Exemestane: Package Insert and Label Information (Page 3 of 5)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

A 2-year carcinogenicity study in mice at doses of 50, 150, and 450 mg/kg/day exemestane (gavage), resulted in an increased incidence of hepatocellular adenomas and/or carcinomas in both genders at the high dose level. Plasma AUC (0–24hr) at the high dose were 2575 ± 386 and 5667 ± 1833 ng.hr/mL in males and females (approx. 34 and 75 fold the AUC in postmenopausal patients at the recommended clinical dose). An increased incidence of renal tubular adenomas was observed in male mice at the high dose of 450 mg/kg/day. Since the doses tested in mice did not achieve an MTD, neoplastic findings in organs other than liver and kidneys remain unknown.

A separate carcinogenicity study was conducted in rats at the doses of 30, 100, and 315 mg/kg/day exemestane (gavage) for 92 weeks in males and 2 years in females. No evidence of carcinogenic activity up to the highest dose tested of 315 mg/kg/day was observed in females. The male rat study was inconclusive since it was terminated prematurely at Week 92. At the highest dose, plasma AUC(0–24hr) levels in male (1418 ± 287 ng.hr/mL) and female (2318 ± 1067 ng.hr/mL) rats were 19 and 31 fold higher than those measured in postmenopausal cancer patients receiving the recommended clinical dose.

Exemestane was not mutagenic in vitro in bacteria (Ames test) or mammalian cells (V79 Chinese hamster lung cells). Exemestane was clastogenic in human lymphocytes in vitro without metabolic activation but was not clastogenic in vivo (micronucleus assay in mouse bone marrow). Exemestane did not increase unscheduled DNA synthesis in rat hepatocytes when tested in vitro.

In a pilot reproductive study in rats, male rats were treated with doses of 125–1000 mg/kg/day exemestane, beginning 63 days prior to and during cohabitation. Untreated female rats showed reduced fertility when mated to males treated with ≥ 500 mg/kg/day exemestane (≥ 200 times the recommended human dose on a mg/m2 basis). In a separate study, exemestane was given to female rats at 4–100 mg/kg/day beginning 14 days prior to mating and through day 15 or 20 of gestation. Exemestane increased the placental weights at ≥ 4 mg/kg/day (≥ 1.5 times the human dose on a mg/m2 basis). Exemestane showed no effects on ovarian function, mating behavior, and conception rate in rats given doses up to 20 mg/kg/day (approximately 8 times the recommended human dose on a mg/m2 basis); however, decreases in mean litter size and fetal body weight, along with delayed ossification were evidenced at ≥ 20 mg/kg/day. In general toxicology studies, changes in the ovary, including hyperplasia, an increase in the incidence of ovarian cysts, and a decrease in corpora lutea were observed with variable frequency in mice, rats, and dogs at doses that ranged from 3–20 times the human dose on a mg/m2 basis.

14 CLINICAL STUDIES

14.1 Adjuvant Treatment in Early Breast Cancer

The Intergroup Exemestane Study 031 (IES) was a randomized, double-blind, multicenter, multinational study comparing exemestane (25 mg/day) vs. tamoxifen (20 or 30 mg/day) in postmenopausal women with early breast cancer. Patients who remained disease-free after receiving adjuvant tamoxifen therapy for 2 to 3 years were randomized to receive an additional 3 or 2 years of exemestane or tamoxifen to complete a total of 5 years of hormonal therapy.

The primary objective of the study was to determine whether, in terms of disease-free survival, it was more effective to switch to exemestane rather than continuing tamoxifen therapy for the remainder of five years. Disease-free survival was defined as the time from randomization to time of local or distant recurrence of breast cancer, contralateral invasive breast cancer, or death from any cause.

The secondary objectives were to compare the two regimens in terms of overall survival and long-term tolerability. Time to contralateral invasive breast cancer and distant recurrence-free survival were also evaluated.

A total of 4724 patients in the intent-to-treat (ITT) analysis were randomized to exemestane tablets 25 mg once daily (N = 2352) or to continue to receive tamoxifen once daily at the same dose received before randomization (N = 2372). Demographics and baseline tumor characteristics are presented in Table 5. Prior breast cancer therapy is summarized in Table 6.

