Six-Year Survival Outcomes for Patients with HER2-Positive Early Breast Cancer Treated with CT-P6 or Reference Trastuzumab: Observational Follow-Up Study of a Phase 3 Randomised Controlled Trial

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. 1figure 1

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.

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