Oncologist

The

Regulatory Issues: FDA

Approval Summary: Letrozole (Femara Tablets) for Adjuvant and Extended Adjuvant Postmenopausal Breast Cancer Treatment: Conversion of Accelerated to Full Approval
MARTIN H. COHEN, JOHN R. JOHNSON, ROBERT JUSTICE, RICHARD PAZDUR Office of Oncology Drug Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA
Key Words. Letrozole Femara Postmenopausal breast cancer Adjuvant treatment
Disclosures: Editor-in-Chief Bruce Chabner: PharmaMar (Board member); Thomas McNerney and Partners, Eli Lilly, Epizyme (SAB); Allergan, OvaGen, Peregrine, GlaxoSmithKline, Merrimack (C/A); Covidien, Celgene, Seattle Genetics, Pharmasett, Exelixis, Gilead, Rigel, Onyx, Syngenta, Bristol-Myers Squibb, Human Genome Sciences, Zeltia (O). Reviewers A and B: None. (C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific Advisory Board.

LEARNING OBJECTIVES
After completing this course, the reader will be able to: 1. Compare the efficacy of letrozole and tamoxifen. 2. Contrast the adverse effect profile of letrozole with those of tamoxifen and placebo.
CME

This article is available for continuing medical education credit at CME.TheOncologist.com.

ABSTRACT
On April 30, 2010, the U.S. Food and Drug Administration converted letrozole (Femara; Novartis Pharmaceuticals Corporation, East Hanover, NJ) from accelerated to full approval for adjuvant and extended adjuvant (following 5 years of tamoxifen) treatment of postmenopausal women with hormone receptorpositive early breast cancer. The initial accelerated approvals of letrozole for adjuvant and extended adjuvant treatment on December 28, 2005 and October 29, 2004, respectively, were based on an analysis of the disease-free survival (DFS) outcome of patients followed for medians of 26 months and 28 months, respectively. Both trials were double-blind, multicenter studies. Both trials were unblinded early when an interim analysis showed a favorable letrozole effect on DFS. In updated intention-to-treat analyses of both trials, the risk for a DFS event was lower with letrozole than with tamoxifen (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.77 0.99; p .03) in the adjuvant trial and was lower than with placebo (HR, 0.89; 95% CI, 0.76 1.03; p .12) in the extended adjuvant trial. The latter analysis ignores the interim switch of 60% of placebo-treated patients to letrozole. Bone fractures and osteoporosis were reported more frequently following treatment with letrozole whereas tamoxifen was associated with a higher risk for endometrial proliferation and endometrial cancer. Myocardial infarction was more frequently reported with letrozole than with tamoxifen, but the incidence of thromboembolic events was higher with tamoxifen than with letrozole. Lipid-lowering medications were required for 25% of patients on letrozole and 16% of patients on tamoxifen. The Oncologist 2011;16: 17621770

Correspondence: Martin H. Cohen, M.D., U.S. Food and Drug Administration, White Oak Campus, 10903 New Hampshire Avenue, Building 22, Room 2102, Silver Spring, Maryland 20993-0002, USA. Telephone: 301-796-1344; Fax: 301-796-9845; e-mail: martin.cohen@fda.hhs.gov Received August 20, 2011; accepted for publication September 16, 2011; first published online in The Oncologist Express on November 16, 2011. AlphaMed Press 1083-7159/2011/$40.00/0 http://dx.doi.org/10.1634/theoncologist.20110287

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INTRODUCTION
Letrozole was initially granted accelerated approval by the U.S. Food and Drug Administration for the adjuvant (December 28, 2005) and extended adjuvant following 5 years of tamoxifen (October 29, 2004) treatment of postmenopausal women with hormone receptorpositive early breast cancer. Accelerated approval was based on promising disease-free survival (DFS) results, but follow-up was insufficient to determine long-term outcomes for both safety and efficacy. The treatment duration was 24 months for both studies and patients were followed for a median of 26 months and 28 months in the adjuvant and extended adjuvant trials, respectively. Products approved under the subpart H accelerated approval regulations, 21 CFR 314.510, require further adequate and wellcontrolled studies to verify and describe clinical benefit. For the above two indications, the DFS interval is considered an established surrogate for clinical benefit and may be an acceptable basis for full approval. However, only accelerated approval was granted because the follow-up was too short to determine the ultimate outcome regarding both safety and efficacy. Sponsor commitments, under these regulations, were (a) to follow all patients in the adjuvant trial for safety and efficacy until death or at least 5 years from randomization, (b) to follow all patients in the extended adjuvant trial for safety and efficacy until death or at least 5 years from randomization, and (c) to complete an open-label, randomized, multicenter study to evaluate the skeletal and lipid profile effects of letrozole and tamoxifen in postmenopausal women with resected, hormone receptorpositive breast cancer. The final trial reports of the letrozole adjuvant and extended adjuvant studies are the subjects of this manuscript.

