sNDA 20-726 Letrozole (Femara®)

• Indication: First-line therapy in post-menopausal women with advanced breast cancer.

• Prior approval: Second-line therapy for same patient population with disease progression following antiestrogen treatment.

Letrozole Pivotal Trial

Double blind, double dummy, randomized, multicenter, 2-arm, phase III trial comparing letrozole 2.5mg v tamoxifen 20mg in postmenopausal women with advanced breast cancer

Comparator Treatment

• Generic Tamoxifen (Tamofen®, manufactured by Leiras, OY of Finland)

• Bioequivalent to Nolvadex®

Trial Objectives• Primary Endpoint

Time to Progression• Secondary Endpoints

-Objective response rate & duration-Clinical benefit (CR+PR+NC 24 weeks)

-Time to treatment failure-Survival-Safety

Eligibility• Postmenopausal• Stage IIIB or IV• ER and/or PR positive or both unknown• Measurable or evaluable disease. Patients with

bone only disease were eligible • May have had adjuvant chemo or 1 chemo

regimen for advanced disease• May have had adjuvant tamoxifen if recurred >1

year after stopping therapy

Tumor Evaluations

–Baseline –1 month - optional–Every 3 months thereafter

Response Determination

Measurablediseaseresponse

Non-measurevaluabledisease resp

Non-measurnon-evaluabledisease resp

Overallresponse

CR,PR NC (b of d) CR or not CR NC

NC CR,PR (b of d) CR or not CR PRCR,PR (b of d) NC CR or not CR PRNC (b of d) CR,PR CR or not CR NC

(b of d) = bulk of disease – Defined as number oflesions

Patients Studied• From 11/96 to 1/99 939 pts randomized• 29 countries participated• Largest site-52 pts-Blokhin Cancer

Research Center, Moscow• 2nd site-51 pts-Petrov Institute, St.

Petersburg• 3rd site-48 pts-Cancer Hospital, Beijing• 91 patients from USA institutions

Study Patients

Description Letrozole Tamoxifen Both

Randomized 458 458 23GCP compliance ? 2 2 1No active cancer 3 2 1ITT Population 453 454 -

Study Patients

Letrozole Tamoxifen

Stage IIIB 25 (6%) 32 (7%)ER and/or PR +ER and PR unknown

296 (65%)157 (35%)

308 (68%)146 (32%)

Prior Adjuvant Therapy Chemotherapy only Hormone Therapy only Both Prior tamoxifen

171 (38%) 74 68 29 86 (19%)

183 (40%) 90 59 34 83 (18%)

Prior adv disease chemo 27 (6%) 25 (6%)

Patient Characteristics

Patients are comparable for:

–Age –Race–Performance status–Dominant disease site –Number of Involved Sites

Efficacy

FDA analyses to be presented

FDA analyses do not differ substantially fromsponsor’s analyses

Median Treatment Duration

Letrozole - 11 months

Tamoxifen - 6 months

Time to Progression

Median TTP(mo)

95% C.I.

Letrozole 9.87* 9.11-12.20

Tamoxifen 6.15 5.79-8.45* p=0.0001 HR (95% C.I.)=0.73 (0.61-0.84)

Response Rate

ResponseLetrozole (n=453)Number (%)

Tamoxifen (n=454)Number (%)

CR 39 (9) 14 (3)

PR 108 (24) 84 (18)

Total 147 (32)* 98 (21)

* p = 0.0003

Response Duration

Rx# of

Responders

MedianResponse

Duration (m)Let 147 11.5

Tam 98 10.3

Response by Dominant Site

DominantSite

LetrozoleNo. (%)

TamoxifenNo. (%) p

SoftTissue

57/120 (48) 43/123 (35) 0.051

Bone 36/153 (24) 20/137 (15) 0.10

Visceral - liver

46/122 (38) 29/141 (21) 0.003

Liver 8/61 (13) 6/55 (11) 0.7

Response by Receptor Status

LetrozoleNo. (%)

TamoxifenNo. (%) p

ER+ or PR+or both

97/295 (33) 67/306 (22) 0.0025

ER & PRunknown

50/161 (31) 31/150 (21) 0.04

Performance Status Improvement(Exploratory FDA Analysis)

10% Improvement (2 or moreconsecutive observations)

Rx Number Percent

Let 110/344 32*

Tam 65/336 19

* p = 0.0002

Performance Status ImprovementInitial PS 50-70

PS Improvement( 2 consecutive visits)

Rx # of Pts +10 +20 +30

Let 83 18 16 6Tam 79 13 6 4

Serious Vascular Adverse Events

Let (453 pts) Tam (454 pts)

Cardiovascular 7 (2%) 4 (1%)

Cerebrovascular 5 (1%) 6 (2%)

PeripheralThromboembolic

8 (2%) 11 (2%)

Serious Adverse Events

Let (453 pts) Tam (454 pts)

Fractures 21 (5%) 18 (4%)Ocular (retinopathy,cataracts)

7 (2%) 5 (1%)

Endometrial cancer 0 (0%) 1 (0.2%)

Hot Flashes 82 (18%) 72 (16%)

Vaginal discomfort 12 (3%) 9 (2%)

Early Therapy Discontinuation

Principal Cause Let (11 pts) Tam (18 pts)

Bone pain 6 9Thrombosis 3 4Heart failure 0 1Respiratory failure 0 1New Primary 0 1Other 2 2

AE’s Special Populations____________________• Age 55, 56 to 69, 70

Comparable for each age group• Ethnicity 85% Caucasian, 3% Black, 11%

Asian/other

_____________________

Efficacy Summary

Letrozole Tamoxifen pResponse rate 32% 21 0.0003Response Duration 11.5 mo 10.3 moTime to Progression 9.87 mo 6.15 0.0001Improved P.S. 32% 19% 0.0002

Safety Summary______________________

• Letrozole and tamoxifen were equally well tolerated. Most AE’s (88%L/84%T) were mild to moderate in severity.

• Cardiovascular or cerebrovascular events occurred in < 2% of patients.

• Fractures occurred in <5% of patients. Appeared to be disease-related.

_____________________

Approval Based on a Single Study

Substantial evidence of effectiveness

- large multicenter study

- internal consistency

- clinically persuasive

- statistically persuasive

Review Team Recommendation_________________________

_Letrozole should be approved for first-line hormonal therapy in postmenopausal women with advanced hormone receptor positive or hormone receptor unknown breast cancer. ________________________