FormalPara Key Points

The equivalent efficacy and comparable safety and immunogenicity of CT-P6 to reference trastuzumab was demonstrated in the randomised, Phase 3 CT-P6 3.2 study, which compared the products administered as neoadjuvant and post-surgery adjuvant treatment in patients with human epidermal growth factor receptor-2 (HER2)-positive early breast cancer.

The current study, CT-P6 4.2, was a further 3-year extension to the 3 years of follow-up included in the CT-P6 3.2 study, providing efficacy data after a median of 76.4 months of follow-up.

Our data extend the findings of the CT-P6 3.2 study, demonstrating the comparable long-term effects of CT-P6 and reference trastuzumab on overall survival, disease-free survival, and progression-free survival over up to 6 years.

1 Introduction

CT-P6 is a biosimilar of reference trastuzumab that is approved for the treatment of human epidermal growth factor receptor (HER2)-positive early and metastatic breast cancer by the US Food and Drug Administration and European Medicines Agency [1, 2]. Equivalence in terms of efficacy and comparable safety was demonstrated between CT-P6 and reference trastuzumab in patients with HER2-positive early breast cancer in a randomised, Phase 3 clinical trial (the CT-P6 3.2 study, NCT02162667; EudraCT number: 2013-004525-84) [3,4,5]. After 3 years’ follow-up, disease-free survival (DFS), progression-free survival (PFS) and overall survival (OS) rates remained similar between patients treated with CT-P6 and reference trastuzumab, supporting the conclusion of equivalence in terms of efficacy over the long term [5]. Findings agreed with 3-year time-to-event rates reported for neoadjuvant and adjuvant reference trastuzumab in other studies, including HannaH [6], NeoALTTO [7] and JBCRG-10 [8]. CT-P6 was well tolerated, with a safety profile comparable to that of reference trastuzumab throughout the 3-year follow-up, including in terms of drug-related cardiac disorders and decreases in left ventricular ejection fraction [5]. Immunogenicity was also similar between groups [5]. After a median of 38.7 months and 39.6 months of follow-up in the CT-P6 and reference trastuzumab groups, respectively, median DFS, PFS and OS were not reached [5].

This article reports the findings of the CT-P6 4.2 study—an extended observational follow-up study of patients in the CT-P6 3.2 study—which was conducted to provide additional long-term data on the efficacy of CT-P6 relative to reference trastuzumab. We report survival outcomes after a period of up to 6 years.

2 Methods

2.1 Study Design

The CT-P6 4.2 study (EudraCT number: 2019-003518-15) was a multicentre, observational, extended follow-up study of patients who completed the last follow-up visit in the CT-P6 3.2 study. In countries where CT-P6 had already received regulatory approval, CT-P6 4.2 was conducted as a Phase 4 study. In all other countries (Belarus, Russia and Ukraine), it was considered a Phase 3 study.

Full details of the study design for the randomised, double-blind, active-controlled CT-P6 3.2 study, including randomisation procedures, have been published previously [3, 4]. In brief, patients were recruited into the CT-P6 3.2 study from 112 centres across 23 countries. Neoadjuvant treatment consisted of eight 3-week cycles of CT-P6 (Herzuma®; Celltrion, Inc., Incheon, Republic of Korea) or reference trastuzumab (Herceptin®; Genentech, San Francisco, CA, USA), consisting of a loading dose of 8 mg/kg on Day 1 of Cycle 1 followed by 6 mg/kg on Day 1 of Cycles 2–8, with docetaxel and fluorouracil, epirubicin and cyclophosphamide, followed by surgery. Post-surgery, patients received up to ten cycles of adjuvant CT-P6 or reference trastuzumab (6 mg/kg administered every 3 weeks, per original randomisation), and were followed for up to 3 years from the date of enrolment of the last patient.

Patients who completed the last follow-up visit of the CT-P6 3.2 study could participate in the CT-P6 4.2 study, and could be enrolled irrespective of their study treatment completion status (Fig. 1). No study drugs were administered during the CT-P6 4.2 study.

Fig. 1
figure 1

Study design

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At the on-site enrolment visit, data regarding survival status, disease progression/recurrence and initiation of any anticancer therapies since the end of the CT-P6 3.2 study were collected directly from the patients or obtained from medical charts. For patients who died during the ~ 1-year period between the end of their participation in the CT-P6 3.2 study and the beginning of the current study, survival data, assessment dates for progressive/recurrent disease, and the start date of breast cancer-related therapy were retrospectively collected from medical charts or patients’ relatives, where possible.

