Clinical Trial Result Information

Protocol number
BO16216

Title of Study
A randomized, controlled, open-label study to evaluate the efficacy and safety of Herceptin® (trastuzumab) in combination with the oral aromatase inhibitor Arimidex® compared with Arimidex® alone as first line (and second line hormonal) treatment administered to post menopausal, hormone receptor positive (ER+ and/or PgR+) patients with HER2 overexpressing metastatic breast cancer.

Sponsor
Hoffmann-La Roche Ltd /Genentech Inc

Company division
Pharmaceutical

Product name
Herceptin

Generic name
trastuzumab

Therapeutic area
Breast Cancer

Clinical study summary
This was a two-arm, randomized, controlled, open-label, multi-centre study. The data presented here focus on the comparison of efficacy and safety of Arimidex® (anastrazole) alone versus anastrozole plus Herceptin at the time of database lock, when 186 events had been observed. Patients are still in the survival follow-up phase of the study.

Study center(s)
77 centers in Australia, Brazil, Bulgaria, Canada, China, France, Germany, Hungary, India, Israel, Lithuania, Mexico, Poland, Russian Federation, South Africa, Spain, Sweden, Taiwan, Turkey, Ukraine, United Kingdom and USA.

Phase of development
III

Objectives
Primary: To evaluate the efficacy of the combination of Herceptin and anastrozole as compared with anastrozole alone in patients with HER2 overexpression and hormone-sensitive metastatic breast cancer. Efficacy was determined by progression-free survival (PFS).
Secondary: To characterize the safety profile of the combination of Herceptin and anastrozole as compared to anastrozole alone. To determine and compare the overall clinical benefit rate (CBR) between the two treatment arms. CBR is defined as stable disease for ≥6 months, complete response, or partial response. To determine and compare the overall survival, duration of response, and 2-year survival in the two treatment arms.

Methodology
Eligible patients were randomized to receive either anastrozole alone (1 mg/day) or anastrozole plus Herceptin (loading dose 4 mg/kg followed by 2 mg/kg every week thereafter). Tumor assessments were performed at baseline, at week 9 and every 2 months in the main phase of the study. Adverse events were assessed continuously throughout.
The study consisted of a main phase in which patients were treated with anastrozole alone or anastrozole plus Herceptin for up to 730 days or disease progression, whichever came first. Those on the anastrozole alone arm, with disease progression, were allowed to crossover to a Herceptin-containing regimen. At this crossover point, the patient entered the extension phase. Once entering the extension phase, patients were followed up until subsequent disease progression. Patients had a safety follow up 28 days after their last dose of treatment.

Number of patients (planned/analyzed)
208 patients were randomized; 207 received study drug treatment.

Diagnosis and main criteria for inclusion
Postmenopausal women with hormone receptor positive HER2 over-expressing metastatic breast cancer (determined by IHC 3+ and / or FISH positive) who have measurable or evaluable disease.

Test product, dose and mode of administration or test procedure
Herceptin (trastuzumab) - loading dose 4 mg/kg iv infusion on day 1, followed by weekly doses of 2 mg/kg iv infusion plus anastrozole 1mg/day po.

Duration of treatment
Up to 730 days, or until disease progression (main study phase).

Reference therapy, dose and mode of administration or reference procedure
Anastrozole 1 mg/day po.

Criteria for evaluation (efficacy, safety)
Efficacy: In the main phase of the study, tumors were initially assessed by the investigator, and subsequently by an independent Response Evaluation Committee (REC), for response and/or progression of disease. When there was a discrepancy between the investigator’s assessment of tumor response, date of first response noted and date of progression, and the REC assessment, a reconciliation was done by an independent oncologist.
Criteria evaluated were progression-free survival, tumor response, time to progression, time to response, and duration of response. Clinical benefit rate, overall survival and two-year survival were calculated.
Pharmacokinetics: Cmin, Cmax, t1/2, AUC of Herceptin and anastrozole in combination.
Safety: Adverse events, laboratory test parameters, cardiac safety.

Statistical methods
For the primary endpoint, the difference in progression-free survival between treatments was tested with a log rank test.
For secondary endpoints, difference in clinical benefit rate between treatments was tested with a chi-squared test, with rates and 95%-confidence limits calculated and presented. Hauck-Anderson approach was used to calculate confidence limits for the difference. For time to progression and overall survival the difference between treatments was tested with a log rank test.

Summary (efficacy, safety, other results)
Efficacy: The primary objective of the study was met. Statistically significant improvement in progression-free survival was seen when Herceptin was added to anastrozole, compared to anastrozole alone, in all three assessments.

