"The U.S. Food and Drug Administration today approved Kadcyla (ado-trastuzumab emtansine), a new therapy for patients with HER2-positive, late-stage (metastatic) breast cancer.
HER2 is a protein involved in normal cell growth. It is foun"...
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Mechanism of Action
The growth of some cancers of the breast is stimulated or maintained by estrogens. Treatment of breast cancer thought to be hormonally responsive (i.e., estrogen and/or progesterone receptor positive or receptor unknown) has included a variety of efforts to decrease estrogen levels (ovariectomy, adrenalectomy, hypophysectomy) or inhibit estrogen effects (antiestrogens and progestational agents). These interventions lead to decreased tumor mass or delayed progression of tumor growth in some women.
In postmenopausal women, estrogens are mainly derived from the action of the aromatase enzyme, which converts adrenal androgens (primarily androstenedione and testosterone) to estrone and estradiol. The suppression of estrogen biosynthesis in peripheral tissues and in the cancer tissue itself can therefore be achieved by specifically inhibiting the aromatase enzyme.
Letrozole is a nonsteroidal competitive inhibitor of the aromatase enzyme system; it inhibits the conversion of androgens to estrogens. In adult nontumor- and tumor-bearing female animals, letrozole is as effective as ovariectomy in reducing uterine weight, elevating serum LH, and causing the regression of estrogen-dependent tumors. In contrast to ovariectomy, treatment with letrozole does not lead to an increase in serum FSH. Letrozole selectively inhibits gonadal steroidogenesis but has no significant effect on adrenal mineralocorticoid or glucocorticoid synthesis.
Letrozole inhibits the aromatase enzyme by competitively binding to the heme of the cytochrome P450 subunit of the enzyme, resulting in a reduction of estrogen biosynthesis in all tissues. Treatment of women with letrozole significantly lowers serum estrone, estradiol and estrone sulfate and has not been shown to significantly affect adrenal corticosteroid synthesis, aldosterone synthesis, or synthesis of thyroid hormones.
In postmenopausal patients with advanced breast cancer, daily doses of 0.1 mg to 5 mg Femara (letrozole) suppress plasma concentrations of estradiol, estrone, and estrone sulfate by 75%-95% from baseline with maximal suppression achieved within two-three days. Suppression is dose-related, with doses of 0.5 mg and higher giving many values of estrone and estrone sulfate that were below the limit of detection in the assays. Estrogen suppression was maintained throughout treatment in all patients treated at 0.5 mg or higher.
Letrozole is highly specific in inhibiting aromatase activity. There is no impairment of adrenal steroidogenesis. No clinically-relevant changes were found in the plasma concentrations of cortisol, aldosterone, 11-deoxycortisol, 17-hydroxy-progesterone, ACTH or in plasma rennin activity among postmenopausal patients treated with a daily dose of Femara 0.1 mg to 5 mg. The ACTH stimulation test performed after 6 and 12 weeks of treatment with daily doses of 0.1, 0.25, 0.5, 1, 2.5, and 5 mg did not indicate any attenuation of aldosterone or cortisol production. Glucocorticoid or mineralocorticoid supplementation is, therefore, not necessary.
No changes were noted in plasma concentrations of androgens (androstenedione and testosterone) among healthy postmenopausal women after 0.1, 0.5, and 2.5 mg single doses of Femara or in plasma concentrations of androstenedione among postmenopausal patients treated with daily doses of 0.1 mg to 5 mg. This indicates that the blockade of estrogen biosynthesis does not lead to accumulation of androgenic precursors. Plasma levels of LH and FSH were not affected by letrozole in patients, nor was thyroid function as evaluated by TSH levels, T3 uptake, and T4 levels.
Absorption and Distribution
Letrozole is rapidly and completely absorbed from the gastrointestinal tract and absorption is not affected by food. It is metabolized slowly to an inactive metabolite whose glucuronide conjugate is excreted renally, representing the major clearance pathway. About 90% of radiolabeled letrozole is recovered in urine. Letrozole's terminal elimination half-life is about 2 days and steady-state plasma concentration after daily 2.5 mg dosing is reached in 2-6 weeks. Plasma concentrations at steady state are 1.5 to 2 times higher than predicted from the concentrations measured after a single dose, indicating a slight non-linearity in the pharmacokinetics of letrozole upon daily administration of 2.5 mg. These steady-state levels are maintained over extended periods, however, and continuous accumulation of letrozole does not occur. Letrozole is weakly protein bound and has a large volume of distribution (approximately 1.9 L/kg).
