Femara (Page 9 of 11)

1 4 .2 Extended Adjuvant Treatment of Early Breast Cancer , Median Treatment Duration of 24 M onths

A double-blind, randomized, placebo-controlled trial of Femara was performed in over 5,100 postmenopausal women with receptor-positive or unknown primary breast cancer who were disease free after 5 years of adjuvant treatment with tamoxifen.

The planned duration of treatment for patients in the study was 5 years, but the trial was terminated early because of an interim analysis showing a favorable Femara effect on time without recurrence or contralateral breast cancer. At the time of unblinding, women had been followed for a median of 28 months, 30% of patients had completed 3 or more years of follow-up and less than 1% of patients had completed 5 years of follow-up.

Selected baseline characteristics for the study population are shown in Table 7.

Table 7: Selected Study Population Demographics (Modified ITT Population)
Baseline Status Femara Placebo
N=2582 N=2586
Hormone Receptor Status (%)
ER+ and/or PgR+9898
Both Unknown22
Nodal Status (%)
Node Negative5050
Node Positive4646
Nodal Status Unknown44
Chemotherapy 4646

Table 8 shows the study results. Disease-free survival was measured as the time from randomization to the earliest event of loco-regional or distant recurrence of the primary disease or development of contralateral breast cancer or death. DFS by hormone receptor status, nodal status and adjuvant chemotherapy were similar to the overall results. Data were premature for an analysis of survival.

Table 8: Extended Adjuvant Study Results
Femara N = 2582 Placebo N = 2586 Hazard Ratio (95% CI) P-Value
Disease Free Survival (DFS) 1 Events 122 (4.7%)193 (7.5%)0.62 (0.49, 0.78)2 0.00003
Local Breast Recurrence922
Local Chest Wall Recurrence28
Regional Recurrence74
Distant Recurrence55920.61 (0.44 — 0.84)0.003
Contralateral Breast Cancer1929
Deaths Without Recurrence or Contralateral Breast Cancer3038
CI = confidence interval for hazard ratio. Hazard ratio of less than 1.0 indicates difference in favor of Femara (lesser risk of recurrence); hazard ratio greater than 1.0 indicates difference in favor of placebo (higher risk of recurrence with Femara).1 First event of loco-regional recurrence, distant relapse, contralateral breast cancer or death from any cause 2 Analysis stratified by receptor status, nodal status and prior adjuvant chemotherapy (stratification factors as at randomization). P -value based on stratified logrank test.

14.3 Updated Analyses of Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 60 Months

Table 9: Update of Extended Adjuvant Study Results
Femara N = 2582 (%) Placebo N = 2586 (%) Hazard Ratio 1 (95% CI) P-Value 2
Disease Free Survival (DFS) events 3 344 (13.3)402 (15.5)0.89 (0.77, 1.03)0.12
Breast cancer recurrence (Protocol definition of DFS events4) 2092860.75 (0.63, 0.89)0.001
Local Breast Recurrence1544
Local Chest Wall Recurrence614
Regional Recurrence108
Distant Recurrence140167
Distant recurrence (first or subsequent events) Contralateral Breast Cancer14237 169530.88 (0.70,1.10)0.246
Deaths Without Recurrence or Contralateral Breast Cancer135116
1 Adjusted by receptor status, nodal status and prior chemotherapy2 Stratified logrank test, stratified by receptor status, nodal status and prior chemotherapy3 DFS events defined as earliest of loco-regional recurrence, distant metastasis, contralateral breast cancer or death from any cause, and ignoring switches to Femara in 60% of the placebo arm.4 Protocol definition does not include deaths from any cause

Updated analyses were conducted at a median follow-up of 62 months. In the Femara arm, 71% of the patients were treated for a least 3 years and 58% of patients completed at least 4.5 years of extended adjuvant treatment. After the unblinding of the study at a median follow-up of 28 months, approximately 60% of the selected patients in the placebo arm opted to switch to Femara.

In this updated analysis shown in Table 9, Femara significantly reduced the risk of breast cancer recurrence or contralateral breast cancer compared with placebo (HR 0.75; 95% CI 0.63, 0.89; P =0.001). However, in the updated DFS analysis (interval between randomization and earliest event of loco-regional recurrence, distant metastasis, contralateral breast cancer, or death from any cause) the treatment difference was heavily diluted by 60% of the patients in the placebo arm switching to Femara and accounting for 64% of the total placebo patient- years of follow-up. Ignoring these switches, the risk of DFS event was reduced by a non-significant 11% (HR 0.89; 95% CI 0.77, 1.03). There was no significant difference in distant disease-free survival or overall survival.

1 4 . 4 First-Line Tre atment of Advanced Breast Cancer

A randomized, double-blind, multinational trial compared Femara 2.5 mg with tamoxifen 20 mg in 916 postmenopausal patients with locally advanced (Stage IIIB or loco-regional recurrence not amenable to treatment with surgery or radiation) or metastatic breast cancer. Time to progression (TTP) was the primary endpoint of the trial. Selected baseline characteristics for this study are shown in Table 10.