PATIENTS AND METHODS Adjuvant Trial (Breast International Group 198)

The adjuvant trial (Breast International Group [BIG] 198) is a double-blind, international trial conducted under the auspices of the BIG at 248 sites in 27 countries. Postmenopausal women with operable breast cancer (mastectomy, lumpectomy, or quadrantectomy) who had receptor positive (estrogen receptor and/or progesterone receptor 10 fmol/mg cytosol protein or 10% of tumor cells positive by immunocytochemical evaluation) disease were eligible. Patients had adequate hematologic, hepatic, and renal function and provided written informed consent. Patients with distant metastases, with bilateral breast cancer, with malignancy within the previous 5 years except for adequately treated basal or squamous cell carcinoma, who had received treatment with investigational drugs within 30 days of the start of protocol therapy, or who were known to be HIV were excluded. Trial treatments were letrozole, 2.5 mg once daily, and tamoxifen, 20 mg once daily. Bisphosphonates were permitted and had to be reported during the trial. The trial had two randomization options. Option 1 had four armstamoxifen for 5 years, letrozole for 5 years, tamoxifen for 2 years followed by letrozole for 3 years, and letrozole for 2 years followed by tamoxifen for 3 years. Option 2 had two arms

tamoxifen for 5 years and letrozole for 5 years. Option 1 was initiated approximately 1 year after initiation of option 2. Randomization was stratified by institution (cooperative group), randomization option (four arm versus two arm), and the use of adjuvant or neoadjuvant chemotherapy (none versus completed prior to enrollment versus concurrent with start of trial treatment). Patients were seen for follow-up every 6 months during treatment and yearly thereafter. At each visit, general safety data were reviewed, predefined toxicity data were collected, and trial medications were renewed. If a patient discontinued trial treatment for any reason, data concerning survival, disease status, and cardiac, bone, and endometrial adverse events (AEs) were collected every 6 months for 5 years from randomization, followed by yearly reports. The primary endpoint of this trial was the DFS interval (i.e., the interval between randomization and the earliest occurrence of a local, regional, or distant recurrence, invasive contralateral breast cancer, or death from any cause). Secondary endpoints were the overall survival (OS) duration, systemic DFS (SDFS) interval (i.e., the interval from randomization to invasive regional recurrence, distant metastasis, or death without a prior cancer event), occurrence of invasive contralateral breast cancer, time to breast cancer recurrence, time to distant metastasis (TDM) (i.e., the interval from randomization to distant metastasis), and distant DFS (DDFS) interval (i.e., the interval from randomization to the earlier event of relapse in a distant site or death from any cause). The current analysis of the BIG 198 trial was conducted by the International Breast Cancer Study Group on the database locked on July 3, 2008. Two efficacy analyses were performed. The primary core analysis (PCA) involved 8,010 patients (4,003 in the letrozole group and 4,007 in the tamoxifen group). This analysis included all patients randomized to either letrozole or tamoxifen for either 5 years or 2 years of treatment, with the latter patients censored within 30 days of drug switch. The monotherapy arms analysis (MAA) included only patients randomized to 5 years of monotherapy (2,463 in the letrozole group and 2,459 in the tamoxifen group) and is thus more relevant to answer the primary question as to the superiority of letrozole to tamoxifen. The safety analysis was based on 7,963 patients (3,975 in the letrozole group and 3,988 in the tamoxifen group). The median follow-up was 60 months for the PCA and 73 months for the MAA. The results of an interim PCA led to the decision by the BIG 198 Steering Committee, following a recommendation by the Data Safety Monitoring Committee (DSMC), to inform the 2,459 patients randomly assigned tamoxifen alone of their treatment in order to make informed decisions about their future care. Patients were offered the opportunity to stop tamoxifen and receive letrozole. The protocol was amended in April 2005 to that effect. Patients who were within 4.5 years of randomization could elect to either complete 5 years of treatment with tamoxifen or change to letrozole for the remainder of their 5-year adjuvant therapy. Patients who had been treated for 4.55 years with tamoxifen could choose to receive extended letrozole for up to an additional 5 years. The remaining

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Letrozole Adjuvant Treatment

Table 1. Adjuvant trial: Demographic and disease characteristics (intent to treat population) Primary core analysis Monotherapy arms analysis Letrozole n 4,003 n or % 61 3889 99.7 0.3 52 41 7 24 Tamoxifen n 4,007 n or % 61 3990 99.7 0.3 52 41 7 24 Letrozole n 2,463 n or % 61 3888 99.7 0.3 50 43 7 24 Tamoxifen n 2,459 n or % 61 3990 99.7 0.3 52 41 7 24

Characteristic Median age, yrs Age range, yrs Hormone receptor status, % Estrogen receptor and/or progesterone receptor positive Both unknown Nodal status, % Node negative Node positive Nodal status unknown Prior adjuvant chemotherapy, %

three randomized treatment groups (i.e., letrozole alone and the two switch groups) remained blinded. The question as to whether therapy switch or continued monotherapy is beneficial was not definitively answered. Analyses were underpowered. Sequential therapy results are not discussed further.

