Letrozole (Page 8 of 12)

Reproductive Toxicology

Reproduction studies in rats at letrozole doses equal to or greater than 0.003 mg/kg (about 1/100 the daily maximum recommended human dose on a mg/m2 basis) administered during the period of organogenesis, have shown that letrozole is embryotoxic and fetotoxic, as indicated by intrauterine mortality, increased resorption, increased postimplantation loss, decreased numbers of live fetuses and fetal anomalies including absence and shortening of renal papilla, dilation of ureter, edema and incomplete ossification of frontal skull and metatarsals. Letrozole was teratogenic in rats. A 0.03 mg/kg dose (about 1/10 the daily maximum recommended human dose on a mg/m2 basis) caused fetal domed head and cervical/centrum vertebral fusion.

Letrozole is embryotoxic at doses equal to or greater than 0.002 mg/kg and fetotoxic when administered to rabbits at 0.02 mg/kg (about 1/100,000 and 1/10,000 the daily maximum recommended human dose on a mg/m2 basis, respectively). Fetal anomalies included incomplete ossification of the skull, sternebrae, and fore- and hind legs.

14 CLINICAL STUDIES

14.1 Updated Adjuvant Treatment of Early Breast Cancer

In a multicenter study enrolling over 8,000 postmenopausal women with resected, receptor-positive early breast cancer, one of the following treatments was randomized in a double-blind manner:

Option 1:
A. Tamoxifen for 5 years
B. Letrozole for 5 years
C. Tamoxifen for 2 years followed by letrozole for 3 years
D. Letrozole for 2 years followed by tamoxifen for 3 years

Option 2:
A. Tamoxifen for 5 years B. Letrozole for 5 years

The study in the adjuvant setting, BIG 1-98 was designed to answer two primary questions: whether letrozole for 5 years was superior to tamoxifen for 5 years (Primary Core Analysis) and whether switching endocrine treatments at 2 years was superior to continuing the same agent for a total of 5 years (Sequential Treatments Analysis). Selected baseline characteristics for the study population are shown in Table 5. The primary endpoint of this trial was disease-free survival (DFS) (i.e., interval between randomization and earliest occurrence of a local, regional, or distant recurrence, or invasive contralateral breast cancer, or death from any cause). The secondary endpoints were overall survival (OS), systemic disease-free survival (SDFS), invasive contralateral breast cancer, time to breast cancer recurrence (TBR) and time to distant metastasis (TDM).

The Primary Core Analysis (PCA) included all patients and all follow-up in the monotherapy arms in both randomization options, but follow-up in the two sequential treatments arms was truncated 30 days after switching treatments. The PCA was conducted at a median treatment duration of 24 months and a median follow-up of 26 months. Letrozole was superior to tamoxifen in all endpoints except overall survival and contralateral breast cancer [e.g., DFS: hazard ratio, HR 0.79; 95% CI (0.68, 0.92); P = 0.002; SDFS: HR 0.83; 95% CI (0.70, 0.97); TDM: HR 0.73; 95% CI (0.60, 0.88); OS: HR 0.86; 95% CI (0.70, 1.06).

In 2005, based on recommendations by the independent Data Monitoring Committee, the tamoxifen arms were unblinded and patients were allowed to complete initial adjuvant therapy with letrozole (if they had received tamoxifen for at least 2 years) or to start extended adjuvant treatment with letrozole (if they had received tamoxifen for at least 4.5 years) if they remained alive and disease-free. In total, 632 patients crossed to letrozole or another aromatase inhibitor. Approximately 70% (448) of these 632 patients crossed to letrozole to complete initial adjuvant therapy and most of these crossed in years 3 to 4. All of these patients were in Option 1. A total of 184 patients started extended adjuvant therapy with letrozole (172 patients) or with another aromatase inhibitor (12 patients). To explore the impact of this selective crossover, results from analyses censoring follow-up at the date of the selective crossover (in the tamoxifen arm) are presented for the Monotherapy Arms Analysis (MAA).

The PCA allowed the results of letrozole for 5 years compared with tamoxifen for 5 years to be reported in 2005 after a median follow-up of only 26 months. The design of the PCA is not optimal to evaluate the effect of letrozole after a longer time (because follow-up was truncated in two arms at around 25 months). The Monotherapy Arms Analysis (ignoring the two sequential treatment arms) provided follow-up equally as long in each treatment and did not over-emphasize early recurrences as the PCA did. The MAA thus provides the clinically appropriate updated efficacy results in answer to the first primary question, despite the confounding of the tamoxifen reference arm by the selective crossover to letrozole. The updated results for the MAA are summarized in Table 6. Median follow-up for this analysis is 73 months.

The Sequential Treatments Analysis (STA) addresses the second primary question of the study. The primary analysis for the Sequential Treatments Analysis (STA) was from switch (or equivalent time-point in monotherapy arms) + 30 days (STA-S) with a two-sided test applied to each pair-wise comparison at the 2.5% level. Additional analyses were conducted from randomization (STA-R) but these comparisons (added in light of changing medical practice) were under-powered for efficacy.

