FormalPara Key Points

After 24 weeks of therapy in a phase III, randomized controlled trial setting among patients with human epidermal growth factor receptor 2-positive metastatic breast cancer, the objective response rate was achieved by a similar proportion of patients receiving both BP02 (trastuzumab biosimilar) and Herceptin®-EU.

The 95% confidence interval (CI) of risk difference (−2.03, 95% CI −9.15, 5.09) and 90% CI of risk ratio (0.97, 90% CI 0.89, 1.06) were within equivalence margins of ±13% and (90% CI 0.80, 1.25), respectively.

Safety profiles of both interventions were similar.

BP02 can potentially represent a cost-effective biosimilar alternative to EU-Herceptin®.

1 Introduction

With over 2.2 million new cases and over 684,000 deaths in 2020, breast cancer is the most common cancer among women and the most frequent cause of cancer-related deaths across the world [1]. Even in India, breast cancer is a significant burden, with over 178,361 new cases and 90,408 deaths in 2020, as per World Health Organization (WHO) Globocan [1]. Around 15–20% of all patients with breast cancer overexpress human epidermal growth factor receptor 2 (HER2) [2,3,4].

Human epidermal growth factor receptor 2-positive (HER2+) breast cancer is an aggressive disease that is associated with poor prognosis and high mortality rates: it was estimated that only 2–5% of patients with HER2+ breast cancer were “long-term survivors” [5]. This was because HER2 overexpression was associated with activation of the HER2-related downstream signaling pathway, and the resultant increased rates of proliferation, a higher histologic and nuclear grade, and an increased tendency to metastasize worsened the prognosis [6]. However, with the US Food and Drug Administration (USFDA) approval of HER2-targeted therapy trastuzumab (under the trade name Herceptin®) for treating HER2+ metastatic breast cancer (MBC) in 1998, this biomarker, which was previously classified as a harbinger of poor prognosis, saw a transformation to being a targetable molecular alteration: the availability of trastuzumab improved long-term survival as well as quality of life among patients with HER2+ breast cancers [2]. The European Medicines Agency (EMA) subsequently approved trastuzumab in 2000 for the same indication [7]. As of 2023, in addition to HER2+ MBC, trastuzumab is also approved for the management of HER2+ early-stage breast cancer as adjuvant therapy, and for HER2+ metastatic gastric cancer[7, 8].

Despite the proven efficacy and safety, many barriers exist to the use of trastuzumab in patients with HER2+ MBC, the most important of these barriers being the cost of therapy, especially in areas with limited financial resources [9]. Lowering the cost of therapy, thus, has the potential to improve patient access to trastuzumab. The development and approval of trastuzumab biosimilars is one of the most promising approaches to lowering therapy cost because biosimilars have comparable efficacy and safety to the originator trastuzumab and are generally more affordable to healthcare systems and patients. However, prior to regulatory approval, it is essential to establish that the potential biosimilar does not have a clinically meaningful difference in efficacy, safety, pharmacokinetics, and immunogenicity compared to the originator product [10, 11].

BP02, a recombinant IgG1 kappa humanized monoclonal antibody targeting HER2 receptors, is an investigational medicinal product being developed by CuraTeQ Biologics Limited, India, as a similar biological medicinal product to the originator trastuzumab, Herceptin®, (Genentech/Roche). By evaluating the analytical similarity, pharmacological profile, and toxicological profile of BP02 in non-clinical studies (data on file), it was concluded that BP02 can be administered in carefully monitored clinical studies. As a further step in establishing equivalence and to accumulate a totality of evidence for potential registration as a biosimilar medicinal product, the present phase 3 trial was conducted to evaluate the efficacy and safety of BP02 compared to Herceptin®-EU in the treatment of HER2+ MBC in an equivalence study design.