Table 10: Selected Study Population Demographics
Baseline Status Femara t amoxifen
N=458 N=458
Stage of Disease
IIIB6%7%
IV93%92%
Receptor Status
ER and PgR Positive38%41%
ER or PgR Positive26%26%
Both Unknown34%33%
ER or PgR /Other Unknown<1%0
Previous Antiestrogen Therapy
Adjuvant19%18%
None81%82%
Dominant Site of Disease
Soft Tissue25%25%
Bone32%29%
Viscera43%46%

Femara was superior to tamoxifen in TTP and rate of objective tumor response (see Table 11).

Table 11 summarizes the results of the trial, with a total median follow-up of approximately 32 months. (All analyses are unadjusted and use 2-sided P -values.)

Table 11: Results of First-Line Treatment of Advanced Breast Cancer
Femara tamoxifen Hazard or Odds
2.5 mg 20 mg Ratio (95% CI)
N=453 N=454 P-Value (2-Sided)
Median Time to Progression 9.4 months6.0 months0.72 (0.62, 0.83)1
P <0.0001
Objective Response Rate
(CR + PR)145 (32%)95 (21%)1.77 (1.31, 2.39)2
P =0.0002
(CR)42 (9%)15 (3%)2.99 (1.63, 5.47)2
P =0.0004
Duration of Objective Response
Median18 months 16 months
(N=145)(N=95)
Overall Survival 35 months 32 months
(N=458)(N=458)P =0.51363

1 Hazard ratio

2 Odds ratio

3 Overall logrank test

Figure 2 shows the Kaplan-Meier curves for TTP.

Figure 2  Kaplan-Meier Estimates of Time to Progression (Tamoxifen Study)
(click image for full-size original)

Figure 2 Kaplan-Meier Estimates of Time to Progression (Tamoxifen Study)

Table 12 shows results in the subgroup of women who had received prior antiestrogen adjuvant therapy, Table 13 , results by disease site and Table 14, the results by receptor status.

Table 12: Efficacy in Patients Who Received Prior Antiestrogen Therapy
Variable Femara t amoxifen
2.5 mg 20 mg
N=84 N=83
Median Time to Progression (95% CI)8.9 months (6.2, 12.5) 5.9 months (3.2, 6.2)
Hazard Ratio for TTP (95% CI) 0.60 (0.43, 0.84)
Objective Response Rate
(CR + PR)22 (26%)7 (8%)
Odds Ratio for Response (95% CI)3.85 (1.50, 9.60)

Hazard ratio less than 1 or odds ratio greater than 1 favors Femara; hazard ratio greater than 1 or odds ratio less than 1 favors tamoxifen.

Table 13: Efficacy by Disease Site
Femara tamoxifen
2.5 mg 20 mg
Dominant Disease Site
Soft Tissue: N=113N=115
Median TTP12.1 months6.4 months
Objective Response Rate50%34%
Bone: N=145N=131
Median TTP9.5 months6.3 months
Objective Response Rate23%15%
Viscera: N=195N=208
Median TTP8.3 months4.6 months
Objective Response Rate28%17%
Table 14: Efficacy by Receptor Status
Variable Femara tamoxifen
2.5 mg 20 mg
Receptor Positive N=294N=305
Median Time to Progression (95% CI)9.4 months (8.9, 11.8)6.0 months (5.1, 8.5)
Hazard Ratio for TTP (95% CI)0.69 (0.58, 0.83)
Objective Response Rate (CR+PR)97 (33%)66 (22%)
Odds Ratio for Response 95% CI)1.78 (1.20, 2.60)
Receptor Unknown N=159N=149
Median Time to Progression (95% CI)9.2 months (6.1, 12.3)6.0 months (4.1, 6.4)
Hazard Ratio for TTP (95% CI) 0.77 (0.60, 0.99)
Objective Response Rate (CR+PR)48 (30%)29 (20%)
Odds Ratio for Response (95% CI)1.79 (1.10, 3.00)

Hazard ratio less than 1 or odds ratio greater than 1 favors Femara; hazard ratio greater than 1 or odds ratio less than 1 favors tamoxifen.

Figure 3 shows the Kaplan-Meier curves for survival.

Figure 3  Survival by Randomized Treatment Arm
(click image for full-size original)

Figure 3 Survival by Randomized Treatment Arm

Legend: Randomized Femara: n=458, events 57%, median overall survival 35 months (95% CI 32 to 38 months)

Randomized tamoxifen: n=458, events 57%, median overall survival 32 months (95% CI 28 to 37 months)

Overall logrank P =0.5136 (i.e., there was no significant difference between treatment arms in overall survival).

The median overall survival was 35 months for the Femara group and 32 months for the tamoxifen group, with a P -value 0.5136. Study design allowed patients to cross over upon progression to the other therapy. Approximately 50% of patients crossed over to the opposite treatment arm and almost all patients who crossed over had done so by 36 months. The median time to crossover was 17 months (Femara to tamoxifen) and 13 months (tamoxifen to Femara). In patients who did not cross over to the opposite treatment arm, median survival was 35 months with Femara (n=219, 95% Cl 29 to 43 months) vs 20 months with tamoxifen (n=229, 95% Cl 16 to 26 months).

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