Transcript Document 7508154

sNDA
20-262
TAXOL
for
ADJUVANT BREAST CANCER
THERAPY
REVIEW TEAM
PRIMARY
REVIEWER
SECONDARY
REVIEWER
MEDICAL
James O’Leary, M.D.
Grant Williams, MD
STATISTICS
David Smith, Ph.D.
Gang Chen, Ph.D.
PHARMACOLOGY
Margaret Brower, Ph.D.
Paul Andrews, Ph.D.
CHEMISTRY
Josephine Jee, PhD.
Rebecca Wood, Ph.D.
DSI
Gurston Turner, Ph.D.
PROJECT
MANAGER
Leslie Vaccari
Dotti Pease
PROPOSED INDICATION
“TAXOL is indicated for the adjuvant
treatment of node-positive breast cancer
administered sequentially to standard
combination therapy.”
A Phase III Intergroup Study
INT-0148
Doxorubicin Dose Escalation
With or Without TAXOL,
As Part Of the Cyclophosphamide/Doxorubicin
Adjuvant Chemotherapy Regimen
For Node Positive Breast Cancer
Participating Groups:
CALGB
ECOG
NCCTG
SWOG
Intergroup (0148)
Doxorubicin
Cytoxan
60
600
Doxorubicin
Cytoxan
75
600
Doxorubicin
Cytoxan
90
600
TAXOL
175, 3 hr IV
No TAXOL
Accrual By Study Arm
Regimens
Drugs and Starting Doses
2
(mg/m )
N
(3121)
1
A (60) + C (600) --- T(175)
533
2
A (60) + C (600)
515
3
A (75) + C (600) ---T (175)
517
4
A (75) + C (600)
523
5
A (90) + C (600) ---T (175)
520
6
A (90) + C (600)
513
FDA Analysis of DFS
All Patients and Major Subgroups
PATIENTS
N
RECURRENCES
HAZARD
RATIO
P-VALUE
All
3121
624
0.78
0.0021
ER-/PR-
1033
325
0.66
0.0003
ER+ and/or PR+
2066
293
0.93
0.56
ER+ and/or PR+
on Tamoxifen
1913
258
0.97
0.81
FDA Analysis of DFS
All Patients and Major Subgroups
PATIENTS
N
RECURRENCES
HAZARD
RATIO
P-VALUE
All
3121
624
0.78
0.0021
ER-/PR-
1033
325
0.66
0.0003
ER+ and/or PR+
2066
293
0.93
0.56
ER+ and/or PR+
on Tamoxifen
1913
258
0.97
0.81
Disease Free Survival
Estrogen Receptor Negative
AC
AC+T
1
PROPORTION DISEASE FREE
0.8
0.6
0.4
N
No. events
HR
AC
640
216
1.00
AC+T
623
160
0.70
0.2
0
0
1
2
YEARS
3
4
FDA Analysis of DFS
All Patients and Major Subgroups
PATIENTS
N
RECURRENCES
HAZARD
RATIO
P-VALUE
All
3121
624
0.78
0.0021
ER-/PR-
1033
325
0.66
0.0003
ER+ and/or PR+
2066
293
0.93
0.56
ER+ and/or PR+ on
Tamoxifen
1913
258
0.97
0.81
Disease Free Survival
Estrogen and/or Progesterone
Positive
AC
AC+T
1
PROPORTION DISEASE FREE
0.8
0.6
0.4
N
No. events
HR
AC
1018
149
1.00
AC+T
1048
144
0.92
0.2
0
0
1
2
YEARS
3
4
FDA Analysis of DFS
All Patients and Major Subgroups
PATIENTS
N
RECURRENCES
HAZARD
RATIO
P-VALUE
All
3121
624
0.78
0.0021
ER-/PR-
1033
325
0.66
0.0003
ER+ and/or PR+
2066
293
0.93
0.56
ER+ and/or
PR+ on
Tamoxifen
1913
258
0.97
0.81
Disease Free Survival
Subset: Tamoxifen Therapy
AC
AC+T
P R O P O R T IO N D IS E A S E F R E E
1
0 .8
0 .6
0 .4
N
N o . e v e n ts
HR
AC
1019
158
1 .0 0
AC+T
1054
155
0 .9 4
0 .2
0
0
1
2
YEAR S
3
4
Three Year DFS
(Kaplan-Meier Estimate)
PATIENTS
TAXOL
NO
TAXOL
DIFFERENCE