2 Methods

2.1 Study Design and Participants

This double-blind, 1:1 randomized, parallel-group, active-controlled, phase III equivalence study involved patients from 59 sites across India. Eligible patients were female individuals aged 18–75 years with histologically or cytologically confirmed, locally recurrent breast cancer or MBC that is not amenable to curative surgery and/ or radiation, with at least one measurable lesion as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. To be eligible, HER2+ status was required to be documented by immunohistochemistry (IHC) as IHC3+; for patients with IHC2+, HER2 overexpression was required to be confirmed by fluorescence in-situ hybridization or chromogenic in-situ hybridization. Additional inclusion criteria were Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2, left ventricular ejection fraction (LVEF) ≥ 55% at baseline, probable life expectancy of ≥ 18 months, and adequate renal, hepatic, and hematological functions ascertained through laboratory tests. Exclusion criteria were prior therapy for metastatic disease (except hormonal therapy, bisphosphonates, and palliative radiotherapy), prior cumulative dose of doxorubicin > 400 mg/m2, epirubicin > 800 mg/m2, or mitoxantrone > 120 mg/m2; contralateral breast cancer, cancer of any other site, metastases to the brain and spinal cord; planned major surgery within 4 weeks prior to the first dose; concomitant active severe infection; active uncontrolled cardiac illness, and known hypersensitivity to trastuzumab. A detailed description of eligibility criteria is available in Table 1 of the Electronic Supplementary Material (ESM).

The entire study had two treatment periods: an induction phase lasting a maximum of 8 cycles (24 weeks), and a maintenance phase lasting a maximum of 16 cycles (48 weeks). Patients showing complete response, partial response, or stable disease at the end of the induction phase continued the study medication to which they were originally randomized during the maintenance phase, until disease progression or treatment discontinuation. Maximum per subject follow-up allowed was up to 18 months (72 weeks, which is a total of 24 3-weekly cycles). The current report describes the results of the induction phase of the study.

2.2 Randomization and Blinding

Using a central Interactive Web Response System, patients were stratified by estrogen receptor/progesterone receptor status in a 1:1 ratio to receive BP02 or reference trastuzumab (RT: Herceptin®-EU), combined with docetaxel. The randomization schedule was computer generated by a third party, and the patients, investigators, as well as the research team were blinded to treatment assignments.

2.3 Treatments and Their Doses

BP02 or RT was administered on day 1 of each 3-weekly cycle, via an intravenous infusion. The dose was 8 mg/kg (loading dose) over 90 minutes for cycle 1, and 6 mg/kg (maintenance dose) over 30–90 minutes depending on tolerability for cycles 2–8. For patients missing trastuzumab by more than 1 week, a re-loading dose (8 mg/kg) was administered in the subsequent cycle, except in cases where the delay was because of cardiotoxicity. If the missed dose was within a week of the planned date, the maintenance dose (6 mg/kg) was administered. The dose and 3-weekly schedule used in the study is as per the approved posology of trastuzumab for Herceptin® [12]. Treatments could continue up to a maximum of 8 cycles. Dosage reductions were not permitted for trastuzumab; however, in the case of toxicity, the treatment was temporarily or permanently discontinued depending on the severity of toxicity.

For each cycle, the administration of trastuzumab was followed by administration of docetaxel at a dose of 75 mg/m2, intravenously over 60 ± 5 min, on the same day. Premedication before docetaxel was administered as per the institutional standards unless contraindicated according to the investigator’s discretion. Docetaxel treatment was continued for at least 8 cycles, in the absence of disease progression or unacceptable toxicity as per the investigator’s discretion. A reduction in the docetaxel dose based on institutional or regional standard of care was permitted, depending on the toxicity and investigator discretion.

All standard precautions were strictly taken for dilution, preparation, and administration of the investigational products. Permitted concomitant medications included corticosteroids (premedication, topical applications, inhaled preparations), granulocyte-colony stimulating factor (as neutropenia prophylaxis), bisphosphonates or denosumab (if started prior to randomization), and any other medication or treatment deemed necessary to provide adequate supportive care as per the investigator’s discretion.

