Initial Therapy Anti-ischemic and Analgesic therapy Anti-platelet therapy Anti-coagulant therapy.
SNDA 20-726 Letrozole (Femara®) Indication: First-line therapy in post- menopausal women with...
-
Upload
mariah-copeland -
Category
Documents
-
view
221 -
download
0
description
Transcript of SNDA 20-726 Letrozole (Femara®) Indication: First-line therapy in post- menopausal women with...
![Page 1: SNDA 20-726 Letrozole (Femara®) Indication: First-line therapy in post- menopausal women with advanced breast cancer. Prior approval: Second-line therapy.](https://reader034.fdocuments.us/reader034/viewer/2022052514/5a4d1b2d7f8b9ab059999d1f/html5/thumbnails/1.jpg)
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.
![Page 2: SNDA 20-726 Letrozole (Femara®) Indication: First-line therapy in post- menopausal women with advanced breast cancer. Prior approval: Second-line therapy.](https://reader034.fdocuments.us/reader034/viewer/2022052514/5a4d1b2d7f8b9ab059999d1f/html5/thumbnails/2.jpg)
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
![Page 3: SNDA 20-726 Letrozole (Femara®) Indication: First-line therapy in post- menopausal women with advanced breast cancer. Prior approval: Second-line therapy.](https://reader034.fdocuments.us/reader034/viewer/2022052514/5a4d1b2d7f8b9ab059999d1f/html5/thumbnails/3.jpg)
Comparator Treatment
• Generic Tamoxifen (Tamofen®, manufactured by Leiras, OY of Finland)
• Bioequivalent to Nolvadex®
![Page 4: SNDA 20-726 Letrozole (Femara®) Indication: First-line therapy in post- menopausal women with advanced breast cancer. Prior approval: Second-line therapy.](https://reader034.fdocuments.us/reader034/viewer/2022052514/5a4d1b2d7f8b9ab059999d1f/html5/thumbnails/4.jpg)
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
![Page 5: SNDA 20-726 Letrozole (Femara®) Indication: First-line therapy in post- menopausal women with advanced breast cancer. Prior approval: Second-line therapy.](https://reader034.fdocuments.us/reader034/viewer/2022052514/5a4d1b2d7f8b9ab059999d1f/html5/thumbnails/5.jpg)
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
![Page 6: SNDA 20-726 Letrozole (Femara®) Indication: First-line therapy in post- menopausal women with advanced breast cancer. Prior approval: Second-line therapy.](https://reader034.fdocuments.us/reader034/viewer/2022052514/5a4d1b2d7f8b9ab059999d1f/html5/thumbnails/6.jpg)
Tumor Evaluations
–Baseline –1 month - optional–Every 3 months thereafter
![Page 7: SNDA 20-726 Letrozole (Femara®) Indication: First-line therapy in post- menopausal women with advanced breast cancer. Prior approval: Second-line therapy.](https://reader034.fdocuments.us/reader034/viewer/2022052514/5a4d1b2d7f8b9ab059999d1f/html5/thumbnails/7.jpg)
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
![Page 8: SNDA 20-726 Letrozole (Femara®) Indication: First-line therapy in post- menopausal women with advanced breast cancer. Prior approval: Second-line therapy.](https://reader034.fdocuments.us/reader034/viewer/2022052514/5a4d1b2d7f8b9ab059999d1f/html5/thumbnails/8.jpg)
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
![Page 9: SNDA 20-726 Letrozole (Femara®) Indication: First-line therapy in post- menopausal women with advanced breast cancer. Prior approval: Second-line therapy.](https://reader034.fdocuments.us/reader034/viewer/2022052514/5a4d1b2d7f8b9ab059999d1f/html5/thumbnails/9.jpg)
Study Patients
Description Letrozole Tamoxifen Both
Randomized 458 458 23GCP compliance ? 2 2 1No active cancer 3 2 1ITT Population 453 454 -
![Page 10: SNDA 20-726 Letrozole (Femara®) Indication: First-line therapy in post- menopausal women with advanced breast cancer. Prior approval: Second-line therapy.](https://reader034.fdocuments.us/reader034/viewer/2022052514/5a4d1b2d7f8b9ab059999d1f/html5/thumbnails/10.jpg)
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%)
![Page 11: SNDA 20-726 Letrozole (Femara®) Indication: First-line therapy in post- menopausal women with advanced breast cancer. Prior approval: Second-line therapy.](https://reader034.fdocuments.us/reader034/viewer/2022052514/5a4d1b2d7f8b9ab059999d1f/html5/thumbnails/11.jpg)
Patient Characteristics
Patients are comparable for:
–Age –Race–Performance status–Dominant disease site –Number of Involved Sites
![Page 12: SNDA 20-726 Letrozole (Femara®) Indication: First-line therapy in post- menopausal women with advanced breast cancer. Prior approval: Second-line therapy.](https://reader034.fdocuments.us/reader034/viewer/2022052514/5a4d1b2d7f8b9ab059999d1f/html5/thumbnails/12.jpg)
Efficacy
FDA analyses to be presented
FDA analyses do not differ substantially fromsponsor’s analyses
![Page 13: SNDA 20-726 Letrozole (Femara®) Indication: First-line therapy in post- menopausal women with advanced breast cancer. Prior approval: Second-line therapy.](https://reader034.fdocuments.us/reader034/viewer/2022052514/5a4d1b2d7f8b9ab059999d1f/html5/thumbnails/13.jpg)
Median Treatment Duration
Letrozole - 11 months
Tamoxifen - 6 months
![Page 14: SNDA 20-726 Letrozole (Femara®) Indication: First-line therapy in post- menopausal women with advanced breast cancer. Prior approval: Second-line therapy.](https://reader034.fdocuments.us/reader034/viewer/2022052514/5a4d1b2d7f8b9ab059999d1f/html5/thumbnails/14.jpg)
