sNDA 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

Patients Studied From 11/96 to 1/ 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

Patient Characteristics Patients are comparable for: –Age –Race –Performance status –Dominant disease site –Number of Involved Sites

Efficacy

Median Treatment Duration

Time to Progression

Response Rate

Response Duration

Response by Dominant Site

Response by Receptor Status

Performance Status Improvement (Exploratory FDA Analysis)

Performance Status Improvement Initial PS 50-70

Serious Vascular Adverse Events

Serious Adverse Events

Early Therapy Discontinuation

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

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

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. ________________________