Clinical Trial Result Information

Protocol number
M77001

Title of Study
A Multicenter, Randomized Comparative Study on the Efficacy and Safety of Herceptin (Trastuzumab) Plus Docetaxel (Taxotere) Versus Docetaxel Alone as First Line Treatment in Patients with HER2-Positive Metastatic Breast Cancer

Sponsor
Hoffmann-La Roche Ltd

Company division
Pharmaceutical

Product name
Herceptin

Generic name
trastuzumab

Therapeutic area
Metastatic breast cancer

Clinical study summary
This randomized, open-label, 2-arm study evaluated the efficacy and safety of Herceptin plus docetaxel versus docetaxel alone in patients with HER2-positive metastatic breast cancer (MBC) who have not previously received chemotherapy.

Study center(s)
49 centers in Australia, Belgium, Denmark, France, Hungary, Ireland, Italy, Netherlands, Portugal, Russia, Spain, Sweden and the UK.

Phase of development
II

Objectives
Primary: To determine the overall response rate in each treatment arm.

Secondary: (1) To characterize the safety profile of docetaxel plus Herceptin and of docetaxel as a single agent in patients with HER2-positive MBC; (2) To determine the time to progression (TTP), and time to treatment failure (TTF), progression free survival (PFS), duration of response (DR), and overall survival (OS).

Methodology
Eligible patients were randomized to receive either Herceptin+docetaxel, or docetaxel monotherapy. Docetaxel was administered every 3 weeks, for 6 cycles, +/- Herceptin, which was administered weekly until disease progression. Subsequently, treatment could continue until disease progression, unacceptable toxicities, and death or withdrawal. Patients randomized to docetaxel monotherapy who experienced disease progression could switch to Herceptin. Tumour evaluation was assessed every 3 cycles throughout the study, and safety parameters were assessed at every cycle.

Number of patients (planned/analyzed)
188 randomized; 186 treated.

Diagnosis and main criteria for inclusion
Women with MBC; between 18 and 70 years of age; HER2 overexpression/amplification (IHC3+ and/or FISH-positive); no previous chemotherapy except given as neoadjuvant or adjuvant treatment.

Test product, dose and mode of administration or test procedure
Herceptin, 4 mg/kg (loading dose)/iv over 90 min on Day 1; followed by Herceptin, 2 mg/kg/iv over 30 min/ weekly.

Duration of treatment
A minimum of 6 x 3-week cycles. Patients could receive further cycles of docetaxel at the investigator’s discretion. Herceptin was administered weekly until disease progression.

Reference therapy, dose and mode of administration or reference procedure
Docetaxel, 100 mg/m²/iv on study Day 2; followed by Docetaxel,100 mg/m²/iv every 3 weeks

Criteria for evaluation (efficacy, safety)
Primary efficacy parameter: Overall (complete and partial) response rate.

Secondary efficacy parameters: (1) DR; (2) TTP; (3) OS; (4) PFS; (5) TTF.

Safety parameters: Safety parameters included incidence of common toxicity criteria (CTC)- graded adverse events and laboratory abnormalities (including cardiac monitoring [left ventricular ejection fraction (LVEF)]).

Statistical methods
The primary endpoint (overall response) was compared between treatment groups using a chi-squared test. Standard survival methodology was used to estimate time to event variables. The initial data cutoff date was 6 months after last patient enrollment; efficacy data from the 24 month data cutoff date are also presented. Safety variables were summarized descriptively.

Summary (efficacy, safety, other results)
Efficacy-At the initial 6 month analysis, primary (overall tumour response rate) and secondary (median duration of response, TTP and overall survival) efficacy parameters were significantly higher for patients treated with Herceptin plus docetaxel compared with that for patients treated with docetaxel alone. At the 24 month update, all secondary efficacy endpoints (duration of response, time to progression, overall survival, progression-free survival and time to treatment failure) were significantly prolonged in the Herceptin plus docetaxel arm compared to the docetaxel arm.