Extended Adjuvant Trial (MA-17)

The extended adjuvant trial (MA-17) was initially designed as a double-blinded, placebo-controlled trial enrolling hormone receptorpositive or unknown hormone receptor status postmenopausal women who had completed 5 years of adjuvant treatment with tamoxifen. Eligible patients were randomly allocated letrozole, 2.5 mg daily, or placebo for a period of 5 years. The patients may have previously received adjuvant chemotherapy and/or radiation therapy. At trial entry, patients were to have no evidence of breast cancer recurrence and tamoxifen should have been discontinued no more than 3 months prior to randomization. Randomization was stratified according to hormone receptor status (positive, unknown), lymph node status at diagnosis (negative, positive, or unknown), and prior adjuvant chemotherapy (yes, no). The primary efficacy endpoint was the DFS interval. In the MA-17 trial, the protocol-specified definition of the DFS interval was the interval between randomization and the earliest event of a locoregional recurrence of breast cancer in the breast, chest wall, or nodal sites; relapse at distant sites; or a new contralateral breast cancer (i.e., the protocol definition did not include deaths, and deaths without a breast cancer event were censored). The definition included cases of ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS). Secondary endpoints included the OS duration, occurrence of distant recurrence, DDFS interval, and occurrence contralateral breast cancer. Safety endpoints included cardiovascular morbidity and mortality, bone fractures and osteoporosis, lipid alterations, quality of life (QoL), and second nonbreast primary cancers.

The concomitant use of thyroid medication, calcium, bisphosphonates, and vitamin D was acceptable as was the intermittent use of vaginal estrogens if other local measures for intractable vaginal atrophy were insufficient. Hormone replacement therapy had to be stopped before randomization and the use of other aromatase inhibitors (AIs) or concomitant chemotherapy was proscribed (prior to recurrence). The planned duration of treatment for patients in the trial was 5 years, but the trial was terminated early because of an interim analysis showing a favorable letrozole effect on time without recurrence or contralateral breast cancer. At the time of unblinding, in October 2003, women had been followed for a median of 28 months, 30% of patients had completed 3 years of follow-up and 1% of patients had completed 5 years of follow-up. After unblinding, the trial design was transformed into an open-label, observational, nonrandomized, clinical trial. The trial compared the outcome of patients randomized to letrozole with the outcome of patients initially randomized to placebo who, after unblinding, could opt to receive open-label letrozole or standard care (no treatment). Of the 2,586 patients randomized to placebo, 1,551 switched to letrozole and 1,035 never switched. The amended protocol outlining the option of switching to letrozole did not specify either the period within which switches were to be made or the interval elapsed since stopping placebo. Switches occurred between October 9, 2003 (date of unblinding) and January 17, 2008. Switches occurred in patients who had remained on (double-blind) placebo until the date of switching as well as in patients who had discontinued placebo for various reasons (other than recurrence or relapse) 8 years previously. Patients who switched to letrozole from placebo after unblinding could receive letrozole for up to 5 years. Three substudies, carried out at selected centers, evaluated the influence of the trial treatments on bone mineral density as assessed by dual-emission x-ray absorptiometry scanning of the lumbar spine and total hip and bone markers (bone sub-

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Table 2. Adjuvant trial monotherapy arms analysis (median follow-up, 73 months) Letrozole n 2,463 Tamoxifen n 2,459 Outcome measure DFS
a

Events, ITT Censor ITT ITT ITT ITT ITT ITT ITT ITT ITT ITT ITT ITT Censor ITT ITT ITT ITT ITT 445 445 165 151 123 119 326 401 257 84 173 385 34 303 303 107 99 92 186 117

5-yr rate 87.4 87.4 92.2 85.6 71.2

Events, 500 483 189 163 142 150 350 446 298 109 189 432 44 343 338 121 114 104 203 140

5-yr rate 84.7 84.2 90.3 83.0 62.6

Hazard ratio (95% CI) 0.87 (0.760.99) 0.84 (0.730.95) 0.88 (0.721.09) 0.85 (0.681.06) 0.81 (0.641.03) 0.77 (0.600.98) 0.91 (0.781.06) 0.88 (0.771.01) 0.85 (0.721.00) 0.75 (0.561.00) 0.90 (0.731.11) 0.87 (0.761.00) 0.76 (0.491.19) 0.87 (0.751.02) 0.82 (0.700.96) 0.90 (0.691.16) 0.81(0.621.06) 0.86 (0.651.14) 0.91 (0.741.10) 0.82 (0.641.05)

p .03

0 positive nodes 13 positive nodes 4 positive nodes Adjuvant chemotherapy No chemotherapy Systemic DFSb Time to distant metastasis Adjuvant chemotherapy No chemotherapy Distant DFS Contralateral breast cancer Overall survival 0 positive nodes 13 positive nodes 4 positive nodes Adjuvant chemotherapy No chemotherapy