After enrolment in the CT-P6 4.2 study, survival status, disease progression/recurrence, and anticancer treatment initiation data were collected via telephone every 6 months (± 21 days). Data were collected from the patients, their medical charts, or from relatives in case of patient death. Patient data collection ceased with a final visit or telephone call at the end of the 3-year CT-P6 4.2 study follow-up period, upon withdrawal of the patient from the study, or with the death of the patient.

The study was conducted in accordance with the ethical principles originating in the Declaration of Helsinki, Good Clinical Practice, and all applicable laws or regulations. Before the start of the study, the protocol, informed consent form, advertisements to be used for the recruitment of study patients, and any other written information to be provided to the patients were approved by the institutional review board and/or independent ethics committee at each site (Table S1; Online Supplemental Material (OSM), Resource 1). All patients provided written informed consent before entering the study.

2.2 Eligibility Criteria

Detailed eligibility criteria for the CT-P6 3.2 study have been published previously [3, 4]. In the CT-P6 4.2 study, eligible patients were females aged ≥ 18 years with pathologically confirmed, newly diagnosed, operable, early breast cancer (Stage I, II or IIIA) at initiation of the CT-P6 3.2 study. Patients had completed the last follow-up visit of the CT-P6 3.2 study, which took place around October 2018, regardless of their study treatment completion status. Patients who died during the CT-P6 3.2 study were excluded.

2.3 Endpoints

Follow-up duration for the efficacy endpoints of OS, DFS and PFS was defined as the interval between the date of randomisation in the CT-P6 3.2 study and the date of the last available information. OS was defined as the interval between the date of randomisation in the CT-P6 3.2 study and the date of death from any cause. DFS was defined as the interval between the date of breast surgery in the CT-P6 3.2 study and the date of disease progression/recurrence or death from any cause, whichever occurred first. Only disease progression/recurrence that occurred after breast surgery and before or at anticancer therapy initiation was regarded as an event. PFS was defined as the interval between the date of CT-P6 3.2 study randomisation and the date of disease progression/recurrence or death from any cause, whichever occurred first. Only disease progression/recurrence that occurred before or at anticancer therapy initiation was regarded as an event.

2.4 Statistical Analysis

A sample size justification based on a statistical hypothesis was not relevant in this study. Time-to-event analyses were conducted in the intention-to-treat (ITT) and ITT extension sets. The ITT set comprised all randomised patients in the CT-P6 3.2 study, regardless of whether study treatment was received. The ITT extension study set comprised all patients in the ITT set for whom data were collected during the extension study (the CT-P6 4.2 study), including patients who died or experienced disease progression/recurrence between the end of their participation in the CT-P6 3.2 study and the beginning of the CT-P6 4.2 study. Percentages for event data were calculated based on numbers of patients within the treatment group for the population of interest, unless otherwise indicated. Median survival times for time-to-event endpoints were estimated using the Kaplan–Meier method; corresponding 95% confidence intervals (CIs) are shown in the format [x–y), where a square bracket denotes that the start of the range is inclusive of x, and a parenthesis denotes that the end of the range is exclusive of y. Survival rates after 4, 5 and 6 years were estimated using the Kaplan–Meier method and presented alongside the corresponding 95% CIs. An adjusted, stratified Cox regression model was used to estimate hazard ratios (HRs) and corresponding 95% CIs for CT-P6 compared with reference trastuzumab. Stratification factors from the CT-P6 3.2 study were used as covariates: disease stage (Stage I/II vs. Stage IIIA and above), oestrogen receptor status (positive vs. negative), progesterone receptor status (positive vs. negative), and region (Europe, the Middle East, and Africa vs. America vs. Asia). Statistical analyses were performed using SAS (SAS Institute Inc., Cary, NC, USA), version 9.4.

3 Results

3.1 Patients

Of 549 patients enrolled in the CT-P6 3.2 study (the ITT set), 216 (39.3%) patients were included in the CT-P6 4.2 extension study. The first patient’s first visit for the CT-P6 4.2 study was on 14 January 2020, with the final follow-up visit conducted on 21 October 2021. In total, 107 (39.5%) patients in the CT-P6 group from the CT-P6 3.2 study and 109 (39.2%) patients in the reference trastuzumab group had evaluable data in the CT-P6 4.2 study and made up the ITT extension set. Patient disposition information is presented in Table S2 (OSM Resource 1).

Baseline patient demographics and disease characteristics were balanced overall between the CT-P6 and reference trastuzumab groups in both the ITT and ITT extension sets (Table 1). Most patients had Stage IIA to Stage IIIA disease. More than half were oestrogen receptor-positive and over one-third were progesterone receptor-positive. Of note, the majority of patients (78.5%) in the ITT set were from European sites, with 17.5% from Asian sites and 4.0% from American sites, but all patients (100%) in the ITT extension set were recruited at European sites.

