Long-term trastuzumab (Herceptin®) treatment in a continuation study of patients with HER2-positive breast cancer or HER2-positive gastric cancer

The ROP Study was a single-arm, multicenter, international continuation trial of H in participants who had previously completed a global Roche-sponsored trial with H therapy. The ROP Study was performed in accordance with the guidelines for Good Clinical Practice and the Declaration of Helsinki. Approval for the study protocol and any accompanying information provided to patients was obtained from ethics committees at each site (see Additional file 1). The ROP Study is registered on Clinicaltrials.gov, number NCT02721641.

The ROP Study’s primary objectives were to provide H therapy to patients with HER2-overexpressing locally advanced/metastatic breast or gastric/GEJ cancer who had completed any global Roche-sponsored H clinical study, and to follow the long-term outcomes and long-term overall safety in patients treated with H.

Patients were eligible to participate in the ROP Study if they had stable disease, and had their termination data, including tumor assessment and laboratory data, recorded on the Case Report Form (CRF) while receiving H at the end of their H lead-in trial [1, 2, 6‐12]. Patients had received long-term H therapy, defined as ≥ 5 years for patients with HER2-positive locally advanced/metastatic breast cancer and ≥ 3 years for patients with HER2-positive locally advanced gastric/GEJ cancer. Patients with signs of chronic heart failure during the lead-in trial could be included following a risk–benefit assessment by the investigator. Key exclusion criteria were pregnant or nursing women, women of childbearing potential unless using effective contraception, severe dyspnea requiring supplementary oxygen therapy, and severe uncontrolled systemic disease. Signed, informed consent was obtained from all patients.

Patients previously treated with H therapy continued to receive intravenous H (H IV) therapy administered according to the standard H IV weekly (4 mg/kg loading dose followed by weekly 2 mg/kg maintenance doses starting a week after the loading dose) or 3-weekly (8 mg/kg loading dose followed by 3-weekly 6 mg/kg maintenance doses starting 3 weeks after the loading dose) schedule, at the discretion of the treating physician. H therapy was continued until disease progression, investigator-assessed lack of treatment benefit, unacceptable toxicity, patient decision, or patient death. H administration could be delayed in the event of cardiac toxicity following an algorithm based on left ventricular ejection fraction (LVEF) assessment, but no dose modifications were permitted. If delayed, H was reinitiated in accordance with the reloading guidelines. For patients whose dose was delayed by ≤ 7 days, a maintenance dose was administered as soon as possible and subsequent maintenance doses were continued according to the original schedule. For those whose dose was delayed by > 7 days, a loading dose of 8 mg/kg or 4 mg/kg (depending on the patient’s dosing schedule) was administered and then maintenance doses were reinitiated and administered at regular intervals from that point. In addition to H therapy, continuation of treatment with other anticancer drugs at the same dose and schedule as that received in the H lead-in trial was permitted, provided that the treatment was still ongoing at completion of the lead-in trial and that it was still considered beneficial for the patient.

Tumor assessments for disease progression were performed as clinically indicated and at the discretion of the investigator, and the date of disease progression was recorded in the CRF. Cardiac status was assessed using an echocardiogram or multigated acquisition scan as clinically indicated. Cardiac failure (New York Heart Association [NYHA] class II–IV) was reported as a serious adverse event (SAE), and was graded as per NCI-CTCAE version 3 criteria or NCI-CTC version 2 and the NYHA classification system. SAEs were reported per the ICH Guideline for Clinical Safety Data Management, Definitions and Standards for Expedited Reporting, Topic E2. Hematology and biochemistry laboratory assessments were performed as per the standard medical practice at each site. The date of, and reason for, study completion were recorded in the CRF.

The current analysis is descriptive and safety data are summarized herein. Sample size calculation was not applicable due to the nature of the study, and all eligible patients were included. No formal hypothesis testing was performed.

Sixty-nine patients were enrolled in the ROP Study at 38 medical centers in 17 countries. Of these, 25 patients enrolled in 17 medical centers in 11 countries had received long-term H therapy, defined as ≥ 5 years of H therapy for patients with HER2-positive locally advanced or metastatic breast cancer and ≥ 3 years of H therapy for patients with HER2-positive locally advanced or metastatic gastric/GEJ cancer. These patients were included in the ROP Study after completing one of the nine global Roche-sponsored H trials in Table 1. Their baseline patient demographics and clinical characteristics are shown in Table 2. The median age at baseline of all patients included in the current analysis was 55 years (range 38–75 years) and 80% of patients were female (Table 2). The 19 patients with HER2-positive locally advanced/metastatic breast cancer were female and had a median age of 53 years (range 38–75 years). The remaining six patients (five males and one female) had HER2-positive locally advanced/metastatic gastric/GEJ cancer and had a median age of 61 years (range 52–74 years).

At the end of the ROP Study, all patients included in this analysis had withdrawn from study treatment. Reasons for withdrawal included the occurrence of AEs (n = 1; 4%); insufficient therapeutic response, including disease progression (n = 6; 24%); switch to commercially available H therapy (n = 2; 8%); and refusal of treatment (n = 1; 4%). Other reasons for withdrawal were reported for 15 patients (60%), and included: study completion/closure (n = 5); sponsor request (n = 4); investigator decision (n = 3); switch to subcutaneous trastuzumab (Herceptin® SC, F. Hoffmann-La Roche Ltd) (n = 2); and agreement with the patient to discontinue treatment until further disease progression (n = 1) (Table 3).

The median duration of H treatment in patients with breast cancer was 8 years and 7 months (3124 days), with a range of 5 years and 4 months to 13 years and 11 months (1940–5068 days). For patients with gastric/GEJ cancer, the median duration of H treatment was 5 years and 2 months (1886 days) with a range of 3 years and 4 months to 7 years and 4 months (1214–2677 days).

Figure 1 shows the worst LVEF for each year of treatment. LVEF measurements were available for 20 of the 25 patients included in these analyses. The cardiac status of these patients remained stable over time, with no marked changes in LVEF. The median overall worst LVEF measurement was 57.0% and no patients experienced an LVEF of < 45% (range 47–63%).

In total, seven of the 25 patients (28.0%) reported SAEs (Table 4), none of which was related to study treatment. Reported SAEs were pain, septic arthritis, erysipelas, lung cancer, fibula fracture, urinary tract infection and a broken leg, which all occurred in one patient (4.0%) each (Table 4). There were no reports of any cardiac SAEs or SAEs that led to study withdrawal, and no patients died while on study treatment.