88.5 92.4 89.0 99.2 91.8 91.8 95.2 90.8 80.2 92.8 89.7

86.6 90.1 87.1 98.6 90.9 90.1 94.8 90.6 73.6 92.2 88.1

.05

.05 .23 .08

a ITT analyses ignored selective crossover. Censored analyses censored follow-up/event times at the date of selective crossover in 632 women who crossed over to letrozole or another aromatase inhibitor after the tamoxifen arms were unblinded. b Adjusted by randomization option and use of chemotherapy. Abbreviations: CI, confidence interval; DFS, disease-free survival; ITT, intent to treat.

trial), on serum lipids (lipid subtrial), and on QoL (QoL subtrial) as assessed by the short form 36 and Menopause-specific Quality of Life Questionnaire scales was also assessed. These studies are not discussed in this report.

RESULTS Adjuvant Trial (BIG 198)

Selected baseline characteristics for the BIG 198 trial population are shown in Table 1.Two analyses were performed. The initial PCA that included all enrolled trial patients 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 OS and the occurrence of contralateral breast cancer (DFS hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.68 0.92; p .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). These results led the DSMC to recommend that the tamoxifen arms be unblinded so that tamoxifen-treated patients could choose to complete initial adjuvant therapy with letrozole (if they had received tamoxifen for 2 years) or to start extended adjuvant treatment with letrozole (if they had received tamox-

ifen for 4.5 years) if they remained alive and disease free. In total, 632 patients crossed over to letrozole or to another AI. Of these 632 women, 448 (70%) crossed over to letrozole to complete initial adjuvant therapy. All these women were in option 1 (four treatment arms) and most crossed over in years 3 4, at a median of 43 months from randomization. The median duration of letrozole treatment after cross over was 17 months. The remaining 184 women crossed over to letrozole (172 women) or another AI (12 women) to start extended adjuvant treatment, having received tamoxifen for 4.55 years. The MAA ignores the two sequential treatment arms and thus provides data directly comparing the two treatment arms confounded by the selective crossover of tamoxifen-treated patients to letrozole. The results for the MAA are summarized in Table 2. The median follow-up for this analysis was 73 months. The 5-year DFS rates were 87.4% for letrozole and 84.7% for tamoxifen (HR, 0.87; 95% CI, 0.76 0.99; p .03). The median OS times for both arms were not reached for the MAA. There was no statistically significant difference in terms of OS. The HR for survival in the letrozole arm compared with the tamoxifen arm was 0.87 (95% CI, 0.751.02).

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Letrozole Adjuvant Treatment nodes, distant metastases, or a new contralateral breast cancer, in the mITT population, letrozole resulted in a 25% lower risk for recurrence, compared with placebo (HR, 0.75; 95% CI, 0.63 0.89; stratified log-rank p-value .001). Applying the definition of the DFS time that included all deaths from any cause as well as protocol-specified events of breast cancer recurrence, there was a nonsignificant 11% lower risk for recurrence with letrozole than with placebo (HR, 0.89; 95%, 0.77 1.03; p .12). The OS outcomes were almost the same in the two treatment arms (HR, 1.13; 95% CI, 0.951.36; p .17). Letrozole resulted in a significantly lower odds of a new invasive contralateral breast cancer, compared with placebo, by 36% (odds ratio, 0.64; 95% CI, 0.411.00; p .05). The occurrence of contralateral breast cancer was significantly lower in the letrozole arm regardless of whether invasive cancers were considered or whether DCIS or LCIS were included. Disregarding any switch, letrozole was better than placebo in reducing the risk for breast cancer recurrence both in patients aged 65 years and in patients aged 65 years at enrollment; regardless of tumor size; whether initial disease was node negative or node positive; whether adjuvant radiotherapy had been given or not; whether or not patients had received bisphosphonate therapy; whether or not patients had received adjuvant chemotherapy; in patients whose adjuvant chemotherapy was cyclophosphamide, methotrexate, and 5-fluorouracil; and in patients who had received adjuvant therapy with tamoxifen for 5 years.