Metabolism and Excretion
Metabolism to a pharmacologically-inactive carbinol metabolite (4,4'methanol-bisbenzonitrile) and renal excretion of the glucuronide conjugate of this metabolite is the major pathway of letrozole clearance. Of the radiolabel recovered in urine, at least 75% was the glucuronide of the carbinol metabolite, about 9% was two unidentified metabolites, and 6% was unchanged letrozole. In human microsomes with specific CYP isozyme activity, CYP3A4 metabolized letrozole to the carbinol metabolite while CYP2A6 formed both this metabolite and its ketone analog. In human liver microsomes, letrozole strongly inhibited CYP2A6 and moderately inhibited CYP2C19.
Pediatric, Geriatric and Race
In the study populations (adults ranging in age from 35 to > 80 years), no change in pharmacokinetic parameters was observed with increasing age. Differences in letrozole pharmacokinetics between adult and pediatric populations have not been studied. Differences in letrozole pharmacokinetics due to race have not been studied.
In a study of volunteers with varying renal function (24-hour creatinine clearance: 9-116 mL/min), no effect of renal function on the pharmacokinetics of single doses of 2.5 mg of Femara was found. In addition, in a study of 347 patients with advanced breast cancer, about half of whom received 2.5 mg Femara and half 0.5 mg Femara, renal impairment (calculated creatinine clearance: 20-50 mL/min) did not affect steady-state plasma letrozole concentrations.
In a study of subjects with mild to moderate non-metastatic hepatic dysfunction (e.g., cirrhosis, Child-Pugh classification A and B), the mean AUC values of the volunteers with moderate hepatic impairment were 37% higher than in normal subjects, but still within the range seen in subjects without impaired function.
In a pharmacokinetic study, subjects with liver cirrhosis and severe hepatic impairment (Child-Pugh classification C, which included bilirubins about 2-11 times ULN with minimal to severe ascites) had twofold increase in exposure (AUC) and 47% reduction in systemic clearance. Breast cancer patients with severe hepatic impairment are thus expected to be exposed to higher levels of letrozole than patients with normal liver function receiving similar doses of this drug. [see DOSAGE AND ADMINISTRATION]
Animal Toxicology and/or Pharmacology
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.
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:
- tamoxifen for 5 years
- Femara for 5 years
- tamoxifen for 2 years followed by Femara for 3 years
- Femara for 2 years followed by tamoxifen for 3 years
- tamoxifen for 5 years
- Femara for 5 years
The study in the adjuvant setting, BIG 1-98 was designed to answer two primary questions: whether Femara 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. Femara 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 Femara (if they had received tamoxifen for at least 2 years) or to start extended adjuvant treatment with Femara (if they had received tamoxifen for at least 4.5 years) if they remained alive and disease-free. In total, 632 patients crossed to Femara or another aromatase inhibitor. Approximately 70% (448) of these 632 patients crossed to Femara 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 Femara (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 Femara 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 Femara 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 Femara. 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
|Characteristic||Primary Core Analysis (PCA)||Monotherapy Arms Analysis (MAA)|
|Age (median, years)||61||61||61||61|
|Age range (years)||38-89||39-90||38-88||39-90|
|Hormone receptor status (%)|
|ER+ and/or PgR+||99.7||99.7||99.7||99.7|
|Nodal status (%)|
|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)
|5-year rate||(95% CI)||P|
|Disease-free survival1||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)|
|1-3 positive nodes||ITT||151||85.6||163||83.0||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 DFS2||ITT||401||88.5||446||86.6||0.88 (0.77,1.01)|
|Time to distant metastasis3||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 DFS4||ITT||385||89.0||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)|
|1-3 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)|
1 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
2 Systemic disease-free survival: Interval from randomization to invasive regional recurrence, distant metastasis, or death without a prior cancer event
3 Time to distant metastasis: Interval from randomization to distant metastasis
4 Distant disease-free survival: Interval from randomization to earlier event of relapse in a distant site or death from any cause
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 Femara or another aromatase inhibitor after the tamoxifen arms were unblinded in 2005
Figure 1 shows the Kaplan-Meier curves for Disease-Free Survival Monotherapy Analysis
Figure 1 : Disease-Free Survival (Median follow-up 73 months,
DFS events defined as loco-regional recurrence, distant metastasis, invasive contralateral breast cancer, or death from any cause (i.e., definition excludes second non-breast primary cancers).