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)
![Page 15: SNDA 20-726 Letrozole (Femara®) Indication: First-line therapy in post- menopausal women with advanced breast cancer. Prior approval: Second-line therapy.](https://reader034.fdocuments.us/reader034/viewer/2022052514/5a4d1b2d7f8b9ab059999d1f/html5/thumbnails/15.jpg)
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
![Page 16: SNDA 20-726 Letrozole (Femara®) Indication: First-line therapy in post- menopausal women with advanced breast cancer. Prior approval: Second-line therapy.](https://reader034.fdocuments.us/reader034/viewer/2022052514/5a4d1b2d7f8b9ab059999d1f/html5/thumbnails/16.jpg)
Response Duration
Rx# of
Responders
MedianResponse
Duration (m)Let 147 11.5
Tam 98 10.3
![Page 17: SNDA 20-726 Letrozole (Femara®) Indication: First-line therapy in post- menopausal women with advanced breast cancer. Prior approval: Second-line therapy.](https://reader034.fdocuments.us/reader034/viewer/2022052514/5a4d1b2d7f8b9ab059999d1f/html5/thumbnails/17.jpg)
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
![Page 18: SNDA 20-726 Letrozole (Femara®) Indication: First-line therapy in post- menopausal women with advanced breast cancer. Prior approval: Second-line therapy.](https://reader034.fdocuments.us/reader034/viewer/2022052514/5a4d1b2d7f8b9ab059999d1f/html5/thumbnails/18.jpg)
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
![Page 19: SNDA 20-726 Letrozole (Femara®) Indication: First-line therapy in post- menopausal women with advanced breast cancer. Prior approval: Second-line therapy.](https://reader034.fdocuments.us/reader034/viewer/2022052514/5a4d1b2d7f8b9ab059999d1f/html5/thumbnails/19.jpg)
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
![Page 20: SNDA 20-726 Letrozole (Femara®) Indication: First-line therapy in post- menopausal women with advanced breast cancer. Prior approval: Second-line therapy.](https://reader034.fdocuments.us/reader034/viewer/2022052514/5a4d1b2d7f8b9ab059999d1f/html5/thumbnails/20.jpg)
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
![Page 21: SNDA 20-726 Letrozole (Femara®) Indication: First-line therapy in post- menopausal women with advanced breast cancer. Prior approval: Second-line therapy.](https://reader034.fdocuments.us/reader034/viewer/2022052514/5a4d1b2d7f8b9ab059999d1f/html5/thumbnails/21.jpg)
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%)
![Page 22: SNDA 20-726 Letrozole (Femara®) Indication: First-line therapy in post- menopausal women with advanced breast cancer. Prior approval: Second-line therapy.](https://reader034.fdocuments.us/reader034/viewer/2022052514/5a4d1b2d7f8b9ab059999d1f/html5/thumbnails/22.jpg)
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%)
![Page 23: SNDA 20-726 Letrozole (Femara®) Indication: First-line therapy in post- menopausal women with advanced breast cancer. Prior approval: Second-line therapy.](https://reader034.fdocuments.us/reader034/viewer/2022052514/5a4d1b2d7f8b9ab059999d1f/html5/thumbnails/23.jpg)
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
![Page 24: SNDA 20-726 Letrozole (Femara®) Indication: First-line therapy in post- menopausal women with advanced breast cancer. Prior approval: Second-line therapy.](https://reader034.fdocuments.us/reader034/viewer/2022052514/5a4d1b2d7f8b9ab059999d1f/html5/thumbnails/24.jpg)
AE’s Special Populations____________________• Age 55, 56 to 69, 70
Comparable for each age group• Ethnicity 85% Caucasian, 3% Black, 11%
Asian/other
_____________________
![Page 25: SNDA 20-726 Letrozole (Femara®) Indication: First-line therapy in post- menopausal women with advanced breast cancer. Prior approval: Second-line therapy.](https://reader034.fdocuments.us/reader034/viewer/2022052514/5a4d1b2d7f8b9ab059999d1f/html5/thumbnails/25.jpg)
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
![Page 26: SNDA 20-726 Letrozole (Femara®) Indication: First-line therapy in post- menopausal women with advanced breast cancer. Prior approval: Second-line therapy.](https://reader034.fdocuments.us/reader034/viewer/2022052514/5a4d1b2d7f8b9ab059999d1f/html5/thumbnails/26.jpg)
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.
_____________________
![Page 27: SNDA 20-726 Letrozole (Femara®) Indication: First-line therapy in post- menopausal women with advanced breast cancer. Prior approval: Second-line therapy.](https://reader034.fdocuments.us/reader034/viewer/2022052514/5a4d1b2d7f8b9ab059999d1f/html5/thumbnails/27.jpg)
Approval Based on a Single Study
Substantial evidence of effectiveness
- large multicenter study
- internal consistency
- clinically persuasive
- statistically persuasive
![Page 28: SNDA 20-726 Letrozole (Femara®) Indication: First-line therapy in post- menopausal women with advanced breast cancer. Prior approval: Second-line therapy.](https://reader034.fdocuments.us/reader034/viewer/2022052514/5a4d1b2d7f8b9ab059999d1f/html5/thumbnails/28.jpg)
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. ________________________