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ELLENCE® (epirubicin HCl) Clinical Studies

14 CLINICAL STUDIES

14.1 Adjuvant Treatment of Breast Cancer

Two randomized, open-label, multicenter studies evaluated the use of ELLENCE 100 to 120 mg/m2 in combination with cyclophosphamide and fluorouracil for the adjuvant treatment of patients with axillary-node positive breast cancer and no evidence of distant metastatic disease (Stage II or III). Study MA-5 evaluated 120 mg/m2 of ELLENCE per course in combination with cyclophosphamide and fluorouracil (CEF-120 regimen). This study randomized premenopausal and perimenopausal women with one or more positive lymph nodes to an ELLENCE-containing CEF-120 regimen or to a CMF regimen. Study GFEA-05 evaluated the use of 100 mg/m2 of ELLENCE per course in combination with fluorouracil and cyclophosphamide (FEC-100). This study randomized pre- and postmenopausal women to the FEC-100 regimen or to a lower-dose FEC-50 regimen. In the GFEA-05 study, eligible patients were either required to have ≥4 nodes involved with tumor or, if only 1 to 3 nodes were positive, to have negative estrogen- and progesterone-receptors and a histologic tumor grade of 2 or 3. A total of 1281 women participated in these studies. Patients with T4 tumors were not eligible for either study. Table 5 shows the treatment regimens that the patients received. Relapse-free survival was defined as time to occurrence of a local, regional, or distant recurrence, or disease-related death. Patients with contralateral breast cancer, second primary malignancy, or death from causes other than breast cancer were censored at the time of the last visit prior to these events.

Table 5. Treatment Regimens Used in Phase 3 Studies of Patients with Early Breast Cancer
Treatment GroupsAgentRegimen
*
In women who underwent lumpectomy, breast irradiation was to be administered after completion of study chemotherapy.
Patients also received prophylactic antibiotic therapy with trimethoprim-sulfamethoxazole or fluoroquinolone for the duration of their chemotherapy.
All women were to receive breast irradiation after the completion of chemotherapy.
MA-5*
N=716
CEF-120 (total, 6 cycles) N=356
CMF (total, 6 cycles) N=360
Cyclophosphamide
ELLENCE
Fluorouracil
Cyclophosphamide
Methotrexate
Fluorouracil
75 mg/m2 PO, d 1–14, q 28 days
60 mg/m2 IV, d 1 & 8, q 28 days
500 mg/m2 IV, d 1 & 8, q 28 days
100 mg/m2 PO, d 1–14, q 28 days
40 mg/m2 IV, d 1 & 8, q 28 days
600 mg/m2 IV, d 1 & 8, q 28 days
GFEA-05
N=565
FEC-100 (total, 6 cycles)
N=276
FEC-50 (total, 6 cycles)
N=289
Tamoxifen 30 mg daily × 3 years, postmenopausal women, any receptor status
Fluorouracil
ELLENCE
Cyclophosphamide
Fluorouracil
ELLENCE
Cyclophosphamide
500 mg/m2 IV, d 1, q 21 days
100 mg/m2 IV, d 1, q 21 days
500 mg/m2 IV, d 1, q 21 days
500 mg/m2 IV, d 1, q 21 days
50 mg/m2 IV, d 1, q 21 days
500 mg/m2 IV, d 1, q 21 days

In the MA-5 trial, the median age of the study population was 45 years. Approximately 60% of patients had 1 to 3 involved nodes and approximately 40% had ≥4 nodes involved with tumor. In the GFEA-05 study, the median age was 51 years and approximately half of the patients were postmenopausal. About 17% of the study population had 1 to 3 positive nodes and 80% of patients had ≥4 involved lymph nodes. Demographic and tumor characteristics were well-balanced between treatment arms in each study.

