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Comparator Treatment Generic Tamoxifen (Tamofen®, manufactured by Leiras, OY of Finland) Bioequivalent to Nolvadex®
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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. ________________________