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 Femara 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] Femara 3 years versus tamoxifen beyond 2 years, DFS HR 0.89; 97.5% CI 0.68, 1.15 and [Femara 2 years followed by] tamoxifen 3 years versus Femara 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.
Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 24 Months
A double-blind, randomized, placebo-controlled trial of Femara was performed in over 5,100 postmenopausal women with receptor-positive or unknown primary breast cancer who were disease free after 5 years of adjuvant treatment with tamoxifen.
The planned duration of treatment for patients in the study was 5 years, but the trial was terminated early because of an interim analysis showing a favorable Femara effect on time without recurrence or contralateral breast cancer. At the time of unblinding, women had been followed for a median of 28 months, 30% of patients had completed 3 or more years of follow-up and less than 1% of patients had completed 5 years of follow-up.
Selected baseline characteristics for the study population are shown in Table 7.
Table 7: Selected Study Population Demographics (Modified
|Hormone Receptor Status (%)|
|ER+ and/or PgR+||98||98|
|Nodal Status (%)|
|Nodal Status Unknown||4||4|
Table 8 shows the study results. Disease-free survival was measured as the time from randomization to the earliest event of loco-regional or distant recurrence of the primary disease or development of contralateral breast cancer or death. DFS by hormone receptor status, nodal status and adjuvant chemotherapy were similar to the overall results. Data were premature for an analysis of survival.
Table 8: Extended Adjuvant Study Results
N = 2582
N = 2586
|Hazard Ratio (95% CI)||P-Value|
|Disease Free Survival (DFS)1 Events||122 (4.7%)||193 (7.5%)||0.62 (0.49, 0.78)2||0.00003|
|Local Breast Recurrence||9||22|
|Local Chest Wall Recurrence||2||8|
|Distant Recurrence||55||92||0.61 (0.44 - 0.84)||0.003|
|Contralateral Breast C ancer||19||29|
|Deaths Without Recurrence or Contralateral Breast Cancer||30||38|
|CI = confidence interva l for hazard ratio.
Hazard ratio of less than 1.0 indicates difference in favor of Femara
(lesser risk o f recurrence); hazard ratio greater than 1.0 indicates
difference in favor of placebo (higher risk of recurrence with Femara).
1 First event of loco-regional recurrence, distant relapse, contralateral breast cancer or death from any cause
2 Analysis stratified by receptor status, nodal status and prior adjuvant chemotherapy (stratification factors as at randomizati on).
P-value based on stratified logrank test.
Updated Analyses of Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 60 Months
Table 9: Update of Extended Adjuvant Study Results
N = 2582
|Hazard Ratio1 (95% CI)||P-Value2|
|Disease Free Survival (DFS) events3||344 (13.3)||402(15.5)||0.89 (0.77, 1.03)||0.12|
|Breast cancer recurrence (Protocol definition of DFS events4)||209||286||0.75 (0.63, 0.89)||0.001|
|Local Breast Recurrence||15||44|
|Local Chest Wall Recurre nce||6||14|
|Distant recurrence (first or subsequent events)||142||169||0.88 (0.70,1.10)||0.246|
|Contralateral Breast Cancer||37||53|
|Deaths Without Recurrence or Contralateral Breast Cancer||135||116|
|1 Adjusted by receptor status,
nodal status and prior chemotherapy
2 Stratified logrank test, stratified by receptor status, nodal status and prior chemotherapy
3 DFS events defined as earliest of loco-regional recurrence, distant metastasis, contralateral breast cancer or death from any cause, and ignoring switches to Femara in 60% of the placebo arm.
4 Protocol definition does not include deaths from any cause
Updated analyses were conducted at a median follow-up of 62 months. In the Femara arm, 71% of the patients were treated for a least 3 years and 58% of patients completed at least 4.5 years of extended adjuvant treatment. After the unblinding of the study at a median follow-up of 28 months, approximate ly 60% of the selected patients in the placebo arm opted to switch to Femara.
In this updated analysis shown in Table 9, Femara significantly reduced the risk of breast cancer recurrence or contralateral breast cancer compared with placebo (HR 0.75; 95% CI 0.63, 0.89; P=0.001). However, in the updated DFS analysis (interval between randomization and earliest event of loco-regional recurrence, distant metastasis, contralateral breast cancer, or death from any cause) the treatment difference was heavily diluted by 60% of the patients in the placebo arm switching to Femara and accounting for 64% of the total placebo patient-years of follow-up. Ignoring these switches, the risk of DFS event was reduced by a non-significant 11% (HR 0.89; 95% CI 0.77, 1.03). There was no significant difference in distant disease-free survival or overall survival.
