Clinical Trial Result Information

Protocol number
BO16348

Title of Study
A randomized three-arm multi-center comparison of 1 year and 2 years of Herceptin® versus no Herceptin® in women with HER2-positive primary breast cancer who have completed adjuvant therapy.

Sponsor
F Hoffmann-La Roche Ltd

Company division
Pharmaceutical

Product name
Herceptin

Generic name
trastuzumab

Therapeutic area
Breast Cancer

Clinical study summary
This study was set up as a three-arm, randomized, open-label, multi-center study in women with primary breast cancer that overexpress HER2, comparing the effect of 1 year or 2 years of Herceptin treatment and standard adjuvant treatment without Herceptin. The data presented here focus on the comparison of efficacy and safety of the 1 year Herceptin arm versus the observation only arm based on a protocol-specified interim analysis of the data performed after half of the required (951) events of disease-free survival were recorded on the database. The study is ongoing; data from the 2 year Herceptin arm have not yet been released by the Independent Data Monitoring Committee (IDMC).

Study center(s)
478 centers in Argentina, Australia, Austria, Belgium, Brazil, Canada, Chile, China, Costa Rica, Croatia, Denmark, France, Germany, Greece, Guatemala, Hungary, Ireland, Israel, Italy, Japan, Mexico, Netherlands, New Zealand, Norway, Panama, Poland, Portugal, Republic of Korea, Russian Federation, Singapore, Slovakia, South Africa, Spain, Sweden, Switzerland, Taiwan, Thailand and UK.

Phase of development
III

Objectives
Primary: To compare disease-free survival (DFS) in patients with HER2 overexpressing primary breast cancer who have been randomized to Herceptin versus no Herceptin.
Secondary: To compare overall survival (OS) in patients randomized to Herceptin versus no further therapy; to compare recurrence-free survival (RFS); to compare distant disease-free survival (DDFS); to evaluate the safety and tolerability of Herceptin; to compare the incidence of cardiac dysfunction in patients treated and not treated with Herceptin.

Methodology
Eligible patients were randomized into one of three arms to begin therapy with Herceptin (loading dose 8 mg/kg followed by 6 mg/kg every three weeks thereafter) for one year or two years, or standard treatment (observation only). HER2 determination was performed at baseline. A radiologic examination including chest X-ray, bone scan, bilateral mammogram and liver imaging was performed at baseline and week 52. A physical exam and assessment of biochemistry and hematology parameters was performed at baseline and at regular intervals throughout the study. Cardiac monitoring (ECG, LVEF, signs/symptoms and cardiac questionnaire) was performed at baseline and at subsequent regular intervals. Adverse events were assessed continuously throughout. On completion of the treatment period, patients were to be followed for up to year 10.

Number of patients (planned/analyzed)
Overall 5102 women were enrolled into the study. Data from 3386 patients were available for the interim efficacy analysis comparing treatment with 1 year of Herceptin, with observation. (1 year Herceptin: full analysis set – 1693, safety population – 167

Diagnosis and main criteria for inclusion
Women with primary invasive breast cancer that overexpress HER2 (determined as IHC 3+ and/or FISH positive) who have undergone definitive surgery and have completed (neo-) adjuvant systemic chemotherapy, and radiotherapy, if applicable.

Test product, dose and mode of administration or test procedure
Herceptin (trastuzumab). Loading dose 8 mg/kg i.v. infusion over ~90 minutes on day 1, followed by maintenance dose of 6 mg/kg i.v. infusion over ~90 minutes three weeks later and thereafter every 3 weeks.

Duration of treatment
1 year, or until disease progression (Data of the 2 years Herceptin arm have not yet been released).

Reference therapy, dose and mode of administration or reference procedure
N/A

Criteria for evaluation (efficacy, safety)
Breast cancer recurrence (assessed by CT or MRI scans, X-ray, bone scan, physical examination); second primary cancer (contralateral breast or non-breast malignancy); death from any cause as first event. OS as determined by death from any cause.
Safety: Adverse events, laboratory test parameters, cardiac safety.

Statistical methods
For primary and secondary efficacy parameters, comparisons were made between the 1 year Herceptin and observation only arms using an unstratified log rank test. Hazard ratios and 95 % confidence limits were given. All safety parameters were analyzed descriptively.