2.4 Outcomes and Assessments

The primary efficacy endpoint was the objective response rate (ORR), defined as the proportion of patients in each group who achieved the best ORR according to RECIST 1.1, at the end of the induction phase of the study, as assessed by an independent radiologist. The risk ratio and risk difference of ORRs (BP02 and RT) were used to determine if BP02 is equivalent to RT. This primary analysis was conducted in the intent-to-treat (ITT) population. Secondary efficacy endpoints included progression-free survival (PFS, defined as the time in months from the date of first dose to subsequent progression as per RECIST 1.1) and overall survival (OS, defined as the time in months from the date of the first dose to subsequent death). Additional secondary endpoints to support the assessment of similarity were safety, trough serum concentrations of BP02 and RT (to establish pharmacokinetic similarity), and the presence of antidrug antibodies (to establish immunogenicity) at selected cycles of the study. The current report focusses on efficacy and safety endpoints during the induction phase of the study.

At screening, laboratory investigations, physical examination, vital signs, demographic details, concomitant medication recording, as well as detailed medical and medication history were noted. Electrocardiogram (ECG), two-dimensional echocardiogram/multi-gated acquisition, ECOG performance status, laboratory tests, and a serum pregnancy test were also performed. Tumor assessment at screening was conducted through computed tomography of the chest, abdomen, pelvis, and additional sites if clinically indicated. Bone scan, computed tomography/magnetic resonance imaging of the brain, or positron emission tomography/computed tomography of the brain were performed at screening and were performed again if deemed necessary by the investigator. HER2 status was confirmed at screening through IHC, and fluorescence in situ hybridization/chromogenic in situ hybridization as applicable. During each of the treatment cycles, physical examination, vital signs, ECOG performance status, laboratory tests, urine pregnancy test, electrocardiogram, concomitant medication monitoring, and adverse event (AE) monitoring were performed. Blood samples were collected at cycles 1, 4, and the end of induction for the immunogenicity assessment, and at cycles 2, 4, 6, 8, and the end of induction for the trough concentration sampling and pharmacokinetic assessment. Disease status and tumor response were assessed as per modified RECIST 1.1 criteria. Tumor assessments were conducted at cycle 3, cycle 6, and the end of the induction phase or early withdrawal.

Adverse events were monitored throughout the study duration, and AE reports (including laboratory abnormalities) were characterized by type, timing, severity, seriousness, and relationship to study treatment. Reported AEs were coded using Medical Dictionary for Regulatory Activities (MedDRA) version 25.1. Causality of AEs was reported as related, unrelated, and unknown. Severity of AEs were graded as mild, moderate, severe, life threatening, and fatal as per Common Terminology Criteria for Adverse Events Version 5.0. Serious AEs were defined as AEs that were fatal, life threatening, required hospitalization, prolonged existing hospitalization, or resulted in disability. Treatment-emergent AEs (TEAEs) were AEs that began or worsened in severity after administration of at least one dose of the study drugs, and up to 30 days after the last administration of the study drug, and the TEAE outcomes were reported as resolved/recovered, recovering/resolving, fatal, and persisted.

2.5 Statistical Analysis

The primary efficacy analysis of the induction phase was planned prospectively to be performed after administration of 8 cycles of treatment to all randomized patients. Similarity was deemed to be established if the 95% confidence interval (CI) of the risk difference between BP02 and RT was within ± 13% for EMA and other regulatory agencies, and the 90% CI of the risk ratio between BP02 and RT was within 0.80–1.25 for the US FDA [13].

Assuming an ORR of 60% in both treatment groups [13], a sample of 630 patients (n = 315 per arm) was calculated to provide 85% power with a 2.5% type 1 error rate to establish equivalence between the formulations. Considering a 10% drop out rate, a sample size of 690 patients (n = 345 per arm) was planned for the study.

Baseline was defined as the last available pre-treatment assessment, and the end of the study was defined as the last available post-treatment assessment. Missing data were not replaced, unless defined otherwise for specific summaries. Statistical analysis was performed using SAS® Version 9.4 in a secure and validated environment. Data used for an induction phase analysis were cleaned prior to the analysis after the induction phase database lock.