Relapse-free survival (RFS) and overall survival (OS) were analyzed using Kaplan-Meier methods in the intent-to-treat (ITT) patient populations in each study. Results were initially analyzed after up to 5 years of follow-up and these results are presented in the text below and in Table 6. Results after up to 10 years of follow-up are presented in Table 6. In Study MA-5, ELLENCE-containing combination therapy (CEF-120) showed significantly longer RFS than CMF (5-year estimates were 62% versus 53%, stratified logrank for the overall RFS p=0.013). The estimated reduction in the risk of relapse was 24% at 5 years. The OS was also greater for the ELLENCE-containing CEF-120 regimen than for the CMF regimen (5-year estimate 77% versus 70%; stratified logrank for overall survival p=0.043; non-stratified logrank p=0.13). The estimated reduction in the risk of death was 29% at 5 years.

In Study GFEA-05, patients treated with the higher-dose ELLENCE regimen (FEC-100) had a significantly longer 5-year RFS (estimated 65% versus 52%, logrank for the overall RFS p=0.007) and OS (estimated 76% versus 65%, logrank for the overall survival p=0.007) than patients given the lower dose regimen (FEC-50). The estimated reduction in risk of relapse was 32% at 5 years. The estimated reduction in the risk of death was 31% at 5 years. Results of follow-up up to 10 years (median follow-up = 8.8 years and 8.3 years, respectively, for Study MA-5 and Study GFEA-05) are presented in Table 6.

Although the trials were not powered for subgroup analyses, in the MA-5 study, improvements in favor of CEF-120 vs. CMF were observed, in RFS and OS both in patients with 1–3 node positive and in those with ≥4 node positive tumor involvement. In the GFEA-05 study, improvements in RFS and OS were observed in both pre- and postmenopausal women treated with FEC-100 compared to FEC-50.

Table 6. Efficacy Results from Phase 3 Studies of Patients with Early Breast Cancer*
MA-5 StudyGFEA-05 Study
CEF-120
N=356
CMF
N=360
FEC-100
N=276
FEC-50
N=289
*
Based on Kaplan-Meier estimates
Hazard ratio: CMF:CEF-120 in MA-5, FEC-50:FEC-100 in GFEA-05
Patients in MA-5 were stratified by nodal status (1–3, 4–10, and >10 positive nodes), type of initial surgery (lumpectomy versus mastectomy), and by hormone receptor status (ER or PR positive (≥10 fmol), both negative (<10 fmol), or unknown status). Patients in GFEA-05 were stratified by nodal status (1–3, 4–10, and >10 positive nodes).
RFS at 5 yrs (%)62536552
  Hazard ratio0.760.68
  2-sided 95% CI(0.60, 0.96)(0.52, 0.89)
  Logrank Test(p = 0.013)(p = 0.007)
  stratified
OS at 5 yrs (%)77707665
  Hazard ratio0.710.69
  2-sided 95% CI(0.52, 0.98)(0.51, 0.92)
  Logrank Test(p = 0.043)(p = 0.007)
  stratified(unstratified p = 0.13)
RFS at 10 yrs (%)51444943
  Hazard ratio0.780.78
  2-sided 95% CI(0.63, 0.95)(0.62, 0.99)
  Logrank Test(p = 0.017)(p = 0.040)
  stratified(unstratified p = 0.023)(unstratified p = 0.09)
OS at 10 yrs (%)61575650
  Hazard ratio0.820.75
  2-sided 95% CI(0.65, 1.04)(0.58, 0.96)
  Logrank Test(p = 0.100)(p = 0.023)
  stratified(unstratified p = 0.18)(unstratified p = 0.039)

The Kaplan-Meier curves for RFS and OS from Study MA-5 are shown in Figures 3 and 4 and those for Study GFEA-05 are shown in Figures 5 and 6.

Figure 3. Relapse-Free Survival in Study MA-5

Figure 3

Figure 4. Overall Survival in Study MA-5

Figure 4

Figure 5. Relapse-Free Survival in Study GFEA-05

Figure 5

Figure 6. Overall Survival in Study GFEA-05

Figure 6

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