Letrozole (Page 11 of 12)

14.5 Second-Line Treatment of Advanced Breast Cancer

Letrozole 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 40 patients treated with letrozole 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 letrozole 0.5 mg daily, letrozole 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

Study

Aminoglutethimide

Study

No. of Participants

552

557

Receptor Status

ER/PR Positive

57%

56%

ER/PR Unknown

43%

44%

Previous Therapy

Adjuvant Only

33%

38%

Therapeutic +/- Adj.

66%

62%

Sites of Disease

Soft Tissue

56%

50%

Bone

50%

55%

Viscera

40%

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 to 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 letrozole 0.5 mg, letrozole 2.5 mg, and megestrol acetate 160 mg daily. (All analyses are unadjusted.)

Table 16: Megestrol Acetate Study Results
*
two-sided P-value

Letrozole

0.5 mg

N = 188

Letrozole

2.5 mg

N = 174

Megestrol

Acetate

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 days

170 days

168 days

Median Survival

633 days

730 days

659 days

Odds Ratio for Response

letrozole 2.5: letrozole 0.5 = 2.33

letrozole 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

letrozole 2.5: letrozole 0.5 = 0.81

letrozole 2.5: megestrol = 0.77

(95% CI: 0.63, 1.03); P = 0.09*

(95% CI: 0.60, 0.98), P = 0.03*

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 letrozole to aminoglutethimide, with a minimum follow-up of 9 months, are shown in Table 17. (Unadjusted analyses are used.)

Table 17: Aminoglutethimide Study Results
*
two-sided P -value

Letrozole

0.5 mg

N = 193

Letrozole

2.5 mg

N = 185

Aminoglutethimide

N = 179

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

letrozole 2.5:

letrozole 2.5:

letrozole 0.5 = 1.05

aminoglutethimide = 1.61

(95% CI: 0.62, 1.79);

P = 0.85*

(95% CI: 0.90, 2.87);

P = 0.11*

Relative Risk of Progression

letrozole 2.5:

letrozole 2.5:

letrozole 0.5 = 0.86

aminoglutethimide = 0.74

(95% CI: 0.68, 1.11);

P = 0.25*

(95% CI: 0.57, 0.94),

P = 0.02*

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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