Clinical Trial Result Information

Protocol number
M77998

Title of Study
Expanded access programme: treatment with Herceptin (trastuzumab) in patients with metastatic breast cancer (MBC) who overexpress HER2

Sponsor
Roche Products Ltd

Company division
Pharmaceutical

Product name
Herceptin

Generic name
trastuzumab

Therapeutic area
Breast Cancer

Clinical study summary
This was an expanded access, Phase IV, open-label, non-randomized, multi-center study of patients with metastatic breast cancer with tumors that overexpress HER2, who were not eligible for other Herceptin studies. Patients received weekly intravenous (iv) Herceptin 2 mg/kg for a minimum of 8 weeks and until disease progression, in combination with either paclitaxel 100 mg/m2 or docetaxel 175 mg/m2 3 times weekly for 18 weeks.

Study center(s)
32 centers in the United Kingdom.

Phase of development
IV

Objectives
The original program objective was to assess the safety of Herceptin in patients with metastatic breast cancer who were not eligible for other Herceptin study protocols. Although the program was not set up to assess survival, it was noted that patients in the study were surviving longer than originally expected, which led to clinical hypotheses being generated that form the basis of the following analysis objectives: To investigate (1) Pre-treatment characteristics of patients with short- and long-term survival; (2) If there are any differences in the duration of disease-free remission in patients who receive Herceptin alone compared with those who receive Herceptin in combination with either paclitaxel or docetaxel.

Methodology
Patients received Herceptin either as a single agent or in combination with a taxoid (paclitaxel or docetaxel). Patients were treated with weekly infusions of Herceptin until disease progression (a minimum of 8 Herceptin infusions was recommended). The recommended duration of taxoid treatment was 18 weeks. Dose modification for the taxoid was allowed according to accepted clinical practice; if Herceptin was not tolerated, the infusion was discontinued.

Number of patients (planned/analyzed)
170 enrolled

Diagnosis and main criteria for inclusion
Eligible women 18–75 years of age (>75 included at investigators’ discretion) with metastatic breast cancer and HER2 overexpression at the level of 12/13 on immunohistochemistry (IHC). Pregnant, lactating, or women of childbearing potential with inadequate contraception were excluded from the trial, as well as patients with clinically significant cardiac disease, prior treatment with doxorubicin at a cumulative dose of >300 mg/m2 or epirubicin >750 mg/m2. Prior treatment with a taxoid was allowed only in the Herceptin monotherapy arm.

Test product, dose and mode of administration or test procedure
iv Herceptin, loading dose of 4 mg/kg, then 2 mg/kg/week.

Duration of treatment
Herceptin, until disease progression; taxoid, 18 weeks.

Reference therapy, dose and mode of administration or reference procedure
Docetaxel, 100 mg/m2/tiw; or paclitaxel, 175 mg/m2/tiw.

Criteria for evaluation (efficacy, safety)
Duration of disease-free progression; safety parameters

Statistical methods
The survival curves of the 2 treatment groups were compared using the Cox proportional hazards regression model. The analysis was adjusted for pre-treatment (baseline) characteristics. The adjusted hazard ratio for treatment effect and other pre-treatment characteristics was presented along with the associated 95% confidence interval (CI) and significance level.

Summary (efficacy, safety, other results)
Efficacy: Few patients (n=4) received paclitaxel with Herceptin and were not included in the final analysis. Kaplan-Meyer curves for time on treatment are shown in Figure 1. The median time on treatment was 6 and 10 months for the Herceptin alone and Herceptin plus docetaxel arms, respectively. The difference can be largely attributed to the fact that Herceptin alone was used mainly as a second/third-line treatment whereas the combination was used as a first/second-line treatment. At the cutoff for the current analysis, 12 patients from the Herceptin monotherapy group (16.0%) and 21 from the Herceptin plus docetaxel group (24.1%) were still on treatment. Table 1 presents the results of the Cox proportional hazards analysis. The hazard ratios (95% CI) indicate that higher numbers of previous hormonal treatments and lower performance status were associated with shorter times on treatment. Higher albumin levels and longer initial disease-free survival were associated with longer time on treatment. After adjustment for all the other variables in the model, including the line of treatment, the hazard ratio for disease progression was lower, and
thus, the prognosis was better in patients receiving docetaxel with Herceptin compared with those receiving Herceptin alone (hazard ratio [95%CI] =0.49 [0.311, 0.775]).

Figure 1: Kaplan-Meyer curves for patients with metastatic breast cancer who overexpress HER2, given trastuzumab alone or in combination with docetaxel. Time on treatment is used as a surrogate marker for time to treatment failure.

Table 1: Results from the Cox's proportional hazards model for time to disease progression (days): intention-to-treat population.

*Estimated change in the hazard for each unit increase.

Safety: In regard to cardiac adverse events, 1 patient in the Herceptin monotherapy arm developed supraventricular tachycardia and 2 patients in the combination arm had an episode of atrial fibrillation while on treatment. In 20 patients in the Herceptin monotherapy arm and 36 patients in the combination arm, the left ventricular injection fraction (LVEF) was estimated by multiple gated acquisition (MUGA) scan before treatment and in 3-month intervals. . The average decrease in LVEF was 4% and 7% in the monotherapy and combination arms, respectively. In 1 patient in the Herceptin monotherapy arm, LVEF levels decreased by >15% to absolute LVEF levels 15%, but only 1 to absolute LVEF levels <50%. This patient developed symptomatic heart failure; Herceptin/docetaxel was discontinued and the LVEF returned to normal. Herceptin was re-introduced later, a partial response to the treatment was achieved, and no decrease in LVEF was observed.

Conclusions
The expanded access program gave clinicians experience of Herceptin in settings that more closely reflected normal clinical practice as compared with clinical trials. The program confirmed the feasibility and safety of Herceptin administration both as monotherapy and in combination with docetaxel, with a risk of cardiac events considered to be at an acceptable level.

Publications (references, if available)
Papazisis KT, Habeshaw T, Miles DW et al. Safety and efficacy of the combination of trastuzumab with docetaxel for HER2-positive women with advanced breast cancer. A review of the existing clinical trials and results of the expanded access programme in the UK. Int J Clin Pract 2004; 58: 581-586

Date of report
10/11/2002