Extended Adjuvant Trial (MA-17)

The extended adjuvant trial was performed in postmenopausal women with receptor-positive, or unknown receptor status, primary breast cancer who were disease free after 5 years of adjuvant treatment with tamoxifen. The planned duration of treatment for patients in the trial was 5 years, but the trial was terminated early because of an interim analysis showing a favorable letrozole effect on time without recurrence or contralateral breast cancer. At the time of unblinding, in October 2003, women had been followed for a median of 28 months, 30% of patients had completed 3 years of follow-up, and 1% of patients had completed 5 years of follow-up. The current report provides a final update of safety and efficacy based on a median follow-up of 5 years for the letrozole arm (1,145 patients; 44% had completed their 5 years of extended adjuvant therapy and 64% had completed 4 years of extended adjuvant treatment). Placebo was given for a median of 28 months (placebo was not dispensed after unblinding). The median duration of letrozole after switching from placebo was 40 months. At the time of writing, 79% of the placebotreated patients who switched had completed 2 years of letrozole and 61% had completed 3 years. The maximum duration of letrozole treatment after switching was 46 months. The modified intent to treat (mITT) efficacy population (ITT population minus two patients with recurrent breast cancer at the time of enrollment) consisted of 5,168 patients, 2,852 randomized to letrozole and 2,586 randomized to placebo. After unblinding, 1,551 placebo-treated patients switched to letrozole and 1,035 never switched. When the trial was unblinded, the median duration of trial treatment was 2 years. At the cutoff date for analysis 50% of the patients in the randomized letrozole arm had completed 5 years of extended adjuvant therapy. For patients switching to letrozole, 61% had completed 3 years of letrozole and 15% had competed 4 years. Demographic and disease characteristics for ITT patients are summarized in Table 3. Approximately 54% of patients had received prior adjuvant chemotherapy. The median number of years on tamoxifen was 5.0. While in the trial, the use of both calcium and bisphosphonates appeared to be considerably greater for letrozole-treated patients than for placebotreated patients who opted not to switch. Thus, 33% of letrozole-treated patients received bisphosphonates while in the trial versus 35% of placebo-treated patients. After switching, 28% of letrozole-treated patients received bisphosphonates and 20% of placebo-treated patients received bisphosphonates. DFS events at a median treatment duration of 60 months and a median follow-up of 62 months are summarized in Table 4. Metastasis at a distant site was the most common type of recurrence. The patterns of recurrence at distant sites appeared to be similar in both treatment arms. Bone remained the most commonly involved first site of distant relapse for both treatment arms (letrozole, 96 of the 140 patients with distant metastases; placebo, 102 of the 167 patients with distant metastases). Using the definition of the DFS time as the interval between randomization and the earliest occurrence of a locoregional recurrence in the breast, chest wall, or regional lymph

Safety
In both studies, adverse reactions were analyzed irrespective of whether a symptom was present or absent at baseline. Most adverse reactions reported (with 75% of patients reporting one or more AE) were grade 1 or grade 2 applying the National Cancer Institute Common Toxicity Criteria (CTC), version 2.0/Common Terminology Criteria for Adverse Events, version 3.0. In the adjuvant study comparing letrozole with tamoxifen, letrozole was associated with a higher incidence of fractures (13.8% versus 10.5%), osteoporosis (5.1% versus 2.7%), myocardial infarction (1.0% versus 0.5%), and arthralgia (25.2% versus 20.4%). Tamoxifen was associated with a higher incidence of thromboembolic events (3.6% versus 2.1%), endometrial hyperplasia/cancer (2.9% versus 0.3%), and endometrial proliferation disorders (1.8% versus 0.3%). In the extended adjuvant trial (letrozole: 2,582 patients; median follow-up, 60 months; placebo until switch: 2,586 patients, median follow-up, 28 months; letrozole after switch: 1,551 patients; median follow-up, 41 months), the incidences of new fractures at any time after randomization were 13.3% for letrozole and 7.8% for placebo. The incidences of new osteoporosis were 14.5% for letrozole and 7.8% for placebo. Cardiovascular toxicity included cerebrovascular and thromboembolic AEs. In the adjuvant trial, during trial treatment, myocardial infarction occurred in 1.0% versus 0.5%, cerebrovascular accident occurred in 2.1% versus 1.9%, angina occurred in 1.1% versus 1.0%, and a thromboembolic event occurred in 2.1% versus 3.6% of letrozole-treated versus tamoxifen-treated patients, respectively. In the extended adju-

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Table 3. Extended adjuvant trial: Demographic and disease characteristics As randomized Letrozole n 2,583 n (%) 62 1,485 (57.5) 1,098 (42.5) 2,284 (88.4) 83 (3.2) 47 (1.8) 169 (6.5) Placebo n 2,587 n (%) 62 1,550 (59.9) 1,037 (40.1) 2,339 (90.4) 90 (3.5) 24 (0.9) 134 (5.2)

Placebo after unblinding Placebo not Switching n 1,036 n (%) 64 527 (50.9) 509 (49.1) 930 (89.8) 50 (4.8) 10 (1.0) 46 (4.4) Letrozole after switch n 1,551 n (%) 60 1,023 (66.0) 528 (34.0) 1,409 (90.8) 40 (2.6) 14 (0.9) 88 (5.7)