Summary (efficacy, safety, other results)
Efficacy: The primary endpoint was Disease-Free Survival (DFS). The interim efficacy analysis was based on the data recorded in the database until the clinical cut-off date. The median follow-up was 1 year. A markedly lower number of patients receiving 3-weekly Herceptin treatment experienced any of the following disease events compared with the observation arm (127 patients versus 219 patients): any loco-regional or distant recurrence of BC, the development of contralateral BC or second non-breast malignancy other than basal or squamous carcinoma of the skin and carcinoma in situ of the cervix, or death from any cause without documentation of one of these events. The log rank test was highly statistically significant (p<0.0001). Herceptin treatment was associated with a 46% reduction in the risk of disease (HR = 0.54; 95% CI, 0.44-0.67) which translates into an absolute benefit, in terms of a 2 year DFS rate, of 7.6 percentage points (85.80% vs 78.18%) in favor of the Herceptin arm. The benefit in disease-free survival was seen in all patient subgroups analyzed. The hazard ratio for RFS and DDFS was 0.51 and 0.50, respectively. Similar risk reductions were seen for other parameters including Time to Recurrence, Time to Distant Recurrence and Disease-Free Survival from Surgery. A lower number of patients in the 1 year Herceptin arm died during the study period compared with the observation only arm (31 versus 40, respectively), yet at this point the difference in overall survival was not statistically significant.

An updated efficacy analysis performed 1 year later with a median follow-up of 23 months showed that overall survival between the two arms was statistically significantly different. A total of 59 deaths were reported for Herceptin and 90 for observation. The unadjusted hazard ratio for the risk of death with Herceptin compared with observation was 0.66 (95% confidence interval [CI] 0.47-0.91; p=0.0115). 218 DFS events were reported with Herceptin compared with 321 with observation. The unadjusted hazard ratio for the risk of an event with Herceptin compared with observation was 0.64 (95% CI 0.54-0.76; p<0.0001) There was no evidence of substantial heterogeneity in the relative treatment effect on DFS among subgroups.

General Safety: Based on the results of the interim analysis, a total of 46% (792/1708) of patients in the observation arm and 70% (1179/1678) of patients in the Herceptin arm experienced one or more adverse events during the study. A higher percentage of patients in the Herceptin treatment arm (8.6%) compared with the observation arm (4.6%) experienced one or more grade III adverse events. The most frequent of these were hypertension, hot flush, vomiting, headache, diarrhea and congestive cardiac failure. Ten observation arm patients and 13 Herceptin arm patients experienced a Grade IV adverse event. Two grade IV adverse events (cardiac failure, congestive cardiac failure) were considered related to Herceptin treatment. In both cases, treatment with Herceptin was discontinued and the events resolved without sequelae. There were 5% of patients in the observation arm in whom at one or more serious adverse events were reported compared with 8% of patients in the 1 year Herceptin arm. Congestive cardiac failure (7 patients), cardiac failure (4 patients), chills (4 patients), pyrexia (3 patients) and hypotension (2 patients) were the only adverse events considered related to Herceptin treatment which were recorded by more than one patient each.

Ninety seven patients were prematurely withdrawn from treatment as a result of at least one adverse event. The most common adverse events leading to premature withdrawal from treatment were congestive cardiac failure (23 patients) and ejection fraction decreased (21 patients). Of the 97 patients withdrawn from treatment as a result of an adverse event, 88 were withdrawn due to an adverse event considered related to Herceptin treatment. A total of 40 patients (2.4%) in the observation arm and 31 patients (1.8%) in the Herceptin arm died during the study period (or within 28 days of the study). The most common cause of death was disease progression of the underlying breast cancer. Two patients in the observation arm (suicide, cardiac failure) and 4 patients in the Herceptin arm (cerebral hemorrhage, cerebrovascular accident, sudden death, appendicitis) died as a result of an adverse event. One Herceptin patient died as a result of a road accident.

