Femara (Page 10 of 11)

1 4 . 5 Second-Line Treatment of Advanced Breast Cancer

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.

Table 15: Selected Study Population Demographics
Parameter megestrol acetate aminoglutethimide
study study
No. of Participants 552557
Receptor Status
ER/PR Positive57%56%
ER/PR Unknown43%44%
Previous Therapy
Adjuvant Only33%38%
Therapeutic +/- Adj.66%62%
Sites of Disease
Soft Tissue56%50%
Bone50%55%
Viscera40%44%

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.)

Table 16: Megestrol Acetate Study Results
Femara Femara megestrol
0.5 mg 2.5 mg acetate
N=188 N=174 N=190
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 days170 days168 days
Median Survival 633 days730 days659 days
Odds Ratio for Response Femara 2.5: Femara 0.5=2.33Femara 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=0.81Femara 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)
(click image for full-size original)

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.)

Table 17: Aminoglutethimide Study Results
Femara Femara
0.5 mg 2.5 mg aminoglutethimide
N=193 N=185 N=179
Objective Response (CR + PR) 34 (17.6%)34 (18.4%)22 (12.3%)
Median Duration of Response 619 days706 days450 days
Median Time to Progression 103 days123 days112 days
Median Survival 636 days792 days592 days
Odds Ratio for Response Femara 2.5: Femara 2.5:
Femara 0.5=1.05aminoglutethimide=1.61
(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:
Femara 0.5=0.86aminoglutethimide=0.74
(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)
(click image for full-size original)

Figure 5 Kaplan-Meier Estimates of Time to Progression (Aminoglutethimide Study)

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