2.6 Ethical Conduct of the Study

This study was conducted in accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Guideline for Good Clinical Practice (ICH Guideline E6-R2) [14], following all ethical principles having their origin in the Declaration of Helsinki [15], as well as adhering to all relevant local ethical regulations. The protocol, its amendments, and informed consent documents were reviewed and approved by the institutional ethics committee of each study site, and the institutional ethics committee was duly appraised of all the AEs reported in the study as per prevalent local and international regulations. Patients were required to give written informed consent prior to study enrollment, and it was ensured that the privacy rights of enrolled participants were always observed. The study was registered at the Clinical Trial Registry India prior to initiation of the first patient screening (CTRI/2020/04/024456). Ethics committee approval details of all 59 sites involved in the study are provided in Table 2 of the ESM.

3 Results

3.1 Patient Disposition and Baseline Characteristics

Of the 914 patients screened, 690 patients were randomized between 23 September, 2020 and 16 September, 2022 to BP02 plus docetaxel (BP02 group, N = 345) or RT plus docetaxel (RT group, N = 345); all randomized patients received the first dose of the study medications. Thus, the ITT and safety population comprised 690 patients. Patient disposition is summarized in Fig. 1. The two groups had well-balanced baseline demographics and features, as summarized in Table 1.

Fig. 1
figure 1

Patient disposition. The study is ongoing, with a maintenance phase currently underway. AE adverse event, ITT intent-to-treat

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Table 1 Baseline and demographic characterisitcs 
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At the induction phase completion soft lock date, 488/690 (70.7%) patients were exposed to at least 8 cycles of treatment with BP02 (n = 231, 67.0%) or RT (n = 257, 74.5%). The median duration of trastuzumab exposure was comparable between the arms and was estimated to be 177 days in the BP02 arm, and 178 days in the RT arm. The three most frequent reasons for treatment discontinuation were disease progression (BP02: n = 39, 11.3%; RT: n = 25, 7.2%), loss to follow-up (BP02: n = 24, 7.0%; RT n = 18, 5.2%), and voluntary withdrawal by patient (BP02: n = 23, 6.7%; RT: n = 18, 5.2%).

3.2 Efficacy

3.2.1 ORR

The risk difference of the best ORR in the ITT population at the end of the induction phase (24 weeks) was − 2.03 (BP02 minus RT), with a 95% CI − 9.15, 5.09. Because this 95% CI was within the predefined equivalence boundaries of ± 13%, [14] statistical therapeutic equivalence was met between BP02 and RT. The risk difference was also calculated for the best ORR in the PP population and was observed to be − 0.75 (BP02 minus RT), with a 95% CI − 7.80, 6.29, supporting the ITT analysis of statistical therapeutic equivalence (Table 2).

Table 2 Objective response rates and overall response categories of the intent-to-treat and per-protocol populations
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The risk ratio of the best ORR in the ITT population at the end of the induction phase (24 weeks) was 0.97 (BP02 vs RT), with a 90% CI 0.89, 1.06. Because the 90% CI was within the predefined equivalence boundaries of 0.80, 1.25 [14], statistical therapeutic equivalence was met between BP02 and RT. The risk ratio was also calculated for the best ORR in the PP population and was observed to be 0.99 (BP02 vs RT), with a 90% CI 0.91, 1.07, supporting the ITT analysis of statistical therapeutic equivalence (Table 2).

We also explored the risk difference and risk ratio of the best ORR among different subgroups of patients receiving BP02 and RT, and the results are summarized in Fig. 2. The wide CIs observed with ECOG grade 2 can be explained by the fact that the patient number of this subgroup is smaller. However, it must be noted that the study was not powered enough for any of these subgroup analyses: thus, these results serve as a descriptive analysis.

Fig. 2
figure 2

Forest plots of a risk difference and b risk ratio (intent-to-treat [ITT] and per protocol [PP] population) among patient subgroups at the end of the induction phase. CI confidence interval, ECOG Eastern Cooperative Oncology Group, ER estrogen receptor, PR progesterone receptor

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3.2.2 Survival

At the end of the induction phase, disease progression or death in the ITT population was reported in 41 (11.9%) patients in the BP02 group, and 31 (9.0%) patients in the RT group, with a log-rank test p-value of 0.1581. Likewise, in the same population at the same timepoint, death was reported in 11 (3.2%) patients in the BP02 group, and ten (2.9%) patients in the RT group, with a log-rank test p-value of 0.8099 (Fig. 3). The medians for PFS and OS were not reached in both arms.