Table 1 Patient demographics and baseline disease characteristics
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3.2 Survival Results

In the ITT set, the median [95% CI) follow-up duration was 42.6 [40.3–45.3) months and 42.6 [41.3–44.0) months for the CT-P6 and reference trastuzumab groups, respectively. Correspondingly, in the ITT extension set, the median follow-up duration was 76.4 [75.4–77.7) months and 76.4 [75.1–78.2) months.

Median OS was not reached in either group in the ITT or ITT extension sets owing to an insufficient number of events. Overall, in the ITT set, 22 (8.1%) and 25 (9.0%) patients died in the CT-P6 and reference trastuzumab groups, respectively; correspondingly, four (3.7%) and seven (6.4%) patients died in the ITT extension set (Table S3, OSM Resource 1). Estimated HRs (95% CIs) for OS were 0.95 (0.53–1.68) and 0.59 (0.17–2.02) for the ITT and ITT extension sets, respectively (Fig. 2).

Fig. 2
figure 2

Kaplan–Meier plot of OS. (a) ITT set; (b) ITT extension set. CI confidence interval, HR hazard ratio, ITT intention-to-treat, OS overall survival

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Median DFS was not reached in either group (in either analysis set) owing to an insufficient number of events. In the ITT set, 47 (18.2%) patients in the CT-P6 and 42 (16.1%) patients in the reference trastuzumab group died or had progressive disease (PD)/recurrence after surgery. In the ITT extension set, the respective numbers of patients who died or had PD/recurrence were 13 (12.3%) and 13 (12.1%) (Table S3, OSM Resource 1). The estimated HRs (95% CI) for DFS were 1.18 (0.77–1.80) in the ITT set and 1.07 (0.50–2.32) in the ITT extension set (Fig. 3).

Fig. 3
figure 3

Kaplan–Meier plot of DFS. (a) ITT set; (b) ITT extension set. CI confidence interval, DFS disease-free survival, HR hazard ratio, ITT intention-to-treat

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Median PFS was not reached in the CT-P6 or reference trastuzumab groups in either the ITT or ITT extension sets owing to an insufficient number of events. In the ITT set, 54 (19.9%) patients in the CT-P6 group and 46 (16.5%) patients in the reference trastuzumab group died or had PD/recurrence; corresponding values in the ITT extension set were 13 (12.1%) and 13 (11.9%), respectively (Table S3, OSM Resource 1). The estimated HRs (95% CI) for PFS were 1.25 (0.84–1.87) in the ITT set and 1.08 (0.50–2.34) in the ITT extension set (Fig. 4).

Fig. 4
figure 4

Kaplan–Meier plot of PFS. (a) ITT set; (b) ITT extension set. CI confidence interval, HR hazard ratio, ITT intention-to-treat, PFS progression-free survival

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Kaplan–Meier analyses were used to estimate OS, DFS and PFS rates at 4, 5 and 6 years of follow-up. Rates were comparable between treatment groups in both the ITT and ITT extension sets (Table S4, OSM Resource 1). In the ITT set, the estimated 6-year OS rate (95% CI) was 0.89 (0.84–0.93) in the CT-P6 group and 0.87 (0.81–0.91) in the reference trastuzumab group. Correspondingly, 6-year DFS rates (95% CI) were 0.78 (0.71–0.83) and 0.81 (0.75–0.86), and 6-year PFS rates (95% CI) were 0.76 (0.69–0.81) and 0.80 (0.73–0.85). Estimated 6-year time-to-event rates in the ITT extension set were comparable. For the CT-P6 and reference trastuzumab groups, respectively, rates (95% CI) were 0.96 (0.90–0.99) and 0.94 (0.87–0.97) for OS, 0.87 (0.78–0.92) and 0.89 (0.81–0.94) for DFS, and 0.87 (0.78–0.92) and 0.89 (0.82–0.94) for PFS.

4 Discussion

Approximately 40% of the patients with HER2-positive early breast cancer who enrolled in the CT-P6 3.2 study entered the CT-P6 4.2 extension study. After a median follow-up duration of 76.4 months in each group, OS, DFS and PFS rates were comparable between CT-P6 and reference trastuzumab, providing further support of the biosimilarity of CT-P6 to reference trastuzumab demonstrated in the CT-P6 3.2 study [3,4,5].