Table 5. Demographic and Baseline Tumor Characteristics from the IES Study of Postmenopausal Women with Early Breast Cancer (ITT Population)
ParameterExemestane(N = 2352)Tamoxifen(N = 2372)
*
Results for receptor status include the results of the post-randomization testing of specimens from subjects for whom receptor status was unknown at randomization.
Only one subject in the exemestane group had unknown ER status and positive PgR status.
Age (years):
Median age (range)63.0 (38.0-96.0)63.0 (31.0-90.0)
Race, n (%):
Caucasian2315 (98.4)2333 (98.4)
Hispanic13 (0.6)13 (0.5)
Asian10 (0.4)9 (0.4)
Black7 (0.3)10 (0.4)
Other/not reported7 (0.3)7 (0.3)
Nodal status, n (%):
Negative1217 (51.7)1228 (51.8)
Positive1051 (44.7)1044 (44.0)
1-3 Positive nodes721 (30.7)708 (29.8)
4-9 Positive nodes239 (10.2)244 (10.3)
>9 Positive nodes88 (3.7)86 (3.6)
Not reported3 (0.1)6 (0.3)
Unknown or missing84 (3.6)100 (4.2)
Histologic type, n (%):
Infiltrating ductal1777 (75.6)1830 (77.2)
Infiltrating lobular341 (14.5)321 (13.5)
Other231 (9.8)213 (9.0)
Unknown or missing3 (0.1)8 (0.3)
Receptor status *, n (%):
ER and PgR Positive1331 (56.6)1319 (55.6)
ER Positive and PgR Negative/Unknown677 (28.8)692 (29.2)
ER Unknown and PgR Positive /Unknown288 (12.2)291 (12.3)
ER Negative and PgR Positive6 (0.3)7 (0.3)
ER Negative and PgR Negative/Unknown (none positive)48 (2.0)58 (2.4)
Missing2 (0.1)5 (0.2)
Tumor Size, n (%):
≤ 0.5 cm58 (2.5)46 (1.9)
> 0.5-1.0 cm315 (13.4)302 (12.7)
> 1.0-2 cm1031 (43.8)1033 (43.5)
> 2.0-5.0 cm833 (35.4)883 (37.2)
> 5.0 cm62 (2.6)59 (2.5)
Not reported53 (2.3)49 (2.1)
Tumor Grade, n (%):
G1397 (16.9)393 (16.6)
G2977 (41.5)1007 (42.5)
G3454 (19.3)428 (18.0)
G423 (1.0)19 (0.8)
Unknown/Not Assessed/Not reported501 (21.3)525 (22.1)
Table 6. Prior Breast Cancer Therapy of Patients in the IES Study of Postmenopausal Women with Early Breast Cancer (ITT Population)
ParameterExemestane(N = 2352)Tamoxifen(N = 2372)
*
The 30 mg dose was used only in Denmark, where this dose was the standard of care.
Type of surgery, n (%):
Mastectomy1232 (52.4)1242 (52.4)
Breast-conserving1116 (47.4)1123 (47.3)
Unknown or missing4 (0.2)7 (0.3)
Radiotherapy to the breast, n (%):
Yes1524 (64.8)1523 (64.2)
No824 (35.5)843 (35.5)
Not reported4 (0.2)6 (0.3)
Prior therapy, n (%):
Chemotherapy774 (32.9)769 (32.4)
Hormone replacement therapy567 (24.1)561 (23.7)
Bisphosphonates43 (1.8)34 (1.4)
Duration of tamoxifen therapy at randomization (months):
Median (range)28.5 (15.8-52.2)28.4 (15.6-63.0)
Tamoxifen dose, n (%):
20 mg2270 (96.5)2287 (96.4)
30 mg *78 (3.3)75 (3.2)
Not reported4 (0.2)10 (0.4)

After a median duration of therapy of 27 months and with a median follow-up of 34.5 months, 520 events were reported, 213 in the exemestane group and 307 in the tamoxifen group (Table 7).

Table 7. Primary Endpoint Events (ITT Population)
EventFirst EventsN (%)
Exemestane(N = 2352)Tamoxifen(N = 2372)
Loco-regional recurrence34 (1.45)45 (1.90)
Distant recurrence126 (5.36)183 (7.72)
Second primary- contralateral breast cancer7 (0.30)25 (1.05)
Death- breast cancer1 (0.04)6 (0.25)
Death- other reason41 (1.74)43 (1.81)
Death- missing/unknown3 (0.13)5 (0.21)
Ipsilateral breast cancer1 (0.04)0
Total number of events 213 (9.06) 307 (12.94)

Disease-free survival in the intent-to-treat population was statistically significantly improved [Hazard Ratio (HR) = 0.69, 95% CI: 0.58, 0.82, P = 0.00003, Table 8, Figure 1] in the exemestane arm compared to the tamoxifen arm. In the hormone receptor-positive subpopulation representing about 85% of the trial patients, disease-free survival was also statistically significantly improved (HR = 0.65, 95% CI: 0.53, 0.79, P = 0.00001) in the exemestane arm compared to the tamoxifen arm. Consistent results were observed in the subgroups of patients with node negative or positive disease, and patients who had or had not received prior chemotherapy.

An overall survival update at 119 months median follow-up showed no significant difference between the two groups, with 467 deaths (19.9%) occurring in the exemestane group and 510 deaths (21.5%) in the tamoxifen group.

Table 8. Efficacy Results from the IES Study in Postmenopausal Women with Early Breast Cancer
*
Not adjusted for multiple testing.
ITT Population Hazard Ratio(95% CI) p-value(log-rank test)
Disease-free survival0.69 (0.58-0.82)0.00003
Time to contralateral breast cancer0.32 (0.15-0.72)0.00340
Distant recurrence-free survival0.74 (0.62-0.90)0.00207
Overall survival0.91 (0.81-1.04)0.16*
ER and/or PgR positive
Disease-free survival0.65 (0.53-0.79)0.00001
Time to contralateral breast cancer0.22 (0.08-0.57)0.00069
Distant recurrence-free survival0.73 (0.59-0.90)0.00367
Overall survival0.89 (0.78-1.02)0.09065*

Figure 1. Disease-Free Survival in the IES Study of Postmenopausal Women with Early Breast Cancer (ITT Population)

Figure 1
(click image for full-size original)

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