Fig. 3
figure 3

Kaplan–Meier plots of a progression-free survival and b overall survival (intent-to-treat population) at the end of the induction phase. Medians of progression-free survival and overall survival were not reached

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3.3 Safety

The summary of safety outcomes is available in Table 3. A total of 1621 TEAEs were reported at the end of the induction phase, of which 894 events and 727 events were reported with BP02 and RT, respectively. Treatment-emergent AEs were reported by 200/345 (58.0%) patients in the BP02 arm, and by 208/345 (60.3%) patients in the RT arm. Treatment-emergent AEs of ≥ grade 3 were reported by 39 (11.3%) patients receiving BP02 and by 33 (9.6%) patients receiving RT. The incidence of all categories of TEAEs, including serious TEAEs and TEAEs of special interest, were similar between the two groups. The incidence of TEAEs leading to treatment interruption, study discontinuation, treatment withdrawal, and deaths were also similar between the two groups.

Table 3 Summary of safety outcomes at the end of induction phase in safety population
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The most frequently reported TEAEs in both the groups were general disorders and administration-site conditions; other TEAEs reported by ≥ 5% patients involved gastrointestinal disorders, musculoskeletal and connective tissue disorders, infections and infestations, skin and subcutaneous tissue disorders, blood and lymphatic system disorders, nervous system disorders, metabolism and nutrition disorders, respiratory, thoracic, and mediastinal disorders. Treatment-emergent AEs of all grades as per the MedDRA system organ class reported by ≥ 5% of patients of either group included general disorders and administration-site conditions, gastrointestinal disorders, blood and lymphatic system disorders, musculoskeletal and connective tissue disorders, infections and infestations, and skin and subcutaneous tissue disorders (Table 3).

The outcome of the 1621 TEAEs in 408 patients were comparable between the two arms: 1505 events (in 382 patients) were resolved, nine events (in nine patients) were resolved with sequelae, 53 events (in 45 patients) had persistent outcomes, whereas a fatal outcome was reported for 54 events (in 23 patients). No trends or safety signals were identified in the induction phase through a review of the safety data pertaining to laboratory values and physical examinations, including changes in LVEF, ECOG performance status, and ECG (Table 3).

The frequency and distribution of AEs of special interest were also similar between both arms. Specially, AEs of special interest of cardiac origin were seen in nine patients in the BP02 arm (two patients with tachycardia, and one patient each with acute myocardial infarction, cardiomyopathy, diastolic dysfunction, left ventricular dysfunction, palpitations, sinus bradycardia, and systolic dysfunction), and among five patients in the RT arm (two patients with tachycardia, and one patient each with cardiac arrest, cardiac failure, and cardiac dysfunction). There were no new safety concerns (Table 3, Table 3 of the ESM).

4 Discussion

The results of the induction phase analysis of this phase III trial established the therapeutic equivalence between BP02 and Herceptin® in terms of the ORR, when each drug was administered in combination with docetaxel for 8 cycles in the induction phase, among patients with HER2+ MBC. BP02 was well tolerated, and had a similar safety profile to RT.

BP02 is being developed as a similar biological medicinal product to Herceptin®, the originator trastuzumab developed by Genentech/Roche that targets HER2 receptors. As the objective of this study was to demonstrate similarity in the efficacy and safety of BP02 and RT, it employed an equivalence study design through an adequately powered, randomized, double-blind, parallel-group, active-controlled, comparative clinical trial, and included a blinded central radiological review of lesions [16]. The dose and regimen of trastuzumab for both the BP02 and RT arms used in this study are consistent with the summary of product characteristics of Herceptin® [12]. The efficacy endpoint for this study was ORR, which has been considered by the EMA as a sensitive endpoint for identifying potential differences between an originator biologic and its biosimilar [16], and is also considered as a direct measure of drug activity by the USFDA [17]. The definition of ORR as the proportion of patients in whom a complete or a partial response was observed also aligns with the guidelines [16, 17]. Other efficacy endpoints explored were PFS and OS in this study as supportive measures.