Table 5: Adjuvant Study -- Patient and Disease Characteristics (ITT Population)

Primary Core Analysis

(PCA)

Monotherapy Arms Analysis

(MAA)

Characteristic

Letrozole

N = 4,003

n (%)

Tamoxifen

N = 4,007

n (%)

Letrozole

N = 2,463

n (%)

Tamoxifen

N = 2,459

n (%)

Age (median, years)

61

61

61

61

Age range (years)

38 to 89

39 to 90

38 to 88

39 to 90

Hormone receptor status (%)

ER+ and/or PgR+

99.7

99.7

99.7

99.7

Both unknown

0.3

0.3

0.3

0.3

Nodal status (%)

Node negative

52

52

50

52

Node positive

41

41

43

41

Nodal status unknown

7

7

7

7

Prior adjuvant chemotherapy (%)

24

24

24

24

Table 6: Updated Adjuvant Study Results -- Monotherapy Arms Analysis (Median Follow-up 73 Months)
ITT analysis ignores selective crossover in tamoxifen arms. Censored analysis censors follow-up at the date of selective crossover in 632 patients who crossed to letrozole or another aromatase inhibitor after the tamoxifen arms were unblinded in 2005.
*
Disease-free survival: Interval from randomization to earliest event of invasive loco-regional recurrence, distant metastasis, invasive contralateral breast cancer, or death without a prior event.
Systemic disease-free survival: Interval from randomization to invasive regional recurrence, distant metastasis, or death without a prior cancer event.
Time to distant metastasis: Interval from randomization to distant metastasis.
§
Distant disease-free survival: Interval from randomization to earlier event of relapse in a distant site or death from any cause.

Letrozole

N = 2,463

Tamoxifen

N = 2,459

Hazard Ratio

Events

(%)

5-year rate

Events

(%)

5-year rate

(95%CI)

P

Disease-free survival *

ITT

445 (18.1)

87.4

500 (20.3)

84.7

0.87 (0.76, 0.99)

0.03

Censor

445

87.4

483

84.2

0.84 (0.73, 0.95)

0 positive nodes

ITT

165

92.2

189

90.3

0.88 (0.72, 1.09)

1 to 3 positive nodes

ITT

151

85.6

163

83

0.85 (0.68, 1.06)

> = 4 positive nodes

ITT

123

71.2

142

62.6

0.81 (0.64, 1.03)

Adjuvant chemotherapy

ITT

119

86.4

150

80.6

0.77 (0.60, 0.98)

No chemotherapy

ITT

326

87.8

350

86.1

0.91 (0.78, 1.06)

Systemic DFS

ITT

401

88.5

446

86.6

0.88 (0.77, 1.01)

Time to distant metastasis

ITT

257

92.4

298

90.1

0.85 (0.72, 1.00)

Adjuvant chemotherapy

ITT

84

-

109

-

0.75 (0.56 -- 1.00)

No chemotherapy

ITT

173

-

189

-

0.90 (0.73, 1.11)

Distant DFS §

ITT

385

89

432

87.1

0.87 (0.76, 1.00)

Contralateral breast cancer

ITT

34

99.2

44

98.6

0.76 (0.49, 1.19)

Overall survival

ITT

303

91.8

343

90.9

0.87 (0.75, 1.02)

Censor

303

91.8

338

90.1

0.82 (0.70, 0.96)

0 positive nodes

ITT

107

95.2

121

94.8

0.90 (0.69, 1.16)

1 to 3 positive nodes

ITT

99

90.8

114

90.6

0.81 (0.62, 1.06)

> = 4 positive nodes

ITT

92

80.2

104

73.6

0.86 (0.65, 1.14)

Adjuvant chemotherapy

ITT

76

91.5

96

88.4

0.79 (0.58, 1.06)

No chemotherapy

ITT

227

91.9

247

91.8

0.91 (0.76, 1.08)

Figure 1 shows the Kaplan-Meier curves for Disease-Free Survival Monotherapy Analysis.

Figure 1: Disease-Free Survival (Median follow-up 73 months, ITT Approach)
(click image for full-size original)

Figure 1: Disease-Free Survival (Median follow-up 73 months, ITT Approach)

The medians of overall survival for both arms were not reached for the Monotherapy Arms Analysis (MAA). There was no statistically significant difference in overall survival. The hazard ratio for survival in the letrozole arm compared to the tamoxifen arm was 0.87, with 95% CI (0.75, 1.02) (see Table 6).

There were no significant differences in DFS, OS, SDFS and Distant DFS from switch in the Sequential Treatments Analysis with respect to either monotherapy (e.g., [Tamoxifen 2 years followed by] letrozole 3 years vs. tamoxifen beyond 2 years, DFS HR 0.89; 97.5% CI 0.68, 1.15 and [letrozole 2 years followed by] tamoxifen 3 years vs. letrozole beyond 2 years, DFS HR 0.93; 97.5% CI 0.71, 1.22).

There were no significant differences in DFS, OS, SDFS, and Distant DFS from randomization in the Sequential Treatments Analyses.

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