Characteristic Median age, yrs 65 at enrollment 65 at enrollment Race White Black Oriental Other Eastern Cooperative Oncology Group performance status score 0 1 2 Pathological tumor (T) stage of disease at surgery pT1 pT2 pT3 pT4 Unknown, missing Pathological node (N) stage of disease at surgery pN0 pN1 pN2 pN3 Unknown, missing n of positive nodes 0 or missing 14 59 10 Estrogen receptor status Positive Negative Unknown, missing Progesterone receptor status Positive Negative Unknown, missing Progesterone receptor level of primary tumor at surgery Positive Negative Unknown

2,317 (89.7) 251 (9.7) 13 (0.5)

2,330 (90.1) 248 (9.6) 9 (0.3)

897 (86.6) 133 (12.8) 6 (0.6)

1,433 (92.4) 115 (7.4) 3 (0.2)

1,490 (57.7) 865 (33.5) 141 (5.5) 46 (1.8) 41 (1.6) 1,295 (50.1) 1,125 (43.6) 42 (1.6) 7 (0.3) 114 (4.4) 1,425 (55.2) 848 (32.8) 189 (7.3) 121 (4.7) 1,618 (62.6) 69 (2.7) 896 (34.7) 1,313 (50.8) 220 (8.5) 1,050 (40.7)

1,510 (58.4) 867 (33.5) 137 (5.3) 38 (1.5) 35 (1.4) 1,281 (49.5) 1,153 (44.6) 38 (1.5) 3 (0.1) 112 (4.3) 1,420 (54.9) 870 (33.6) 201 (7.8) 96 (3.7) 1,643 (63.5) 70 (2.7) 874 (33.8) 1,335 (51.6) 237 (9.2) 1,015 (39.2)

605 (58.4) 349 (33.7) 55 (5.3) 16 (1.5) 11 (1.1) 523 (50.5) 440 (42.5) 17 (1.6) 56 (5.4) 588 (56.8) 341 (32.9) 68 (6.6) 39 (3.8) 625 (60.3) 20 (1.9) 391 (37.7) 499 (48.2) 94 (9.1) 443 (42.8)

905 (58.3) 518 (33.4) 82 (5.3) 22 (1.4) 24 (1.6) 758 (48.9) 713 (46.0) 21 (1.4) 3 (0.2) 56 (3.6) 832 (53.6) 529 (34.1) 133 (8.6) 57 (3.7) 1,018 (65.6) 50 (3.2) 483 (31.1) 836 (53.9) 143 (9.2) 572 (36.9)

2,533 (98.1) 1 (0.1) 49 (1.9)

2,536 (98.0) 1 (0.1) 50 (1.9)

1,006 (97.1) 1 (0.1) 29 (2.8)

1,530 (98.6) 21 (1.4)

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Letrozole Adjuvant Treatment

Table 4. Extended adjuvant disease-free survival (DFS) events: Modified intent to treat population, 62-month median follow-up As randomizeda Letrozole n 2,582 n (%) 344 (13.3) 209 15 6 10 142 37 135 Placebo n 2,586 n (%) 402 (15.5) 286 44 14 8 169 53 116 Hazard ratiob (95% confidence interval) 0.89 (0.771.03) 0.75 (0.630.89) 0.88 (0.701.10)

Outcome measure DFS events Breast cancer recurrence (protocol definition of DFS eventse) Local breast recurrence Local chest wall recurrence Regional recurrence Distant recurrence (first or subsequent events) Contralateral breast cancer Deaths without recurrence or contralateral breast cancer
a b
d

p-valuec .12 .001 .246

Ignoring switches to letrozole in 60% of patients in the placebo arm. Adjusted by receptor status, nodal status, and prior chemotherapy. c Stratified log-rank test, stratified by receptor status, nodal status, and prior chemotherapy. d DFS events defined as earliest of locoregional recurrence, distant metastasis, contralateral breast cancer, or death from any cause. e Protocol definition does not include deaths from any cause.

