Letrozole (Page 10 of 12)

14.4 First-Line Treatment of Advanced Breast Cancer

A randomized, double-blind, multinational trial compared letrozole 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

Letrozole

N = 458

Tamoxifen

N = 458

Stage of Disease

IIIB

6%

7%

IV

93%

92%

Receptor Status

ER and PgR Positive

38%

41%

ER or PgR Positive

26%

26%

Both Unknown

34%

33%

ER or PgR /Other Unknown

< 1%

0

Previous Antiestrogen Therapy

Adjuvant

19%

18%

None

81%

82%

Dominant Site of Disease

Soft Tissue

25%

25%

Bone

32%

29%

Viscera

43%

46%

Letrozole 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
*
Hazard ratio
Odds ratio
Overall logrank test

Letrozole

2.5 mg

N = 453

Tamoxifen

20 mg

N = 454

Hazard or Odds

Ratio (95% CI)

P -Value (2-Sided)

Median Time to Progression

9.4 months

6 months

0.72 (0.62, 0.83)*

P < 0.0001

Objective Response Rate

(CR + PR)

145 (32%)

95 (21%)

1.77 (1.31, 2.39)

P = 0.0002

(CR)

42 (9%)

15 (3%)

2.99 (1.63, 5.47)

P = 0.0004

Duration of Objective Response

Median

18 months

16 months

(N = 145)

(N = 95)

Overall Survival

35 months

32 months

(N = 458)

(N = 458)

P = 0.5136

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

Variable

Letrozole

Tamoxifen

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)

Table 13: Efficacy by Disease Site

Letrozole

Tamoxifen

2.5 mg

20 mg

Dominant Disease Site

Soft Tissue:

N = 113

N = 115

Median TTP

12.1 months

6.4 months

Objective Response Rate

50%

34%

Bone:

N = 145

N = 131

Median TTP

9.5 months

6.3 months

Objective Response Rate

23%

15%

Viscera:

N = 195

N = 208

Median TTP

8.3 months

4.6 months

Objective Response Rate

28%

17%

Table 14: Efficacy by Receptor Status
Hazard ratio less than 1 or odds ratio greater than 1 favors letrozole; hazard ratio greater than 1 or odds ratio less than 1 favors tamoxifen.

Variable

Letrozole

Tamoxifen

2.5 mg

20 mg

Receptor Positive

N = 294

N = 305

Median Time to Progression (95% CI)

9.4 months (8.9, 11.8)

6 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 = 159

N = 149

Median Time to Progression (95% CI)

9.2 months (6.1, 12.3)

6 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)

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 letrozole: 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 letrozole 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 (letrozole to tamoxifen) and 13 months (tamoxifen to letrozole). In patients who did not cross over to the opposite treatment arm, median survival was 35 months with letrozole (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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