive early or locally advanced breast cancer. The comparable cardiac safety and survival results during up to 6 years of follow-up provide additional evidence that SB3 has no clinically meaningful difference compared with TRZ.7,10,12
In the main phase 3 trial,12 safety results were comparable between SB3 and TRZ throughout the neoadjuvant and adjuvant treatment. To ensure long-term cardiac safety, an additional 5-year treatment-free follow-up was planned after 52 weeks of neoadjuvant and adjuvant treatment. However, the eventual median follow-up duration was 68 months due to the premature study termination. Cardiac events were rare in both groups during the treatment-free follow-up, even after concomitant administration of trastuzumab and an anthracycline-containing neoadjuvant regimen. This observation is in line with recent cardiac safety studies of trastuzumab-containing regimens2,3,13,14 and suggests that the length of the follow-up had a limited influence on the incidence of heart failure. Interestingly, the incidence of congestive heart failure reported by Moja et al15 in a Cochrane meta-analysis considering all treatment periods was higher compared with incidence reported in the present study and recent individual clinical trials assessing trastuzumab in early settings.2,3,4,6,13,16,17,18,19 The main reasons for the lower rates could be that the inclusion criteria were refined to be more stringent and the cardiac monitoring guidance adopted with early stopping rules avoided further deterioration of cardiac function.
A greater number of patients were included in the 5-year survival analysis compared with the previous study12 at the 3-year follow-up data cutoff, providing robust long-term follow-up data for patients with ERBB2-positive early or locally advanced breast cancer after treatment with either SB3 or TRZ. Five-year EFS and OS rates were comparable between patients treated with SB3 or TRZ. The comparable long-term efficacy results were consistent with earlier findings showing the 2 products to be equivalent based on the ratio of bpCR rates.7 In the exploratory analysis in the current study, bpCR was shown to correlate with longer EFS, with the correlation being more profound in patients with the hormone receptor–negative subtype. This finding is consistent with previous assessments of the correlation between pathological complete response and EFS in the NOAH19 and HannaH18 trials as well as the CTNeoBC pooled analysis,20 although these analyses defined pathological complete response as the absence of invasive cancer in the breast and in the axillary nodes (total pathological complete response [tpCR]). The comparable long-term efficacy observed in this study suggests that bpCR may be used as a surrogate end point along with tpCR in patients with ERBB2-positive early breast cancer. Use of surrogate end points can help address unmet medical needs of patients and may lead to increased access for patients by allowing rapid clinical evaluation of biosimilars and novel drug candidates.21,22,23
As previously reported in the analysis of the main phase 3 trial,7 bpCR rates among patients treated with SB3 and TRZ were 51.7% and 42.0%, respectively, with an adjusted difference of 10.7%. A similar trend was also observed in survival outcomes of the present study, with a difference of 4.8 percentage points in the 5-year EFS rate and 7.1 percentage points in the 5-year OS rate in patients treated with SB3 compared with patients treated with TRZ. This numerical difference was smaller when the SB3 group was compared with the nondrifted TRZ subgroup, with a difference of 2.7 percentage points in the 5-year EFS rate and 1.1 percentage points in the 5-year OS rate. In addition, the HR for OS comparing the SB3 group and nondrifted TRZ subgroup was 0.99 (95% CI, 0.42-2.31), demonstrating comparability between the SB3 group and the nondrifted TRZ subgroup. Conversely, a difference was observed in terms of EFS and OS between the drifted TRZ subgroup and the nondrifted TRZ subgroup. CD16A-158F, the allelic variant of the activating Fcγ receptor CD16A with the lowest binding affinity for immunoglobulin G1, exerts lower ADCC activity; therefore, carriers of this variant appear to have diminished clinical response to trastuzumab.24,25 Margetuximab is a novel Fc-engineered anti-ERBB2 antibody with greater ADCC potency than trastuzumab and pertuzumab in vitro.26 The SOPHIA study suggested clinical benefit of margetuximab over trastuzumab in patients with ERBB2-positive metastatic breast cancer with CD16A-158F polymorphism.27 Findings in the present study and the SOPHIA study support the hypothesis of ADCC activity being one of the anticancer mechanisms of trastuzumab and show how the shift in trastuzumab’s ADCC activity may affect clinical outcomes. Biologic drugs are produced in living cells through complex multistep processes, and their inherent nature prevents any manufacturer from replicating the exact molecule.9,28,29 Thus, maintaining consistency in critical quality attributes of biologic drugs, such as ADCC activity, is essential.30 The findings of the present study are an example demonstrating the importance of ensuring consistent product quality to achieve optimal treatment outcomes with biologic drugs.
Limitations
This study has limitations. Only a subset of patients from the main phase 3 trial was enrolled in this posttreatment follow-up study, and the premature discontinuation of the study led to a shorter-than-planned follow-up duration for cardiac event observation. Lack of racial diversity is another limitation of the current study. A previous study suggested31 that African American or Black and South Asian individuals have increased risk of developing cardiovascular disease. However, most patients in the present study were either Asian or White, and no patients were African American or Black. Among 111 Asian patients, only 14 (12.6%) were Indian. For future research on drug-associated cardiotoxicity, a diverse study population including African American or Black patients should be considered. As secondary end points, survival analyses were not statistically powered, and subgroup analyses were not preplanned. Unbalanced numbers of patients between nondrifted TRZ and drifted TRZ were used for the subgroup analysis, and ADCC status was defined according to whether or not patients received drifted TRZ during neoadjuvant treatment.
Conclusions
In this secondary analysis of a randomized clinical trial, cardiac events were rarely reported in both treatment groups. The EFS and OS were comparable between patients treated with SB3 and TRZ with ERBB2-positive early or locally advanced breast cancer up to 6 years of follow-up. These long-term results provide further evidence supporting the similarity of SB3 and TRZ, which had previously been established through comprehensive analytical, functional, and short-term clinical assessments.7,10,12
Trial Protocol
eTable 1. Ethnicity and Region by Treatment Group in the Survival Follow-up Set
eTable 2. Continuing Medical Conditions by Treatment Group in the Survival Follow-up Set
eTable 3. Event-Free Survival Rates According to Hormone Receptor Status of Patients Who Achieved bpCR Compared With Patients Without bpCR
Data Sharing Statement
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial Protocol
eTable 1. Ethnicity and Region by Treatment Group in the Survival Follow-up Set
eTable 2. Continuing Medical Conditions by Treatment Group in the Survival Follow-up Set
eTable 3. Event-Free Survival Rates According to Hormone Receptor Status of Patients Who Achieved bpCR Compared With Patients Without bpCR
Data Sharing Statement