Femara was initially studied at doses of 0.1 mg to 5.0 mg daily in six non-comparative Phase I/II trials in 181 postmenopausal estrogen/progesterone receptor positive or unknown advanced breast cancer patients previously treated with at least antiestrogen therapy. Patients had received other hormonal therapies and also may have received cytotoxic therapy. Eight (20%) of forty patients treated with Femara 2.5 mg daily in Phase I/II trials achieved an objective tumor response (complete or partial response).
Two large randomized, controlled, multinational (predominantly European) trials were conducted in patients with advanced breast cancer who had progressed despite antiestrogen therapy. Patients were randomized to Femara 0.5 mg daily, Femara 2.5 mg daily, or a comparator (megestrol acetate 160 mg daily in one study; and aminoglutethimide 250 mg b.i.d. with corticosteroid supplementation in the other study). In each study over 60% of the patients had received therapeutic antiestrogens, and about one-fifth of these patients had an objective response. The megestrol acetate controlled study was double-blind; the other study was open label. Selected baseline characteristics for each study are shown in Table 15.
|No. of Participants||552||557|
|Therapeutic +/- Adj.||66%||62%|
|Sites of Disease|
Confirmed objective tumor response (complete response plus partial response) was the primary endpoint of the trials. Responses were measured according to the Union Internationale Contre le Cancer (UICC) criteria and verified by independent, blinded review. All responses were confirmed by a second evaluation 4-12 weeks after the documentation of the initial response.
Table 16 shows the results for the first trial, with a minimum follow-up of 15 months, that compared Femara 0.5 mg, Femara 2.5 mg, and megestrol acetate 160 mg daily. (All analyses are unadjusted.)
|0.5 mg||2.5 mg||acetate|
|Objective Response (CR + PR)||22 (11.7%)||41 (23.6%)||31 (16.3%)|
|Median Duration of Response||552 days||(Not reached)||561 days|
|Median Time to Progression||154 days||170 days||168 days|
|Median Survival||633 days||730 days||659 days|
|Odds Ratio for Response||Femara 2.5: Femara 0.5=2.33||Femara 2.5: megestrol=1.58|
|(95% CI: 1.32, 4.17); P =0.004*||(95% CI: 0.94, 2.66); P =0.08*|
|Relative Risk of Progression||Femara 2.5: Femara 0.5=0.81||Femara 2.5: megestrol=0.77|
|(95% CI: 0.63, 1.03); P =0.09*||(95% CI: 0.60, 0.98); P =0.03*|
* two-sided P -value
The Kaplan-Meier curves for progression for the megestrol acetate study are shown in Figure 4.
Figure 4 Kaplan-Meier Estimates of Time to Progression (Megestrol Acetate Study)
The results for the study comparing Femara to aminoglutethimide, with a minimum follow-up of 9 months, are shown in Table 17. (Unadjusted analyses are used.)
|0.5 mg||2.5 mg||aminoglutethimide|
|Objective Response (CR + PR)||34 (17.6%)||34 (18.4%)||22 (12.3%)|
|Median Duration of Response||619 days||706 days||450 days|
|Median Time to Progression||103 days||123 days||112 days|
|Median Survival||636 days||792 days||592 days|
|Odds Ratio for Response||Femara 2.5:||Femara 2.5:|
|(95% CI: 0.62, 1.79); P =0.85*||(95% CI: 0.90, 2.87); P =0.11*|
|Relative Risk of Progression||Femara 2.5:||Femara 2.5:|
|(95% CI: 0.68, 1.11); P =0.25*||(95% CI: 0.57, 0.94); P =0.02*|
*two-sided P -value
The Kaplan-Meier curves for progression for the aminoglutethimide study is shown in Figure 5.
Figure 5 Kaplan-Meier Estimates of Time to Progression (Aminoglutethimide Study)
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