Our findings are comparable with long-term data from other Phase 3 studies that have evaluated the treatment of HER2-positive early breast cancer with reference trastuzumab or its biosimilars. In the current study, we report 6-year OS rates for CT-P6 and reference trastuzumab of 89% and 87%, respectively, in the ITT set (96% and 94% in the ITT extension set, respectively). The HannaH trial reported a 6-year OS rate for reference trastuzumab of 84% for patients receiving neoadjuvant and adjuvant therapy including intravenous reference trastuzumab [9], and the NeoALTTO trial (BIG 1-06) reported a 6-year OS rate of 79% with neoadjuvant and adjuvant reference trastuzumab [10]. In the APHINITY (BIG4-11) trial, 6-year OS with adjuvant reference trastuzumab was 94% [11], while 5-year OS was 94% in the SafeHER trial [12]. In addition, a long-term follow-up of a Phase 3 study of SB3 (a biosimilar of reference trastuzumab) in the neoadjuvant setting for HER2-positive early or locally advanced breast cancer reported a 5-year OS rate of 93% for SB3 and 87% for reference trastuzumab [13]. Outside of the clinical trial setting, OS rates for reference trastuzumab are similar: a large, population-based cohort derived from the Netherlands Cancer Registry reported 5-year OS rates of 90% in HER2-positive early breast cancer [14], while an extended follow-up of an observational cohort study in Japan (JBCRG-01) reported a 5-year OS rate of 96% [15].

With regards to DFS, the 6-year rates we report for CT-P6 and reference trastuzumab in this study (78% and 81% in the ITT set, and 87% and 89% in the ITT extension set, respectively) are in keeping with 5-year rates from the Phase 3 SafeHER trial (87%) [12] and the Phase 2 NeoSphere trial (81%) [16], as well as with observational data from the JBCRG-01 cohort study (89%) [15].

To our knowledge, there are no PFS data for reference trastuzumab in this patient population over a similar time frame, although some comparison may be drawn with 6-year event-free survival rates from the HannaH (65%) [9] and NeoALTTO trials (67%) [10]. Here we report 6-year PFS rates of 76% and 80% in the ITT set and 87% and 89% in the ITT extension set for CT-P6 and reference trastuzumab, respectively.

Real-world retrospective data from Korea suggest that clinical outcomes with CT-P6 and reference trastuzumab are comparable [17]. A similar percentage of patients with HER2-positive early breast cancer achieved a pathologic complete response with CT-P6 (74.4% [93/125]) compared with reference trastuzumab (69.8% [90/129]) when administered as part of dual HER2-targeted therapy with pertuzumab plus chemotherapy in the neoadjuvant setting [17]. While larger prospective studies are required to confirm these findings, taken together with the 6-year time-to-event results from the present study and earlier findings from the CT-P6 3.2 study [3,4,5], these data support the biosimilarity of CT-P6 to reference trastuzumab in HER2-positive early breast cancer.

The introduction of biosimilars to reference trastuzumab such as CT-P6 increases the available avenues of treatment for patients with early HER2-positive breast cancer. Like most biologics, reference trastuzumab is more costly than traditional chemotherapy; despite improved effectiveness compared with chemotherapy alone, the increased costs may introduce financial barriers to accessing biologic treatment for some patients [18,19,20,21]. Reduced treatment costs, including those associated with biosimilar uptake, could both improve patient access to treatment and reduce the financial burden on healthcare systems [20, 22]. Indeed, a budget impact analysis conducted across France, Germany, Italy, Spain and the UK estimated 5-year savings of €19–172 million with the uptake of biosimilars to reference trastuzumab [23], whereas a larger analysis of CT-P6 for the treatment of breast cancer and gastric cancer conducted across 28 European countries estimated 5-year savings of €0.91–2.27 billion [24]. Real-world findings concur: in a retrospective analysis of 44 patients with HER2-positive early breast cancer, neoadjuvant CT-P6-based treatment was associated with cost savings of €1,474 per patient versus reference trastuzumab, with no difference in efficacy [25]. Lower cost, evidence of long-term clinical equivalence to reference products, and improved education and training are all factors that should influence the future adoption of anti-HER2 biosimilars [26, 27].

This was a multicentre study with a follow-up period of up to 6 years; however, the interpretation of our findings is limited because the study was not powered for survival analysis. Furthermore, data were collected retrospectively for the period between the end of the CT-P6 3.2 study and the start of the CT-P6 4.2 study, and long-term safety data were not collected.

5 Conclusions

Survival data from this extended follow-up of the CT-P6 3.2 study, until up to 6 years after enrolment in the original study, demonstrate the comparable long-term efficacy of CT-P6 and reference trastuzumab in patients with HER2-positive early breast cancer.