Secondary efficacy: Clinical benefit rate: A significantly higher number of patients (42.7%) achieved a clinical benefit in the anastrozole plus Herceptin arm compared to 27.9% in the anastrozole monotherapy arm (p=0.026).
Tumor response rates: For the population of patients evaluable for response with reconciled assessments, a significantly higher number of patients in the anastrozole plus Herceptin arm demonstrated overall tumor response compared to those in the anastrozole arm (20.3% vs 6.8% respectively) (p=0.018).
Time to progression: Addition of Herceptin to anastrozole doubled the time to disease progression, from 2.4 months in the anastrozole arm to 4.8 months in the anastrozole plus Herceptin arm (p=0.0007).
Time to, and duration of, response: There was no significant difference between the 2 groups in terms of time to response (~2 months) or duration of response (~10 months).
Overall survival: Addition of Herceptin to anastrozole extended the estimated median overall survival by 4.6 months. This extension of survival did not reach statistical significance, but shows a trend favoring Herceptin. It should be noted that >70% of the patients in the anastrozole arm received a Herceptin-containing regimen after disease progression.
2 year survival: A total of 52% of patients taking anastrozole plus Herceptin survived after 2 years, compared with 45% of patients taking anastrozole alone.

Pharmacokinetics: Mean levels of estradiol at week 12 were similar in the anastrozole monotherapy arm and the anastrozole plus Herceptin arm. The pharmacokinetic parameters for anastrozole were broadly similar in the presence and absence of Herceptin.

Safety: As expected, there was a higher incidence of common, non-serious adverse events, drug-related adverse events, grade 3 and 4 adverse events, and serious adverse events in patients treated with anastrozole plus Herceptin, reflecting the inherent reporting bias due to longer treatment duration and more contact with study staff due to weekly Herceptin infusions in the anastrozole plus Herceptin arm, as well as the combination of side effects from both drugs.
Despite these overall increases in the incidence of AEs in the anastrozole plus Herceptin arm as compared with anastrozole treatment alone, very few patients in either treatment arm discontinued study drug due to an adverse event (1 patient in the anastrozole arm and 9 in the anastrozole plus Herceptin arm).

Overview of Adverse Events (Safety Population-Before Crossover)
	Anastrozole Arm (n=104)	Anastrozole plus Herceptin Arm (n=103)
	No. of Patients with AE (%)	No. of Patients with AE (%)
At least one AE	68 (65%)	90 (87%)
AEs related to trial treatment	16 (15%)	55 (53%)
Grade III AE	16 (15%)	24 (23%)
Grade IV AE	1 (1%)	5 (5%)
Serious AE	6 (6%)	24 (23%)
Serious AE related to trial treatment	0 (0%)	4 (4%)
AEs leading to discontinuing trial treatment	1 (1%)	9 (9%)
Deaths due to PD*	59 (57%)	56 (53%)
Deaths not due to PD*	5 (5%)	2 (2%)
*Includes all deaths until database lock

Cardiac Safety: In this study, 3 patients were reported to have serious cardiac disorders (2 myocardial infarctions or 1 myocardial ischemia, one in the anastrozole monotherapy group and 2 in the anastrozole plus Herceptin group). The patient who had myocardial infarction in the anastrozole group died. One patient who experienced myocardial ischemia also had an asymptomatic LVEF drop 11 months after the ischemia event.
Based on clinical assessment (not based on LVEF values), 1 case of congestive heart failure (NYHA class II) was reported in the anastrozole plus Herceptin arm. Asymptomatic NYHA class I heart failure was seen in 3 patients in the anastrozole plus Herceptin arm. The cardiac symptoms of these 4 patients were considered related to study treatment by the investigator. It is noted that 2 of the 4 patients receiving the anastrozole plus Herceptin combination had previously received anthracycline chemotherapy before enrolment.
In the anastrozole arm none of the patients experienced congestive heart failure prior to crossing over to a Herceptin containing regimen. However, after cross over, 1 patient developed symptomatic cardiac failure (NYHA class II), and one developed asymptomatic heart failure (NYHA class I); both patients had received prior anthracycline treatment, and both cases were considered treatment related. A further patient had a sudden death, reported as ‘probable cardiac failure’. She did not have prior anthracycline therapy and the event was not considered related to study treatment by the investigator.
These data are in keeping with the known cardiac safety profile of Herceptin.

Conclusions
The combination of Herceptin and anastrozole in the first-line treatment of women with HER2-positive and hormone receptor-positive metastatic breast cancer led to statistically significant improvements in progression-free survival(which was doubled), overall response rate (tripled), clinical benefit rate, and time to progression, compared to treatment with anastrozole alone. Although not statistically significant, the median survival benefit of 4.6 months was achieved despite significant exposure to Herceptin treatment after progression of patients originally randomized to anastrozole monotherapy.
The combination of Herceptin and anastrozole had manageable toxicity and a low incidence of mild-to-moderate congestive heart failure. No new safety signals were observed.
Both the efficacy and safety observations in this trial support the use of Herceptin in combination with an aromatase inhibitor for the treatment of patients with HER2 and hormone receptor-positive breast cancer in the first-line metastatic setting.

Date of report
8/1/2006

Click here for the protocol registry listing of this trial.