Cardiac Safety: Ten patients in the Herceptin arm (0.6%) and 1 patient in the observation arm (0.1%) had a primary cardiac endpoint. A primary cardiac endpoint was defined as either symptomatic congestive heart failure of NYHA class III or IV and a drop in LVEF of at least 10 EF points from baseline and to below 50% or cardiac death due to CHF, myocardial infarction or documented primary arrhythmia, or sudden unexpected death within 24 hrs of a definite or probable cardiac event (syncope, cardiac arrest, chest pain, infarction, arrhythmia, etc.) without documented etiology. All primary cardiac endpoints occurred during the first year of the study. Cardiac failure (probably due to pulmonary embolism) experienced by one observation arm patient led to the death of the patient. None of the cardiac events in the 1 year Herceptin arm led to patient death. Of the Herceptin patients with a primary cardiac endpoint, 8 were classified with NYHA class III CHF and two were classified with NYHA class IV CHF.
Fifty-one (3.0%) Herceptin arm patients and 9 (0.5%) observation arm patients met the criteria for a secondary cardiac endpoint. A secondary cardiac endpoint was defined as a significant asymptomatic (NYHA class I) or mildly symptomatic (NYHA class II) LVEF drop measured by MUGA scan or echocardiogram, unless the following assessment of LVEF indicated a return to levels which did not meet the definition of a significant LVEF drop. A significant LVEF drop was defined as an absolute decrease of 10 EF points or more from baseline and to below 50%. In addition, events which did not meet the above criteria for a secondary cardiac endpoint but which in the opinion of the Cardiac Advisory Board should be classed as secondary cardiac endpoints were included. Most of the secondary cardiac endpoint events occurred during the first half year of treatment. In the majority of cases, following discontinuation of Herceptin therapy, either a stabilization of the LVEF occurred or there was a trend towards the baseline LVEF value.
The percentage of patients with significant LVEF drops (decrease of >=10 EF points and to <50%) at each timepoint during the study was greater in the 1 year Herceptin arm than in the observation arm. Overall, a total of 7.4% of patients in the 1 year Herceptin arm experienced at least one significant LVEF drop during the study compared with 2.3% patients in the observation arm. Only about half of the Herceptin patients who had an initial significant LVEF drop were later confirmed by a subsequent assessment to have a primary or secondary cardiac endpoint. The clinical significance of a single LVEF drop is unclear.
In terms of laboratory test parameter data, fewer Herceptin arm patients experienced grade III or grade IV shifts from baseline compared with the observation arm. There was no clinically relevant difference between treatment arms with respect to the shifts seen. There were no clinically relevant changes from baseline in vital signs and no differences between the study arms with respect to the change from baseline data.

Conclusions
The results of the interim analysis showed that Herceptin given every 3 weeks for one year following (neo-) adjuvant chemotherapy and radiotherapy (if applicable) significantly prolonged DFS, RFS and DDFS for women with HER2 positive early breast cancer. The observed effect of Herceptin was independent of patients’ baseline characteristics (nodal status, hormone receptor status, age) and previous (neo-) adjuvant therapy. Herceptin significantly reduced the risk of distant metastases. A follow-up analysis performed one year later demonstrated a statistically significant overall survival benefit for patients treated with 1 year of Herceptin.
No new or unexpected safety findings were identified with adjuvant Herceptin treatment. Herceptin therapy was associated with a low incidence of NYHA class III or IV congestive heart failure (0.6%). Cardiac dysfunction was clinically manageable; 80% of patients with severe CHF were asymptomatic at the time of database closure, and 60% had a recovery of LVEF to at least 55%.
These data support the use of Herceptin (8 mg/kg loading dose on day 1, followed by 6 mg/kg every 3 weeks thereafter for 1 year or until disease recurrence) as adjuvant treatment for patients with HER2 positive early breast cancer, who have completed (neo-) adjuvant systemic chemotherapy, definitive surgery and radiotherapy, if applicable.

Publications (references, if available)
Piccart-Gebhart MJ, Procter M, Leyland-Jones B et al. A randomized trial of trastuzumab following adjuvant chemotherapy in women with HER2-positive breast cancer. N Engl J Med 2005; 353: 1659-1672.
Smith I et al Accepted by NEJM

Date of report
1/1/2006

Click here for the protocol registry listing of this trial.