First-Line Treatment of Advanced Breast Cancer
A randomized, double-blind, multinational trial compared Femara 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 characterist ics for this study are shown in Table 10.
Table 10: Selected Study Population Demographics
|Stage of Disease|
|ER and PgR Positive||38%||41%|
|ER or PgR Positive||26%||26%|
|ER- or PgR /Other Unknown -||< 1%||0|
|Previous Antiestrogen Therapy|
|Dominant Site of Disease|
Femara was superior to tamoxifen in TTP and rate of objective tumor response (see Table 11). Table 11 summarizes the results of the t rial, with a total median follow-up of approximately 32 months. (All analyses are unadjusted and use 2-sided P-value s.)
Table 11: Results of First-Line Treatment of Advanced Breast
|Femara 2.5 mg
|tamoxifen 20 mg
|Hazard or Odds Ratio (95% CI) P-Value (2-Sided)|
|Median Time to Progression||9.4 months||6.0 months||0.72 (0.62, 0.83)1 P<0.0001|
|Objective Response Rate|
|(CR + PR)||145 (32%)||95 (21%)||1.77 (1.31, 2.39)2 P=0.0002|
|(CR)||42 (9%)||15 (3%)||2.99 (1.63, 5.47)2 P=0.0004|
|Duration of Objective Response|
|Ov erall Survival||35 months
|1 Hazard ratio
2 Odds ratio
3 Overall logrank test Figure 2 shows the Kaplan-Meier curves for TTP.
Figure 2: Kaplan-Meier Estimates of Time to Progression (Tamoxifen
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
|Variable||Femara 2.5 mg
|tamoxifen 20 mg
|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% C I)||3.85 (1.50,||9.60)|
Hazard ratio less than 1 or odds ratio greater than 1 favors Femara; hazard ratio greater than 1 or odds ratio less than 1 favors tamoxifen.
Table 13: Efficacy by Disease Site
|Femara 2.5 mg||tamoxifen 20 mg|
|Dominant Disease Site|
|Median TTP||12.1 months||6.4 months|
|Objective Response Rate||50%||34%|
|Median TTP||9.5 months||6.3 months|
|Objective Response Rate||23%||15%|
|Median TTP||8.3 months||4.6 months|
|Objective Response Rate||28%||17%|
Table 14: Efficacy by Receptor Status
|Variable||Femara 2.5 mg||tamoxifen 20 mg|
|Median Time to Progression (95% CI)||9.4 months (8.9, 11.8)||6.0 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)|
|Median Time to Progression (95% CI)||9.2 months (6.1, 12.3)||6.0 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)|
Hazard ratio less than 1 or odds ratio greater than 1 favors Femara; hazard ratio greater than 1 or odds ratio less than 1 favors tamoxifen.
Figure 3 shows the Kaplan-Meier curves for survival.
Figure 3 : Survival by Randomized Treatment Arm
Legend: Randomized Femara: 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 Femara 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 (Femara to tamoxifen) and 13 months (tamoxifen to Femara). In patients who did not cross over to the opposite treatment arm, median survival was 35 months with Femara (n=219, 95% Cl 29 to 43 months) vs 20 months with tamoxifen (n=229, 95% Cl 16 to 26 months).
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 a nd also may have received cytotoxic therapy. Eight (20%) of fo rty patients treated with Femara 2.5 mg daily in Phase I/II trials achieved an objective tumor response (com plete 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 study||aminoglutethimide study|
|No. of Participants||552||557|
|Sites of Disease|
Confirmed objective tumor respon se (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 0.5 mg
|Femara 2.5 mg
|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||Femara 2.5: Femara 0.5=2.33||Femara 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=0.81||Femara 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
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 0.5 mg
|Femara 2.5 mg
|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 day s||123 day s||112 days|
|Median Survival||636 day s||792 day s||592 days|
|Odds Ratio for Response||Femara 2.5: Femara 0.5=1.05 (95% CI: 0.62, 1.79); (95% CI: 0.90, 2.87); P=0.85*||Femara 2.5:|
|Relative Risk of Progression||Femara 2.5: Femara 0.5=0.86 (95% CI: 0.68, 1.11); (95% CI: 0.57 ,0.94); P=0.25*||Femara 2.5: aminoglutethimide=0.74 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)
Last reviewed on RxList: 1/10/2012
This monograph has been modified to include the generic and brand name in many instances.
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