The ORRs of BP02 and RT observed in the present study were within the range of ORRs with trastuzumab or trastuzumab biosimilars in previously reported HERITAGE study. HERITAGE was a phase III randomized controlled trial (RCT) with an equivalence design reported in 2017 and included 458 women in ITT population; the week-24 ORR was 69.6% (95% CI 63.62, 75.51) for the trastuzumab biosimilar and 64.0% (95% CI 57.81, 70.26) for RT, the ORR ratio was 1.09 (90% CI 0.974, 1.211), and the ORR difference was 5.53 (95% CI −3.08, 14.04), thus establishing therapeutic equivalence [18]. Another international phase III RCT  with an equivalence design reported in 2019 compared PF-05280014 (trastuzumab biosimilar) with Herceptin®, both combined with paclitaxel; this RCT  included 707 women in the ITT population, and reported an ORR after week 25 of 62.5% (95% CI 57.2, 67.6) for the biosimilar, 66.5% (95% CI 61.3, 71.4) for Herceptin®, and a risk difference of − 4.0% (95% CI − 11.0, 3.1), thus establishing therapeutic similarity [19]. The slight difference in the ORRs observed in our study compared with the PF-05280014 study might be attributed to the difference in the population: our study focused on patients from multiple centers in India.

Some previous studies have used the pathologic complete response (pCR) instead of the ORR as the surrogate marker for the efficacy of trastuzumab or a biosimilar in the management of breast cancer [20, 21]. While there are merits for using either the ORR or pCR to evaluate efficacy similarities, regulatory bodies have not shown a preference to either endpoint. Generally, studies involving patients with early breast cancer use the pCR  as the efficacy endpoint, whereas studies involving patients with MBC (such as the present study) use the ORR as the efficacy endpoint [22]. Further, for this indication, PFS and OS are considered supportive endpoints, and because they are dependent on multiple variables relating to mortality, they are generally not considered as sensitive as the ORR to identify therapy response and clinically meaningful differences. Thus, the selection of the ORR as the primary efficacy endpoint in this study aligns with the approved indications for trastuzumab in breast cancer and reflects current trends in high-quality research. Further analysis of the ongoing study will throw additional light on PFS and OS as well and will provide an opportunity to evaluate the degree of agreement between these three efficacy endpoints.

Our study did not reveal any new safety signal of concern, and all TEAEs observed between both the treatment arms were comparable, as per the established safety profile of trastuzumab. Fewer than 1% of the patients discontinued treatment because of an unacceptable AE or a failure to tolerate the study medication. Thus, BP02 was well tolerated, and equally efficacious in this patient cohort, compared to Herceptin®.

Being a targeted therapy, trastuzumab has proven its value in the specific management of HER2+ MBC. In fact, trastuzumab-based therapy is considered the standard of care among patients with HER2 + MBC [23]. Despite this, it is estimated that as much as 12–54% of patients in developed countries, and over 90% of patients in some low-income countries do not have access to trastuzumab, the most important reason being economic restraints [24, 25]. This gains immense significance in the backdrop of the WHO including trastuzumab in its essential medicines list [26]. Development, demonstration of safety and clinical equivalence, and marketing approval of lower cost trastuzumab biosimilars, such as BP02, are therefore important steps to mitigate the lack of patient access to this important medicine, by their potential to lower the cost of medicine without compromising efficacy and safety.

5 Conclusions

In this study, we demonstrated the therapeutic equivalence and tolerability of BP02 compared to Herceptin® in the management of HER2+MBC at the end of the 24-week induction phase consisting of 8 cycles of therapy with trastuzumab in combination with docetaxel, by means of the ORR. Our choice of the ORR as the primary endpoint aligns with existing biosimilar guidelines, emphasizing its sensitivity in MBC to demonstrate therapeutic equivalence. Long-term outcome results covering PFS, OS, and safety data are being collected and will be published in the future.