vant trial, the incidences of cardiovascular disease at any time after randomization were 14.4% for the letrozole arm and 9.8% for the placebo arm (until switch), with 7.6% of patients reporting cardiovascular events after switching to letrozole. The difference appeared to be accounted for by new or worsening angina (letrozole, 2.0%; placebo until switch, 1.4%), myocardial infarction (letrozole, 1.7%; placebo until switch, 1.0%), thromboembolic events (letrozole, 1.3%; placebo until switch, 0.7%), and stroke/ transient ischemic attack (letrozole, 2.6%; placebo, 1.4%). In the adjuvant trial, hypercholesterolemia was reported in 52.3% of letrozole-treated patients and 28.6% of tamoxifentreated patients. CTC grade 3 4 hypercholesterolemia was reported in 0.4% of letrozole-treated patients and 0.1% of tamoxifen-treated patients. Also in the adjuvant setting, an increase 1.5 the upper limit of normal (ULN) in total cholesterol (generally nonfasting) was observed in patients who had baseline total serum cholesterol levels within the normal range (i.e., 1.5 ULN) for 8.2% of patients on letrozole and 3.2% of patients on tamoxifen. Lipid-lowering medications were required for 25% of patients on letrozole and 16% of patients on tamoxifen. In the extended adjuvant trial, hypercholesterolemia was noted in 15% of patients in both treatment groups. Hot flushes, fatigue, and arthralgia/arthritis were the most frequent AEs observed. Generally, AEs were mild or moderate in severity and caused treatment discontinuation in a small number of patients (2.1% in the letrozole arm and 1.2% in the placeboletrozole switching group). As previously indicated, significantly more patients treated with letrozole than with placebo until switch experienced bone fracture and osteoporosis. In both letrozole- and placebo-treated patients, bone fractures occurred more frequently in patients who

were at risk, such as patients who had a history of bone fracture (9.9% of the placebo group, 17.0% of the letrozole group), a history of osteoporosis (9.5% of the placebo group, 16.1% of the letrozole group), or were aged 65 years at enrollment (7.7% of the placebo group, 11.4% of the letrozole group). The wrist was the most common site of fracture in all treatment arms. The overall rate of second primary malignancies was higher in the letrozole group (4.8%) than in the placebo until switch group (2.9%). However, it should be taken into account that a considerable number of patients in the placebo group had switched to letrozole, resulting in a very low number of patients in the latter group with a follow-up comparable with that of the letrozole group. Among the second primary malignancies with a clear diagnosis, only colorectal cancer seemed to be more prominent in the letrozole group (0.6% versus 0.2%). No dose-related effect of letrozole on any hematologic or clinical chemistry parameter was evident. Moderate decreases in lymphocyte counts were observed in some patients receiving letrozole. This depression was transient in about half of those affected. Two patients on letrozole developed thrombocytopenia; its relationship to the trial drug was unclear. Patient withdrawal as a result of laboratory abnormalities, whether related to trial treatment or not, was infrequent. Increases in serum glutamic oraloacetic transaminase, serum glutamic pyruvic transaminase, and -glutamyltransferase 5 ULN and of bilirubin 1.5 ULN were most often associated with metastatic disease in the liver. About 3% of trial participants receiving letrozole had abnormalities in liver chemistries not associated with documented metastases; these abnormalities may have been related to trial drug therapy.

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DISCUSSION
Hormonal therapy has an established role in the adjuvant treatment of postmenopausal women with hormone receptorpositive breast cancer. Initial trials evaluated tamoxifen administered for 12 years. This treatment significantly reduced the risk for recurrence and breast cancer death [1, 2]. Tamoxifen administered for 5 years produced further significant improvements in both these efficacy parameters [1, 3]. Tamoxifen treatment beyond 5 years did not demonstrate similar benefit [1, 4, 5]. Based on these findings, 5 years of tamoxifen is considered an appropriate comparator for newer hormonal agents. The BIG 198 letrozole adjuvant trial [6 17] was initially conceived as a two-arm, blinded, randomized trial comparing 5 years of letrozole with 5 years of tamoxifen treatment. The trial was subsequently expanded to include a four-arm randomization option including the two monotherapy arms and two sequencing arms with patients receiving an initial 2 years of letrozole or tamoxifen therapy followed by a cross over to 3 years of treatment with the opposite drug. The trial was initiated in March 1998 (two-arm randomization) and was modified in April 1999 (four-arm randomization). The two-arm randomization ended in March 2000 and the four-arm randomization ended in May 2003. The first prespecified efficacy analysis, at a median follow-up of 25.8 months, with data cutoff December 20, 2004, included all randomized patients (PCA; 8,010 ITT patients). The DFS outcome was significantly better with letrozole treatment (HR, 0.81; 95% CI, 0.70 0.93; log-rank p .003). These results led the DSMC to recommend that patients randomized to tamoxifen alone be informed of their treatment so that decisions could be made regarding future treatment. Following unblinding, 25% of patients crossed over from tamoxifen to letrozole, mostly in years 35 of tamoxifen treatment. The remaining three randomized groups remained blinded. As evidenced in the current manuscript, in the adjuvant trial, with a median follow-up of 73 months, letrozole-treated patients had a superior DFS outcome (HR, 0.87; 95% CI, 0.76 0.99; log-rank p .03). There was no significant difference in terms of OS. Both the DFS and OS analyses are confounded by the 632 tamoxifen-treated patients who crossed over to letrozole (n 620) or to another AI (n 12). Analyses of the sequential treatment arms were inconclusive because they were underpowered and influenced by the selective crossover of tamoxifen-treated patients. The demonstrated activity and safety of adjuvant letrozole therapy, after prolonged patient follow-up, was sufficient to release the sponsor from the subpart H commitment and to convert accelerated approval to full approval for the proposed indication. Similar to the adjuvant trial, the extended adjuvant trial [18 27] was terminated early because of an interim analysis showing a favorable letrozole effect on time without recurrence or contralateral breast cancer. At the time of unblinding, in October of 2003, women had been followed for a median of 28 months. Subsequent to unblinding, 1,551 of 2,586 placebotreated patients switched to letrozole treatment. The current extended adjuvant trial report provides a final update of safety and efficacy based on a median follow-up of 5