Key Efficacy Results (FAS Population)—24 month data cutoff
Endpoint	Docetaxel (months) N=94	Herceptin plus docetaxel (months) N=92	p value
Duration of response	5.7 (4.6-7.6)	11.7 (9.3-15)	p=0.009
Time to progression	6.1 (5.4-7.2)	11.7 (9.2-13.5)	p=0.0001
Overall survival	22.7 (19.1-30.8)	31.2 (27.3-40.8)	p=0.0325
Progression-free survival	6.5 (5.7-7.7)	11.7 (9.8-15.6)	p=0.0107
Time to treatment failure	5.3 (4.8-5.7)	9.8 (6.5-11.7)	p=0.0001

Safety- Common adverse events were more frequently experienced by patients in the Herceptin plus docetaxel arm and included those typically associated with docetaxel treatment (alopecia, asthenia, nausea, diarrhea, peripheral edema, vomiting, neuropathy, and neutropenia) and influenza-like illness and rigors, which are infusion-related reactions commonly observed with intravenous Herceptin administration. The overall incidence of adverse events (whether drug-related or not) at the 6 month data cutoff is summarized below.

	Docetaxel alone (N=94)	Docetaxel + Herceptin (N=92)
Any AE	93(99%)	92(100%)
Grade 3 AE	52(55%)	62(67%)
Grade 4 AE	22(23%)	31(34%)
Serious AE	29(31%)	37(40%)
AE leading to withdrawl	23(24%)	11(12%)
AE possibly related to treatment	89(95%)	89(97%)
Death due to PD	32(34%)	18(20%)
Death other than PD	2(2%)	2(2%)

Four deaths (2 in each treatment arm) were not attributed to progressive disease (PD). Two patients died with heart failure in the context of progressive disease in the Herceptin plus docetaxel arm. In 1 case, the heart failure was considered by the investigator to be Herceptin-related. In the second case, the cardiac failure occurred after stopping Herceptin and was judged by the investigator to be related to a novel anthracycline drug, which was given to the patient only 1 month after stopping study treatment.

Two patients treated with docetaxel alone died due to septic events and multi-organ failure, which was considered by the investigator to be related to docetaxel treatment.

More than half of all serious adverse events were related to hematologic toxicity (leukopenia/neutropenia) and associated complications (infections/sepsis). More patients in the Herceptin arm (40%) than in the docetaxel alone arm (31%) experienced serious adverse events.

Fewer patients in the Herceptin plus docetaxel arm (12%) than in the docetaxel alone arm (24%) withdrew due to adverse events. Events leading to discontinuation in >1 patient included nail disorders, edema, asthenia, and paresthesia in the docetaxel alone arm and cardiac dysfunction (4 patients; 3 asymptomatic LVEF declines) in the Herceptin plus docetaxel arm.

A total of 12 possible cardiac-related adverse events (mainly tachycardia and palpitations) were reported in the Herceptin plus docetaxel arm as compared with 3 in the docetaxel alone arm. Most of these events were non-serious (CTC grades 1 and 2). However, there were 2 cases (2%) of congestive heart failure in the Herceptin plus docetaxel arm which lead to death (see above) — one was considered by the investigator related to Herceptin treatment.

Addition of Herceptin to docetaxel treatment resulted in an increased incidence of asymptomatic declines in LVEF. Seventeen percent of patients in the Herceptin plus docetaxel arm and 8% in the docetaxel alone arm had decreases in LVEF >=15% at any time during the study. Most were able to continue Herceptin without worsening dysfunction or development of symptoms (3 patients stopped treatment due to asymptomatic LVEF declines).

Hematology: Grade 3 or 4 neutropenia was more frequently observed in patients in the Herceptin plus docetaxel than in the docetaxel alone arm (32% vs 22%). The incidence of febrile neutropenia/neutropenic sepsis was also slightly increased in patients receiving Herceptin plus docetaxel (23% vs 17%). There were 2 drug-related deaths due to septicemia in the docetaxel alone arm. Grades 1 and 2 anemia and thrombocytopenia were also slightly more frequent in the Herceptin plus docetaxel arm.

Conclusions
The combination of Herceptin and docetaxel in first-line treatment of women with HER2-positive metastatic breast cancer led to clinically and statistically significant improvements in tumor response rate, duration of response, progression-free survival, and overall survival compared with treatment with docetaxel alone. The estimated survival benefit of 8.5 months was achieved despite significant crossover to Herceptin treatment in patients randomized to docetaxel treatment alone. The combination of Herceptin and docetaxel had manageable toxicity, although a slight increase in hematologic toxicity No new unexpected safety signals were observed.

Publications (references, if available)
Marty et al, JCO, published ahead of print on May 23rd, 2005 as 10.1200/JCO.2005.04.173

Date of report
9/15/2003