(T vs. No T)
All
76.6%
73.0%
3.6%
ER-/PR-
67.3%
56.8%
10.5%
ER+ and/or PR+
81.2%
81.6%
-0.4%
ER+ and/or PR+
on Tamoxifen
81.9%
82.7%
-0.8%
Patterns of Recurrence
14%
12%
13%
11%
AC
AC+T
10%
8%
•
Cut-off Date: Set. 30, 1998
•
Distant Recurrence: 368 (12%)
– AC:
– AC+T: 166 (11%)
•
7%
Local Recurrence: 189 (6%)
– AC:
6%
202 (13%)
5%
– AC+T: 85 (5%)
•
4%
104 (7%)
Simultaneous Recurrence: 16 (<1%)
– AC:
9 (<1%)
– AC+T: 7 (<1%)
2%
0%
DISTANT LOCAL
Survival Analysis
90%
80%
AC
• Cut-off Date:Sept. 30, 1998
AC+T
•
70%
Dead: 342/3121 (11%)
– AC:
60%
192 (12%)
– AC+T: 150 (10%)
50%
• Alive: 2779/3121 (89%)
– AC:
1359 (88%)
– AC+T: 1420 (90%)
40%
30%
20%
10%
0%
DEAD
ALIVE
Overall Survival
ER Negative
AC
AC+T
1
PROPORTION SURVIVING
0.8
0.6
0.4
N
No. deaths
HR
AC
640
142
1.00
AC+T
623
104
0.72
0.2
0
0
1
2
YEARS
3
4
Overall Survival
E and/or PR Positive
AC
AC+T
1
PROPORTION SURVIVING
0.8
0.6
0.4
N
No. deaths
HR
AC
1018
67
1.00
AC+T
1048
59
0.83
0.2
0
0
1
2
YEARS
3
4
Overall Survival
Subset: Tamoxifen Therapy
AC
AC+T
1
PROPORTION SURVIVING
0.8
0.6
0.4
N
No. deaths
HR
AC
1019
64
1.00
AC+T
1054
61
0.92
0.2
0
0
1
2
YEARS
3
4
Adverse Events Reported
During Taxol Therapy
TOXICITY
EARLY POPULATION
ENTIRE POPULATION
Grade
N
Grade
N
Hypersensitivity
2–3
7 (5%)
2–5
42 (3%)
Neurosensory
2–3
23 (15%)
2–4
113 (8%)
Neuromotor
2–3
2 (1%)
2–4
25 (2%)
Arthralgia/Myal
gia
2–3
34 (23%)
2–4
149 (10%)
Alopecia
2
68 (46%)
2–3
242 (17%)
Diarrhea
2–3
3 (2%)
2–4
11 (1%)
Treatment Discontinuation
Secondary to Toxicity
(AC vs. AC+T)
AC :
AC+T:
17 patients withdrew
15 patients withdrew during
AC
81 patients withdrew during
Taxol
DEATHS WITHIN 30 DAYS
(AC vs. AC+T)
AC : 1 Death
AC+T: 2 Deaths
• Respiratory Failure
• Brain Infarct Subsequent
to Sepsis
• Hypersensitivity Reaction
ISSUES TO CONSIDER
• Overall, results of the trial are very positive
• Effects of Taxol on DFS and OS are strong
• Results of Subset Analyses based on receptor
status:
– large number of patients and events
– these subsets are medically plausible
– positive overall results driven by receptor
negative subgroup
• Cytotoxic agents are not without toxicity
• Four additional cycles of chemotherapy
RECOMMENDATION
FOR APPROVAL
Taxol + AC in patients with ER-/PR- tumors
Improvement in DFS



3 Year DFS: 67.3% AC+T vs 56.8% AC
Hazard Ratio: 0.66 (0.53 - 0.83)
P-value: 0.0003
Improvement in OS


Hazard Ratio: 0.69 (0.53 - 0.91)
P-value: 0.0079
RECOMMENDATION:
CONTINUED FOLLOW-UP
Taxol sequential to AC in patients with ER+
and/or PR+ tumors who received Tamoxifen
No Improvement in DFS



3 Year DFS: 81.9% AC+T vs. 82.7% AC
Hazard Ratio: 0.98 (0.77 - 1.25)
P-value: 0.87
No Improvement in OS


Hazard Ratio: 0.89 (0.60 - 1.32)
P-value: 0.57