years for the letrozole arm. When interpreting these results, the early crossover of 60% of placebo-treated patients to letrozole might be expected to eliminate any long-term statistically significant differences between the two treatment groups. The fact that a statistically significant difference was observed using the DFS criteria of locoregional recurrence in the breast, distant metastases, or a new contralateral breast cancer suggests that letrozole has activity in the extended adjuvant setting. The demonstrated activity and safety of extended adjuvant letrozole therapy following 5 years of tamoxifen, after prolonged patient follow-up, was sufficient to release the sponsor from the subpart H commitment and to convert the accelerated approval to full approval for the proposed indication. Among current issues is the timing of initiation of AI therapy, that is, whether an AI should replace a selective estrogen receptor modulator (SERM) as first-line hormonal therapy or AI therapy should follow 5 years of tamoxifen or other SERM therapy [28, 29]. The DFS curves of trials comparing an AI with tamoxifen are of interest in this regard. The observation that the curves start to diverge 18 months after the start of treatment and continue to diverge throughout treatment and for the duration of the follow-up period suggests that hormonal therapy should be initiated with an AI. Efficacy is not the only issue, however. Safety concerns raised by treatment with AIs primarily concern bone metabolism. One question was whether or not initial treatment with tamoxifen would ameliorate the negative effect of AIs on bone. Data from the letrozole extended adjuvant trial, in which 5 years of tamoxifen therapy preceded AI treatment, suggest that this is not the case. Thus, for women with or without preexisting osteoporosis, tamoxifen might be a reasonable treatment option despite the higher risk for endometrial cancer and thromboembolic and ischemic cerebrovascular events. Another option to address the issue of osteoporosis and fracture is treatment with zoledronic acid, a drug shown to maintain or increase bone mineral density in several hypogonadal states [30]. Two trials compared early with delayed treatment with zoledronic acid (4 mg i.v. every 6 months up to a maximum of 5 years along with a daily calcium supplement and vitamin D). Eligible women had pretreatment lumbar spine (LS) and total hip (TH) bone mineral density (BMD) T scores 2. Delayed treatment was initiated when the LS and/or TH BMD T scores were two or more standard deviations below normal (i.e., the T score decreased to 2.0) or a nontraumatic fracture occurred. Interim results, at 12 months, demonstrated that LS BMD was 5.2% higher and TH BMD was 3.5% higher in the upfront group than in the delayed group. Because no patients with normal BMD at baseline developed severe osteopenia/osteoporosis by 12 months, it is uncertain whether or not these patients should receive bisphosphonate therapy at baseline [31, 32]. Because estrogen levels naturally decline during menopause, postmenopausal women are predisposed to bone loss even without receiving AI treatment. Thus, in the two zoledronic acid trials discussed above 30% of patients had mild to moderate osteopenia at baseline. Upfront treatment of these patients resulted in normalization of BMD scores in a significant percentage of patients [31].

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Letrozole Adjuvant Treatment

Zoledronic acid is usually well tolerated, with bone pain and pyrexia as the most common adverse reactions. Renal impairment and jaw osteonecrosis are less common toxicities [31]. In conclusion, AIs appear to be a more effective adjuvant hormonal therapy than SERMs for postmenopausal patients with hormone receptorpositive breast cancer. Moreover, AIs are associated with fewer thromboembolic and gynecological AEs than are seen with tamoxifen. Potential negative effects of AIs on lipids and the cardiovascular system have not conclusively been demonstrated [33].

ACKNOWLEDGMENT
The views expressed are the result of independent work and do not necessarily represent the views and findings of the U.S. Food and Drug Administration.

AUTHOR CONTRIBUTIONS
Conception/Design: Martin H. Cohen Collection and/or assembly of data: Martin H. Cohen Data analysis and interpretation: Martin H. Cohen, Richard Pazdur, Robert Justice, John R. Johnson Manuscript writing: Martin H. Cohen, Richard Pazdur, Robert Justice, John R. Johnson Final approval of manuscript: Martin H. Cohen, Richard Pazdur, Robert Justice, John R. Johnson

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